Tetrahydronaphthalene derivatives and tetrahydroisoquinoline derivatives as estrogen receptor degraders

Abstract

To provide bifunctional compounds which find utility as modulators of the estrogen receptor (target protein).SOLUTION: The invention provides piperazine derivatives having specific structures.SELECTED DRAWING: Figure 5-1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure was filed on December 1, 2016, and is incorporated herein by reference in its entirety. U.S. Provisional Patent Application No. 2006 / 023636 entitled "INOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS" No. 62 / 429,041, and the application filed on August 1, 2017, entitled "TETRAHYDRO APHTHALENES AND TETRAHYDRO A U.S. Provisional Patent entitled "ISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS" This application claims priority to application Ser. No. 62 / 540,049, the contents of which are incorporated herein by reference in their entirety. No. 6,313,935, filed on Oct. 23, 2006, and is incorporated herein by reference for all purposes. Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed August 5, 2016, and U.S. Patent Application No. 15 / 230,354, filed July 11, 2016 No. 15 / 206,497, filed on July 13, 2016, and U.S. patent application Ser. No. 5 / 209,648, and U.S. Patent Application No. 15 / 730,728, filed October 11, 2017, and U.S. Patent Application Publication No. 2015 / 0291562, filed April 14, 2015 Application No. 14 / 686,640, and U.S. Patent Application Publication No. 2016 / 0058872, filed July 6, 2015. No. 14 / 792,414, filed on July 11, 2014, and U.S. Patent Application No. No. 14 / 371,956, published as U.S. Patent Application Publication No. 2014 / 0356322; and "INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS" filed on September 15, 2016 No. 62 / 395,228, filed March 18, 2016, entitled "Compounds for a Polymeric Material That Can be Used to Produce a Novel Polymeric Material," and U.S. Patent Application ... No. 15 / 074,820, published as Publication No. 2016 / 0272639, and U.S. Pat. U.S. Provisional Patent Application No. 62 / 452,972, filed on December 1, 2016; Patent application Ser. No. 62 / 429,041, filed on March 18, 2016, and published international patent application WO2016 / 14 No. PCT / US2016 / 023258, published at 9668, all of which are incorporated herein by reference. In addition, all references cited herein are incorporated by reference in their entirety. No. 6,399,433, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to compounds, compositions and medicaments containing the compounds, and methods for making the same. The present disclosure also relates to methods for inhibiting the degradation of estrogen receptors, including, for example, The present invention relates to the use of compounds, compositions and medicaments as inhibitors of stromal receptor activity. for the treatment of diseases and conditions regulated by the estrogen receptor, such as the treatment of breast cancer. Regarding. [Background technology]

[0003] The estrogen receptor (ER) is a member of the nuclear hormone receptor family that mediates gene expression. It functions as a ligand-activated transcription factor involved in up- and down-regulation of estrogen receptors. The natural hormone of the hormone receptor is 17-beta-estradiol (E2) and its closely related metabolic products. When estradiol binds to the estrogen receptor, it causes receptor dimerization. This dimer then binds to the estrogen response element (ERE) on DNA. The ER-DNA complex binds to the ERE, which acts as a transcription factor that transcribes the DNA downstream of the ERE into mRNA. Alternatively, the ER and DNA interact to secrete the endothelial endothelial protein, which is then translated into protein. The function may be indirect, mediated by other transcription factors, the most notable being fos and j Many gene expressions are regulated by estrogen receptors, and estrogen The ER receptor is expressed in many cell types and is therefore amenable to the use of natural hormones or synthetic ER ligands. By modulating the estrogen receptor through binding to either This can have a profound effect on metabolic function.

[0004] A variety of diseases have an etiology and / or pathology that is mediated by the ER. Collectively, these The disorders are called estrogen-dependent disorders. Estrogen is essential for female sexual development. Furthermore, estrogen plays an important role in maintaining bone density and regulating blood lipid levels. It is also believed to play a role in neuroprotection. Decreased estrogen production due to osteoporosis, atherosclerosis, depression, and cognition Conversely, certain types of proliferative diseases, such as breast and uterine cancer, are associated with Cancer, as well as endometriosis, are stimulated by estrogen. Therefore, anti-estrogen drugs ( i.e. estrogen antagonists) have potential in the prevention and treatment of these types of disorders. It has utility in

[0005] There are two different types of estrogen receptors, commonly called α and β, which act in different ways. Both ERs are encoded by the ESR1 and ESR2 genes, respectively. Although it is widely expressed, there are some clear differences in its expression pattern. ERa is expressed in the uterus. It is present in the endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In men, ERa protein ERβ is present in the epithelium of the efferent duct. ERβ protein expression is found in the kidney, brain, bone, heart, lung, and intestine. It has been reported in mucosal, prostate, and endothelial cells. Therefore, the development of selective ligands is essential. This would allow the beneficial aspects of strogen to be preserved.

[0006] Breast cancer is the most common malignant tumor affecting women, and disease incidence is increasing worldwide. In particular, estrogen acts as an endocrine growth factor in at least one-third of breast cancers. Depriving tumors of this stimulus could provide a treatment for aggressive disease in premenopausal women. This treatment can be surgical, radiotherapeutic, or medically This can be achieved by removing ovarian function and, in postmenopausal women, aromatase inhibitors. This can be achieved by using inhibitors.

[0007] Another method for estrogen withdrawal is to antagonize estrogen using anti-estrogen drugs. Antiestrogens inhibit the production of estrogen in estrogen-responsive tissues. It is a drug that binds to and competes with genoceptors (ER). Nonsteroidal antiestrogens compete efficiently for ER binding, but their efficacy varies depending on the These agents are often limited by their partial agonism, which results in low levels of estrogen It has high affinity for ER and has agonistic effect. Specific or "pure" antiestrogens that do not have the These compounds may have advantages over conventional nonsteroidal antiestrogens in the treatment of Fulvestrant is a novel class of potent, pure anti-estrogen agents. It is the first drug to be approved for use in the treatment of estrogen-related disorders, and is a new class of drug that is different from currently available anti-estrogen drugs such as tamoxifen. It has no estrogenic activity, partial agonist activity, or any associated estrogenic activity.

[0008] Thus, there is a need for other methods to antagonize ER receptors. One method is to transactivate transcription Selective ER downregulators that reduce ER expression at either the ER level or protein level or to develop ER degraders.

[0009] Most small molecule drugs bind closely and in well-defined pockets to enzymes or receptors. On the other hand, small molecules are used to detect protein-protein interactions. Targeting is notoriously difficult because of the large size of the protein contact surfaces. Due to the large surface area and shallow grooves or flat interfaces involved E3 ubiquitin ligases, of which several hundred are known in humans, mediate the synthesis of ubiquitin. It confers substrate specificity to the catalysis. Therefore, it has specificity for certain protein substrates and is generalizable. This makes it a more attractive therapeutic target than conventional proteasome inhibitors. The development of new drugs requires disrupting protein-protein interactions. However, recent developments have made it possible to Specific ligands that bind to these ligases have been developed. For example, the first small molecule E3 ligases Since the discovery of the E3 ligase inhibitor nutrin, additional compounds targeting E3 ligases have been reported. However, there are still many areas in this field that are underdeveloped. For example, Since the discovery of natrienol, an inhibitor of mouse double minute 2 homolog (MDM2), Additional compounds targeting the E3 ligase, human double minute 2 or HDM2, have been reported. (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0010] The tumor suppressor p53 mediates cell proliferation arrest and apoptosis in response to DNA damage or stress. (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7 , 979-982), and inactivation of p53 has been proposed as one of the important pathways for tumor cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310). Approximately 50% of cancer patients have p53 mutations. % of the population (M. Hollstein, et al. Science (1991), 233, 49-53), whereas in the wild Patients with p53-positive encephalomyelitis have a mutated MDM2-associated phenotype via a protein-protein interaction between p53 and MDM2. Downregulation of p53 by cancer cells has been reported in many cancers (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). In normal cells, without oncogenic stress signals, MDM2 inhibits p53 at low concentrations. In response to DNA damage and cellular stress, p53 levels increase, and p53 / MDM The feedback loop from the autoregulatory system of 2 also causes an increase in MDM2. In other words, p53 regulates MDM2 at the transcriptional level, and MDM2 regulates p53 at the activity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

[0011] Several mechanisms could explain the downregulation of p53 by MDM2. DM2 binds to the N-terminal domain of p53 and inhibits the expression of p53-responsive genes (J. Momand, et al. l. Cell (1992), 69, 1237-1245). MDM2 then shuttles p53 from the nucleus to the cytoplasm, where it is converted into a protein. It promotes soluble degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 p53 has an intrinsic E3 ligase activity and binds ubiquitin to p53, facilitating ubiquitin-dependent transcription. Degradation of ATP via the 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). MDM2 functions as an E3 ligase, which may contribute to the pathogenesis of disease. It is highly likely that the ubiquitin-binding domain of the ribosomal protein is involved in the ubiquitination and degradation of the ribosomal protein. This is an interesting approach to drug development.

[0012] One E3 ligase with attractive therapeutic potential is the von Hippel-Lindau (VHI) ligase. VHL is a tumor suppressor that binds to the substrate recognition subunit of the E3 ligase complex VCB. This complex is further composed of elongins B and C, Cul2, and Rbx1. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), which is expressed at low levels. In response to oxygen, for example, the angiogenic growth factor VEGF, and the erythrocyte-derived cytokine It is a transcription factor that upregulates genes such as erythropoietin in the The first small molecule ligand of von Hippel-Lindau (VHL) for the substrate recognition subunit of enzyme The compound was synthesized and its crystal structure obtained, and it was confirmed that this compound is a major substrate of VHL, the transcription factor HIF It was confirmed that it mimics the binding mode of -1α.

[0013] Cereblon is a protein that in humans is encoded by the CRBN gene. BN orthologs are highly conserved from plants to humans, which suggests that their physiological roles This clearly shows the importance of cereblon. DDB1), Cullin-4A (CUL4A), and Regulator of Cullins1 (RO C1), which forms an E3 ubiquitin ligase complex with many other proteins. ubiquitinates target proteins through a mechanism that is not fully understood. Cereblon ubiquitination regulates fibroblast growth factor 8 (FGF8) and fibroblast growth factor FGF8 then promotes the formation of, for example, the limbs and the otic vesicle. In the embryo, this ubiquitin ligase complex regulates many developmental processes, such as limb It was ultimately concluded that cereblon is important for growth. DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0014] Inhibitors of Apoptosis Proteins (IAPs) are a set of proteins that regulate apoptosis. It is a family of proteins involved in cell death. The human IAP family contains eight members. Many other organisms also contain IAP homologs. IAPs have an E3 ligase-specific domain and a basal domain. These contain baculoviral IAP repeat (BIR) domains, IAPs recognize substrates and promote their ubiquitination. IAPs promote ubiquitination and then catalyze Caspases can directly bind to and inhibit caspases, which are the proteins that execute apoptosis. Proteases (e.g., caspase-3, caspase-7, and caspase-9). Moreover, through binding of caspases, IAPs inhibit cell death, but not proapoptotic The stimulation of mitochondrial protein DIABLO (second mitrochondria-derived activator of caspases, or SMAC) and HTRA2 (also known as Omi) The binding of DIABLO to HTRA2 is thought to inhibit IAP activity.

[0015] SMAC is a complex of essentially all IL-1 deficiency-associated proteins, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin. It interacts with all known IAPs. The first four amino acids (AVPI) of mature SMAC are part of IAPs. This is thought to be essential for inhibiting the anti-apoptotic effects of IAPs.

[0016] Nos. 2015-0291562 and 2014-0356322, which are incorporated herein by reference. (including compounds described in SensualityCompounds bind endogenous proteins via E3 ubiquitination In particular, the patent publication discloses that Sensuality sex or proteolysis targeting chimeric (PROTAC) The present invention describes compounds that bind to target ubiquitin of various polypeptides and other proteins. These polypeptides and other proteins have been found to be useful as regulators of chitinylation. The quality of the two Sensuality The enzyme is degraded and / or otherwise inhibited by reactive compounds.

[0017] The present disclosure provides compounds that inhibit estrogen receptors, including compounds that degrade the estrogen receptor. The present invention identifies compounds capable of inhibiting the function. Summary of the Invention

[0018] This disclosure relates to two Sensuality The present invention describes a compound having a specific activity and a method for using the compound. , which functions to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, this disclosure Sensuality Proteolytic or proteolytic targeting chimeras (PROTACs) The present invention provides a targeting chimeric compound, which is capable of binding to various polypeptides and These proteins have been shown to be useful as regulators of targeted ubiquitination of ubiquitin-dependent ubiquitination of other proteins. The polypeptides and other proteins described herein Sensuality Decomposition by volatile compounds The advantage of the compounds provided herein is that they can be used in a wide range of therapeutic applications. Potentially active targets from virtually any protein class or family The present disclosure further relates to the use of agonists in the treatment of diseases such as cancer, e.g., breast cancer. The present invention provides a method of using an effective amount of a compound described herein for the treatment or amelioration of a condition. Provide.

[0019] Thus, in one aspect, the present disclosure provides two Sensuality Providing active compounds or PROTAC compounds and the compound is an E3 ubiquitin ligase binding moiety (i.e., The ligand for the enzyme, or "ULM" group, and the moiety that binds to the target protein (i.e. (i.e., protein / polypeptide targeting ligands, or "PTM" groups), thereby The target protein / polypeptide is placed in close proximity to the ubiquitin ligase, and the target protein / polypeptide is In a preferred embodiment, ULM (ultra-molecular-weight leukocytes) are used. ubiquitination ligase regulator) is a von Hippel-Lindau E3 ubiquitin ligase ( VHL) binding domain (VLM), or cereblon E3 ubiquitin ligase binding domain (CLM ), or mouse double miniute 2 homolog (MDM2) E3 ubiquitin ligase binding domain (MLM ), or an IAP E3 ubiquitin ligase binding moiety (i.e., an "ILM"). For example, Sensuality The structure of the reactive compound can be shown as follows:

[0020] [ka]

[0021] The PTM and CLM moieties exemplified herein (e.g., VLM, CLM, MLM, ILM , or combinations thereof), as well as their respective positions and numbers, are provided as examples only. and are not intended to limit the compounds in any manner. As will be better understood, the two methods described herein Sensuality The compounds are Sensuality sexual part can be synthesized such that the number and position of can be varied as desired.

[0022] In certain embodiments, two Sensuality The reactive compound further comprises a chemical linker (L). Leave it, two Sensuality The structure of the reactive compound can be shown as follows:

[0023] [ka]

[0024] where PTM is a protein / polypeptide targeting moiety and L is a linker, e.g., a linker between PTM and ULM. ULM is a bond or chemical group that binds IAP E3 ubiquitin ligase-binding Interleukin-Lymogen (ILM) or Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding site (VLM) or cereblon E3 ubiquitin ligase binding domain (CLM), or mouse do ubiquitin ligase binding moiety (MLM).

[0025] For example, Sensuality The structure of the reactive compound can be shown as follows:

[0026] [ka]

[0027] wherein PTM is a protein / polypeptide targeting moiety, and "L" represents the combination of the PTM and the VLM, A linker that connects at least one of the CLM, MLM, ILM, or a combination thereof. (e.g., a bond or chemical linker group), and VLM is a von Hippel-Lindau E3 ubiquitin ligase binding moiety, CLM binds to cereblon The cerobron E3 ubiquitin ligase binding site is the MDM2 E3 ubiquitin ligase binding site. The ILM is a binding moiety that binds to an IAP.

[0028] In some embodiments, the present disclosure provides a compound of formula (I) or formula (II):

[0029] [ka]

[0030] During the ceremony: each X PTM are independently CH, N; ULM is an ILM or VLM or CLM or MLM; L is a tetrahydronaphthalene or tetrahydroisoquinoline moiety and VLM, C A coupling portion for coupling at least one of the LM, ILM, VLM, or a combination thereof. a linker moiety; Each R PTM1 are independently OH, halogen, alkoxy (e.g., methoxy or ethoxy), , O(CO)R PTM wherein the substitution may be mono-, di- or tri-substituted; R PTM is an alkyl or cycloalkyl group with 1 to 6 carbons or an aryl group can be; Each R PTM2 are independently H, halogen, CN, or CF 3 , straight or branched alkyl, alkoxy (e.g., methoxy or ethoxy), where the substitutions are mono- or di-substituted. Well, often; Each R PTM3 are independently H, halogen, where the substitution may be mono- or di-substituted. and R PTM4 is H, alkyl, methyl, ethyl.

[0031] In certain preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. In certain additional embodiments, two Sensuality The ILM of the cyclic compound is the amino acid alanine (A), valine (Va), (V), proline (P), and isoleucine (I) or their non-natural mimetics. In additional embodiments, the amino acids of the AVPI tetrapeptide fragment are linked together via an amide bond (such as That is, they are bonded to each other via -C(O)NH- or -NHC(O)-.

[0032] In certain embodiments, the compounds described herein comprise a ULM, multiple PTMs, multiple chemical ligands, and / or multiple agonists. anchors, or combinations thereof.

[0033] In certain embodiments, the ILM comprises a chemical moiety, such as a chemical moiety described herein. Includes.

[0034] In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Other anticipated VLMs include those disclosed in U.S. Patent Application Publication No. 2014 / 0302, as discussed above. No. 2523, which is incorporated herein in its entirety.

[0035] In certain embodiments, the CLM is selected from the group consisting of an imide, a thioimide, an amide, or a thioamide. In certain embodiments, the chemical group is a phthalimide group, or or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, Lenalidomide, pomalidomide, its analogs, its isosteres, or its derivatives Other anticipated CLMs include those described in U.S. Patent Application Publication No. 2015 / 0291562. No. 60 / 339,933, filed on Oct. 23, 2007, which application is incorporated herein in its entirety.

[0036] In certain embodiments, the MLM can be nutrin or a derivative thereof. As discussed above, the MLMs discussed herein are those disclosed in U.S. Patent Application No. 2016 / 0136644, filed on July 11, 2016. No. 15 / 206,497, which is incorporated herein in its entirety. In certain additional embodiments, two Sensuality The MLM of the reactive compound is, for example, a substituted imidazoline, a substituted spinel rho-indolinone, substituted pyrrolidine, substituted piperidinone, substituted morpholinone, substituted piperidinone Loropyrimidines, substituted imidazolopyridines, substituted thiazolimidazolines, substituted pyrrolopyridines These include chemical moieties such as lysinones, lysinones, and substituted isoquinolinones.

[0037] In further embodiments, the MLMs are adjacent and positioned in a cis or trans configuration. It comprises the core structure shown above with bis-aryl substitutions.

[0038] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is A connector with a linear number of non-hydrogen atoms in the range of ~20. The "L" of the connector is For example, ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylates, These may include functional groups such as carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may be, but is not limited to, aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic. Substitution with halogens such as Cl, F, Br and I may also be included in the linker. In the case of fluorine substitution, single or multiple fluorines may be included.

[0039] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, Here, both the nitrogen and the carboxylic acid in trans-3-hydroxyproline function as amides. There is a gender.

[0040] In certain embodiments, the CLM is selected from the group consisting of an imide, a thioimide, an amide, or a thioamide. In certain embodiments, the chemical group is a phthalimide group, or or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, Lenalidomide, pomalidomide, its analogs, its isosteres, or its derivatives Other anticipated CLMs include those described in U.S. Patent Application Publication No. 2015-0291562. The present application is hereby incorporated in its entirety. is a derivative of piperidine-2,6-dione, in which the piperidine-2,6-dione is substituted at the 3-position and the 3-substitution is a bicyclic ring with a bond as a CN bond or a CC bond. Examples of CLMs include pomalidomide, lenalidomide, and thalidomide and their derivatives.

[0041] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is A connector with a linear number of non-hydrogen atoms in the range of ~20. The "L" of the connector is For example, ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylates, These may include functional groups such as carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may be, but is not limited to, aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic. Substitution with halogens such as Cl, F, Br and I may also be included in the linker. In the case of fluorine substitution, single or multiple fluorines may be included.

[0042] In an additional aspect, the present disclosure provides an effective amount of a compound described herein, or a salt form thereof, and and a pharma- ceutical acceptable carrier. The therapeutic composition may be administered to a patient or modulates protein degradation and / or inhibition in a subject, e.g., an animal, such as a human; Use for treating or ameliorating a disease state or condition regulated via the degraded protein In certain embodiments, the therapeutic compositions described herein can be used to: Degradation of a protein of interest may be caused with the aim of treating or ameliorating a disease, for example cancer. In certain additional embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, uterine cancer, In yet another embodiment, the present invention is directed to at least one of the following: In this regard, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method preferably comprises the steps of: ILM and PTM, PTM and VLM, PTM and CLM, or PTM and MLM linked via a linker moiety The two described herein include Sensualitywherein the VLM / ILM / CLM / MLM is attached to the PTM via a linker and targets proteins that bind to the PTM for degradation. Similarly, PTMs (e.g., tetrahydronaphthalene moieties, or tetrahydroisoquinolinyl moieties) can be used. The VLM, CLM, MLM, ILM, or combination thereof is connected via a linker. The method comprises the steps of: targeting a protein or polypeptide by binding to at least one of the Degradation of a target protein occurs when the target protein is in close proximity to an E3 ubiquitin ligase. This occurs when the target protein is placed in a target region, resulting in degradation of the target protein / effectiveness of the target protein. The present disclosure provides a method for the inhibition of IL-1, and a method for the regulation of protein levels. Controlling protein levels provides a treatment for a disease state or condition, which may include the following: It is regulated through a target protein by reducing the levels of that protein.

[0043] In yet another aspect, the present disclosure provides a method for the treatment of a cancer in a subject or patient, e.g., an animal, e.g., a human. The present invention provides a method for treating or ameliorating a disease, disorder, or a symptom thereof, The method includes administering to a subject an effective amount, such as a therapeutically effective amount, of a compound described herein or a salt form thereof, and a pharmaceutical and administering to a subject in need thereof a composition comprising a carrier acceptable for The composition is useful for treating or ameliorating a disease or disorder or a symptom thereof in a subject. is valid.

[0044] In another aspect, the present disclosure provides methods for the treatment of cancer in biological systems using compounds according to the present disclosure. A method for identifying the effect of degradation of a protein of interest is provided.

[0045] The foregoing general description of utility is presented for illustrative purposes only and is not intended to be limiting of the present disclosure. and are not intended to limit the scope of the appended claims. Additional objects and advantages associated with the process are set forth in the claims, detailed description, and examples. For example, various aspects and implementations of the present disclosure will be apparent to those skilled in the art in light of the above. The forms can be used in many combinations, all of which are expressly incorporated herein by reference. These additional aspects and embodiments are expressly included within the scope of this disclosure. To explain the background of the disclosure and, in certain cases, to provide additional details regarding the implementation. Publications and other materials used herein are incorporated by reference in their entirety. To be incorporated.

[0046] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure. The drawings illustrate embodiments and, together with the written description, serve to explain the principles of the present disclosure. It is for the purpose of illustrating the embodiments of the present disclosure only and is not to be construed as limiting the present disclosure. Further objects, features and advantages of the present disclosure are set forth in the accompanying drawings, which illustrate exemplary embodiments of the present disclosure. This will become apparent from the following detailed description taken in conjunction with the drawings. [Brief description of the drawings]

[0047] [Figure 1A] Figure 1. Schematic of the general principles of PROTAC function. (A) An exemplary PROTAC contains a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and an optional linker moiety (L; black line) connecting the PTM and ULM. [Figure 1B](B) Illustrates the functional applications of PROTACs described herein. Briefly, ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits a target protein, bringing it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and catalyzes the attachment of ubiquitin via an isopeptide bond to a lysine on the target protein, either alone or through the E2 protein (dark circle). Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteosome machinery. [Diagram 2] Figure 2. Degradation of ERα in MCF7 cells by exemplary compounds of the present disclosure: Example 1 and Example 62. MCF7 cells were treated with compounds at seven concentrations (100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM) in the presence of 10% FBS. Cells were incubated for 48 hours and then lysed. Lysates were analyzed by immunoblotting. D: DMSO. [Diagram 3] Figure 3. Degradation of ERα in MCF7 cells by exemplary compounds of the present disclosure: Example 341, Example 510, Example 511 and Example 515. MCF7 cells were treated with five concentrations of compounds (100 nM, 33 nM, 11 nM, 3.7 nM and 1.2 nM) or 100 nM Fulvestrant in the presence of 10% FBS. Cells were incubated for 72 hours and then lysed. Lysates were analyzed by immunoblotting. F: Fulvestrant. [Figure 4] Figure 4. Degradation of ERα in T47D cells by exemplary compounds of the present disclosure: Examples 1 and 62. T47D cells were treated with compounds or DMSO at seven concentrations (100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM) in the presence of 10% FBS. Cells were incubated for 72 hours and then lysed. Lysates were analyzed by immunoblotting. D: DMSO. [Diagram 5] [Figure 5-1] to [Figure 5-104]. Table 1: Activity, synthesis and characterization of exemplary ER PROTACs. [Figure 6] [Figure 6-1] to [Figure 6-23]. Table 2: Activity, synthesis and characterization of exemplary ER PROTACs. [Figure 7] [Figure 7-1]~[Figure 7-44]. Table 3. ERα degradation activity, chemical name, and NMR data of exemplary ER PROTACs. Degradation DC50 range: DC50 < 5nM (A); 5nM < DC50 < 50nM (B); DC50 > 50nM (C); Degradation Dmax range: Dmax > 75% (A); 50% < Dmax < 75 (B); Dmax < 50% (C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art will be able to easily implement the present invention without departing from the spirit or scope of the present disclosure. Modifications and variations of the embodiments described herein may be made. All publications, patent applications, patents, drawings and other references are expressly incorporated herein by reference in their entireties. It is implicitly incorporated.

[0049] E3 ubiquitin ligase proteins (e.g., inhibitors of apoptosis (IAPs), von Hippel-Impact VHL, Cereblon E3 ubiquitin ligase, and is a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase that binds to target proteins. Combined Two Sensuality The E3 ubiquitin ligase protein is expressed by a sex or chimeric construct. When the protein and the target protein are brought into close proximity, the E3 ubiquitin ligase protein Compositions and methods relating to the surprising and unexpected discovery of ubiquitinating target proteins The present disclosure thus provides a method for the preparation of a protein target binding moiety (PTM)-linked E. coli. 3. Compounds and compositions comprising ubiquitin ligase binding moieties (ULM) This allows ubiquitination of selected target proteins (e.g., the estrogen receptor [ER]). This leads to the degradation of the target protein by the proteasome (see Figures 1A and 1B). The disclosure also provides libraries of compositions and uses thereof.

[0050] In certain aspects, the present disclosure provides methods for the preparation of, for example, small molecule ligands (i.e., 2,000, 1,000, 500 or and (b) a ligand having a molecular weight of less than 200 Daltons and a moiety such as The ligand is an E3 ubiquitin ligand, such as an IAP, VHL, MDM2, or cereblon. The moiety can bind to a tyrosine ligase and bind to a target protein (e.g., the ER). by placing it in close proximity to an E3 ubiquitin ligase, leading to its degradation (and / or inhibition) In addition to the above, small molecules can be This means that the molecule is non-peptidyl, i.e., has fewer than, e.g., 4, 3, or 2 In many cases, they are not considered peptides because they contain amino acids that are not included in the peptide. The TM, ULM, or PROTAC molecule may be a small molecule.

[0051] Unless otherwise defined, all technical and scientific terms used herein are It has the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains. The terminology used in the specification is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure. It is not intended to determine

[0052] When a range of values ​​is provided, unless the context clearly dictates otherwise (e.g. a certain number For groups containing carbon atoms, the respective numbers of carbon atoms falling within the range are provided), Each intervening value between the upper and lower limits of a range and any other specified range, to one tenth of the unit of the lower limit It is understood that any value within that stated range is encompassed within the scope of the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, are also encompassed within the present disclosure, as are any specifically excluded limits in the specified ranges. If one or both of the bounds are included, either or both of the bounds are excluded. The scope of the present disclosure is also encompassed within the scope of the present disclosure.

[0053] The following terms are used to describe this disclosure. If a term is not defined, it is understood that the term is intended to be used in connection with its use in the description of this disclosure. are given their art-recognized meanings by those of ordinary skill in the art as they apply the term.

[0054] As used herein, the articles "a" and "an" shall be understood to mean any article that is clearly intended to be Unless otherwise indicated, the grammatical object of the article or of more than one (i.e. As an example, an "element" is used herein to refer to one or more of the following: "" means an element or a plurality of elements.

[0055] As used herein in the specification and claims, the term "and / or" means The phrase "either or both" of the elements so combined is intended to mean "either or both" of the elements so combined. It should be understood that in some instances the elements are conjugated and in other instances they are disjointed. Multiple elements listed with "and / or" should be interpreted in the same way. That is, "one or more" of the elements are so combined. "Other elements than those specifically identified by the "Article" shall not affect those specifically identified elements. Thus, non-limiting examples include: When used in conjunction with open-ended language, such as "including," the term "A and / or B" is used interchangeably. In one embodiment, the reference refers only to A (and optionally to elements other than B) and not to another. In one embodiment, it refers to only B (optionally including elements other than A), and in another embodiment, In this case, it refers to both A and B (and optionally other elements).

[0056] As used herein in the specification and claims, "or" means any of the above. should be understood to have the same meaning as the defined "and / or." For example, When separating items within a list, "or" or "and / or" shall be deemed inclusive. i.e., any one of many elements or lists of elements. Both include one, but also include more than one, and optionally include additional items not listed. For example, For example, "one of," or "exactly one of," or when used in the claims. Only terms that clearly suggest the contrary, such as "consisting of" when referring to a number of elements or refers to the inclusion of exactly one element of a list of elements. In this case, the term "or" is used in place of, for example, "any," "one of," or "of Only when preceded by an exclusive term such as "only one of" or "exactly one of" Those indicating exclusive alternatives (i.e. "one or the other, but not both") should be interpreted.

[0057] In the claims and the above specification, the words "comprising" and "containing" "including," "carrying," "having," "containing" "involving," "holding," "composed of All transitional phrases, such as "(a)" and "(b)" are open-ended, i.e., include but are not limited to, "consisting of" and "consisting essentially of" should be understood to mean Only the transitional phrase "consisting essentially of" is used to define "The transitional phrase is a transitional phrase that is consistent with the principles of the Patent Examining Manual, Section 2111.03 of the United States Patent and Trademark Act." It is being done.

[0058] As used herein, in the specification and claims, one or more elements With respect to a list of elements, the phrase "at least one" means any one of the elements in the list, or should be understood to mean at least one element selected from a plurality of elements. It is not necessary for the invention to include at least one of all elements specifically listed in the list of elements. It does not include or exclude any combination of elements in the list of elements. This definition applies to any element specifically identified in the list of elements referred to by the phrase "at least one." In addition to the elements, any elements may be included, regardless of the relevance of those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" may be used. "at least one of" (or, equivalently, "at least one of A or B" or, equivalently, "A and and / or B) may, in one embodiment, be any combination of A, B, C, and / or B. At least one A contains elements A, and B does not exist (optionally including elements other than B). In the embodiment, it refers to at least one B, optionally including multiple Bs, and A is not present (optionally). In yet another embodiment, at least one element optionally containing multiple A's is It also refers to one A and at least one B, optionally including multiple Bs (optionally including other elements). ).

[0059] In certain methods described herein that include multiple steps or actions, The order of the method steps or acts is not necessarily specified unless otherwise indicated by context. The order in which the information is displayed is not necessarily limited to the order in which it is displayed.

[0060] "Co-administration" and "co-administering" " or "combination therapy" refers to simultaneous administration (the simultaneous administration of two or more therapeutic agents) time-based administration) and time-based administration while the therapeutic agent is simultaneously present in the patient's body in some, preferably effective, amount. administration of one or more therapeutic agents at a time that differs from the administration of an additional therapeutic agent; In certain preferred embodiments, the present invention refers to both administration at a time that is consistent with the methods described herein. One or more of the present compounds may be used in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In a particularly preferred embodiment, the co-administration of the compounds provides a therapeutic effect, including anti-cancer activity. Synergistic activity and / or therapy results.

[0061] As used herein, unless otherwise indicated, the term "compound" refers to any compound that is It refers to any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and the like. and, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereoisomers). stereoisomers, including isomers, and, where appropriate in the context, prodrugs and / or proisomers thereof or deuterated forms and pharma- ceutically acceptable salts and derivatives thereof. A small molecule is a drug in which one or more of the hydrogen atoms contained in the drug molecule are replaced with deuterium. It is a small molecule.

[0062] Within its use in context, the term compound generally refers to a single compound, e.g. Stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) of the disclosed compounds as well as other compounds such as specific enantiomers or mixtures enriched in a specific enantiomer. The term may also include, in context, a compound that facilitates administration and delivers the compound to the site of activity. In describing the compounds, many of the substituents, and particularly the variables associated therewith. It will be understood by those skilled in the art that the molecules to be synthesized are stable compounds as outlined below. Where bonds are shown, both double and single bonds are These are expressed or understood in the context of known rules regarding the interaction of charge and valence.

[0063] The term "ubiquitin ligase" refers to the enzyme that transfers ubiquitin to specific substrate proteins. This refers to a family of proteins that promote the degradation of substrate proteins. ubiquitination, either in conjunction with E2 ubiquitin-conjugating enzymes or alone, to ubiquitinate lysines on target proteins. IA, which adds a cleavage inhibitor to the IL-1 domain and subsequently targets the specific protein substrate for proteasomal degradation. P is an E3 ubiquitin ligase protein. Therefore, in complex with an E2 ubiquitin-conjugating enzyme, Alternatively, E3 ubiquitin ligases alone can transfer ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, which results in the secondary A ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are restricted to monoubiquitination, in which case only one Only ubiquitin is added to the substrate molecule by ubiquitin ligase. The proteins that are isolated are not targeted for degradation by the proteasome but are instead cleaved by, for example, ubiquitin. Through binding to other proteins that have domains capable of binding chitin To further complicate matters, ubiquitin can alter the intracellular location and function of the ubiquitin. This means that another lysine on chitin can be targeted by E3 to form the chain. The lysine that was passed through is Lys48 on the ubiquitin chain, which is recognized by the proteasome. It is the lysine that is used to generate polyubiquitin, which is

[0064] The terms "patient" or "subject" are used throughout this specification to refer to a subject who is receiving the compositions of the present disclosure. To describe the animals, preferably humans or livestock, to whom treatment, including prophylactic treatment, is provided. For example, to treat an infection, condition, or pathology that is specific to a particular animal, such as a human patient. In medical practice, the term patient refers to a domestic animal, e.g. a dog or cat, or a horse. In general, the term "patient" refers to a specific animal, including agricultural animals such as cattle, sheep, etc. The term "product" refers to a product or service that is not intended to be used unless otherwise indicated or implied from the context in which the term is used. Unless otherwise specified, the term refers to a human patient.

[0065] The term "effective" means, when used within the context of its intended use, The term is used to describe the amount of a compound, composition, or component that produces a desired result. The term effective includes all other effective amount or effective concentration terms, which are included in this application. as otherwise described or used in.

[0066] Compounds and Compositions In one embodiment, the present disclosure provides an IAP E3 ubiquitin ligase binding moiety (ILM), a selenium ligase. Bron E3 ubiquitin ligase binding moiety (CLM), von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), and / or mouse double minute 2 homologue (M DM2) E3 ubiquitin ligase binding moiety (MLM), E3 ubiquitin ligase binding moiety (ULM In an exemplary embodiment, ULM is provided having a chemical structure according to the following structure: is linked to a target protein binding moiety (PTM) via a linker (L): (A) PTM-L-ULM where L is a bond or chemical linker group and ULM is an E3 ubiquitin ligase binding moiety. and PTM is a target protein binding moiety. The number and / or relative positions of the moieties are provided for illustrative purposes only. As will be appreciated, the compounds described herein may be prepared using any desired number of each functional moiety. and / or the relative positions of each functional moiety.

[0067] The terms ULM, ILM, VLM, MLM and CLM refer to The term ULM is used in a comprehensive sense. For example, the term ULM includes IAP (i.e. ILM), MDM2 ( i.e. MLM), cereblon (i.e. CLM), and VHL (i.e. VLM) Furthermore, the term ILM encompasses all possible IAP E3 units. The term MLM encompasses all possible MDM2 binding sites. The term VLM encompasses all possible V The term CLM encompasses all cereblon-binding moieties. .

[0068] In another aspect, the present disclosure provides a method for inhibiting protein activity by inducing degradation of a target protein. Two useful for controlling sexuality Sensuality Compounds or multi- Sensuality The present invention provides a novel, novel, and novel therapeutically effective compound (e.g., PROTAC). In certain embodiments, the compound comprises a moiety that binds to a target protein (i.e., a protein target). a targeting moiety or "PTM") attached directly or indirectly, e.g., covalently, to In certain embodiments, ILM / VLM / CLM / MLM and PTM are linked or attached via a chemical linker (L). The ILM binds to the IAP E3 ubiquitin ligase VLM binds to VHL, CLM binds to cereblon E3 ubiquitin ligase, and The MLM and MDM2 E3 ubiquitin ligase bind to the PTM, which recognizes target proteins. By recognizing the target protein and placing it in close proximity to the ubiquitin ligase protein, The interaction of the moiety with its target promotes the degradation of the target protein. Government Noh The reactive compound may be represented as follows: (B) PTM-ILM (C) PTM-CLM (D) PTM-VLM (E) PTM-MLM In certain embodiments, two Sensuality The compound further comprises a chemical linker (L). Sensuality The reactive compound can be depicted as follows: (F) PTM-L-ILM (G) PTM-L-CLM (H) PTM-L-VLM (I) PTM-L-MLM where PTM is a protein / polypeptide targeting moiety, L is a chemical linker, and ILM is the IAP E3 ubiquitin ligase binding site, and CLM is the cereblon E3 ubiquitin ligase binding site. VLM is the VHL binding site, and MLM is the MDM2 E3 ubiquitin ligase binding site. minutes.

[0069] In certain embodiments, the ULM (e.g., ILM, CLM, VLM, or MLM) is less than about 200 μM IC 50 In addition, E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, etc.) Chitin ligase, VHL, MDM2 E3 ubiquitin ligase) IC 50 is determined according to any method known in the art, such as, for example, a fluorescence polarization assay. It is possible.

[0070] In certain additional embodiments, the two Sensuality The compounds are approximately 100, 50, 10, 1, Less than 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or about 100, 50, 10, 1, 0.5, 0.1, 0.05 , 0.01, 0.005, 0.001 μM or less, or about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 , less than 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM IC 50 The activity of

[0071] In certain embodiments, the compounds described herein may comprise multiple PTMs (either the same or different proteins). targeting protein targets), multiple ULMs, more than one ULM (i.e., multiple / different E3 ubiquitin Moieties that specifically bind to ligases, such as VHL, IAP, cereblon, and / or MDM2 ) or combinations thereof. In this case, the PTM and ULM (e.g., ILM, VLM, CLM, and / or MLM) may be directly or indirectly linked to one or more They may be attached via chemical linkers, or combinations thereof. In this case, when a compound has multiple ULMs, the ULMs bind to the same E3 ubiquitin ligase. Alternatively, each ULM may be specific for a different E3 ubiquitin ligase. In yet a further embodiment, when the compound has multiple PTMs, The PTMs may bind to the same target protein, or each PTM may bind to a different target protein. The antibody may specifically bind to a protein.

[0072] In certain embodiments, when a compound comprises multiple ULMs, the ULMs are identical. In certain embodiments, the compound may be a combination of multiple ULMs (e.g., ULM, ULM'), direct or chemical phosphorylation. The ULM comprises at least one PTM linked via a carrier (L), or both. In certain additional embodiments, the compound comprising multiple ULMs further comprises multiple PTMs. In additional embodiments, the PTMs are the same or, optionally, different. In some embodiments, when the PTMs are different, each PTM may bind to the same protein target. , or may specifically bind to different protein targets.

[0073] In certain embodiments, a compound may include multiple ULMs and / or multiple ULM's. In further embodiments, at least two different ULMs, multiple ULMs, and / or multiple Compounds containing ULM's can be linked directly, through chemical linkers, or both. The embodiments described herein further comprise at least one PTM linked to ULM or ULM'. In any of the embodiments, the compound containing at least two different ULMs further comprises multiple PTMs. In yet further embodiments, the PTMs are identical or optionally In yet a further embodiment, when the PTMs are different, each PTM is the same protein. The antibodies may bind to a protein target or may specifically bind to different protein targets. In further embodiments, the PTM itself is, for example, an ILM, a VLM, a CLM, a MLM, an ILM', a VLM', a CLM' , and / or a ULM (or ULM'), such as an MLM'.

[0074] In additional embodiments, the present disclosure relates to enantiomers, diastereomers, solvates and the like thereof. and polymorphs thereof, including pharma- ceutically acceptable salt forms thereof, such as acid and base salt forms. The compounds described herein are provided.

[0075] In some embodiments, the present disclosure provides a compound of formula (I) or formula (II):

[0076] [ka]

[0077] During the ceremony: each X PTM are independently CH, N; ULM is an ILM or VLM or CLM or MLM; L is a tetrahydronaphthalene or tetrahydroisoquinoline moiety and VLM, C A coupling portion for coupling at least one of the LM, ILM, VLM, or a combination thereof. a linker moiety; Each R PTM1 are independently OH, halogen, alkoxy (e.g., methoxy or ethoxy), O (CO)R PTM wherein the substitution may be mono-, di- or tri-substituted; and R PTM is an alkyl or cycloalkyl group with 1 to 6 carbons or an aryl group. the law of nature; Each R PTM2 are independently H, halogen, CN, or CF 3 , straight or branched alkyl, alkoxy (e.g., methoxy or ethoxy), where the substitutions are mono- or di-substituted. Well, often; Each R PTM3 are independently H, halogen, where the substitution may be mono- or di-substituted. and R PTM4 is H, alkyl, methyl, ethyl.

[0078] A target protein (e.g., an estrogen receptor) can be conjugated to a PTM group in accordance with the present disclosure. The present disclosure includes oligonucleotide and polypeptide sequences of sufficient length to The PTM group by the method described above specifically binds, for example, to the estrogen receptor (binding to the target protein). The compositions described below include any moiety that binds to a series of small molecule target protein binding molecules. Examples of such small molecule target protein binding moieties include those Pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of the subject proteins. These binding moieties preferably include a linker. ubiquitin ligase is bound to the ubiquitin ligase binding site via the ubiquitin ligase. A target protein (to which a protein targeting moiety is attached) for catalysis and degradation. ) is presented.

[0079] The present disclosure may be used to treat a number of disease states and / or conditions, including and / or the condition is that the protein is deregulated and the patient is includes any disease state and / or condition that would benefit from inhibition.

[0080] In an additional aspect, the present disclosure provides an effective amount of a compound described herein, or a salt form thereof, and and a pharma- ceutically acceptable carrier, excipient or vehicle, and, optionally, an additional bioactive agent. The therapeutic composition is administered to a patient or subject, e.g., an animal, such as a human. The present invention provides a method for regulating the degradation and / or inhibition of proteins in a subject, the method comprising: The present invention relates to a method for treating or ameliorating a disease state or condition regulated through an impaired protein. In certain embodiments, the therapeutic compositions described herein can be used to treat diseases, For example, degradation of a protein of interest may be caused for the purpose of treating or ameliorating cancer. In further embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometrial or a combination thereof.

[0081] In another aspect, the present disclosure provides a method for the preparation of a protein or polypeptide by degrading the protein or polypeptide. Methods for treating a pathology or ameliorating a symptom of a disease or condition in a subject in need thereof wherein a disease state or condition is regulated via said protein or polypeptide. The method further comprises administering to the patient or subject a therapeutically effective amount of at least one compound as described above. An effective amount, e.g., a therapeutically effective amount, may be administered in the presence of, optionally, a pharma- ceutically acceptable carrier, excipient, or vehicle, and and optionally an additional bioactive agent, wherein the composition is administered in combination with said The disclosed method is useful for treating or ameliorating a disease or disorder or a symptom thereof in an elephant. The administration of an effective amount of at least one compound described herein is intended to prevent or alleviate the symptoms of cancer and / or It may be used to treat a number of conditions or conditions, including endometriosis. The organism may be a microbial organism, such as a virus, bacteria, fungus, protozoa, or other microorganism. It may be a disease caused by a foreign agent or a pathological condition and / or state. The pathology may be caused by overexpression of a protein that results in the pathology.

[0082] In another aspect, the present disclosure provides methods for the treatment of cancer in biological systems using compounds according to the present disclosure. A method for identifying the effect of degradation of a protein of interest is provided.

[0083] The term "target protein" as used herein below refers to a protein to which the disclosed compounds bind, Describes a protein or polypeptide that is a target for degradation by ubiquitin ligase. Such small molecule target protein binding moieties are used to and, for example, estrogen receptors, and polymorphs thereof. Also included are other small molecules that can target proteins of interest, such as receptors. These binding moieties include: at least one ULM group (e.g., VLM and and / or CLM).

[0084] The term "protein targeting moiety" or "PTM" refers to a target protein or other molecule of interest. and binds to a protein or polypeptide of the present invention by ubiquitin ligase. or ubiquitinating the protein or polypeptide so that degradation of the polypeptide can occur. Used to describe small molecules that are placed / presented in close proximity to chitin ligase. Non-limiting examples of specific protein binding moieties include selective estrogen receptor modulators. The compositions described below are illustrative of some of the small molecule target proteins. do.

[0085] The compounds and compositions described herein are directed to a series of small molecule targeting proteins of these types. Examples of such small molecule target protein binding moieties include: Pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of the compositions of the invention are also disclosed. Also included are other small molecules that can target proteins of the invention. This reference is incorporated herein by reference in its entirety.

[0086] Example ILM AVPI tetrapeptide fragment In any of the compounds described herein, the ILM is alanine-valine-proline. The peptide may include an isoleucine-isoleucine (AVPI) tetrapeptide fragment, or a non-naturally occurring mimetic thereof. In certain embodiments, the ILM is represented by the following formula (I), formula (II), formula (III), formula (IV) and formula (IV): (V) is selected from the group consisting of chemical structures represented by:

[0087] [ka]

[0088] During the ceremony: R in formulas (I), (II), (III), (IV), and (V) 1 is selected from H or alkyl ; R in formulas (I), (II), (III), (IV), and (V) 2 is selected from H or alkyl ; R in formulas (I), (II), (III), (IV), and (V) 3 is H, alkyl, cycloalkyl and heterocycloalkyl; R in formulas (I), (II), (III), (IV), and (V) 5 and R 6 are independently H, alkyl , cycloalkyl, heterocycloalkyl, or more preferably selected from the group consisting of: , (II), (III), (IV), and (V) R 5 and R 6 Both are pyrrolidine or piperidin rings. The ring may further optionally contain 1 to 2 cycloalkyl, heterocycloalkyl, , aryl or heteroaryl rings, each of which can then be fused to yet another cycloalkyl group. Fused to an alkyl, heterocycloalkyl, aryl, or heteroaryl ring Can R in formulas (I), (II), (III), (IV), and (V) 3 and R 5 Both have 5-8 membered rings The ring can be optionally further formed with 1 to 2 cycloalkyl, heterocycloalkyl, fused to an alkyl, aryl or heteroaryl ring; R in formulas (I), (II), (III), (IV), and (V) 7 is cycloalkyl, cycloalkenyl alkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl arylalkyl, heteroaryl, or heteroarylalkyl, each of which is further Optionally, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hexane substituted with 1 to 3 substituents selected from (hetero)cycloalkyl, (hetero)aryl, or R 7 is -C(O)NH-R 4 and R 4 is an alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, Heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroa arylalkyl, which are optionally further substituted with 1 to 3 substituents as described above. will be done.

[0089] As described above, P1, P2, P3, and P4 in formula (II) are each an AVPI tetrapeptide fragment. or a non-natural mimetic thereof. Similarly, the formulas (I) and (III) Each of (a) through (b) is selected from the A, V, P, and P of an AVPI tetrapeptide fragment or a non-natural mimetic thereof. and a portion that correlates with I.

[0090] In any of the compounds described herein, the ILM may be represented by formula (VI), or a non-natural The structure of the IAP antagonists described in WO 2008 / 014236 can be a natural mimetic of the IAP antagonists described in WO 2008 / 014236. or a pharma- ceutically acceptable salt or hydrate thereof.

[0091] [ka]

[0092] During the ceremony: R in formula (VI) 1 , H, C 1 -C 4 -Alkyl, C 1 -C 4 -Alkenyl, C 1 -C 4 -alkynyl, or C 3 - C 1O -cycloalkyl, which are unsubstituted or substituted; R in formula (VI) 2 , H, C 1 -C 4 -Alkyl, C 1 -C 4 -Alkenyl, C 1 -C 4 -alkynyl, or C 3 - C 1O -cycloalkyl, which are unsubstituted or substituted; R in formula (VI) 3 -H, -CF 3 , -C 2 H 5、 C1 -C 4 -Alkyl, C 1 -C 4 -Alkenyl, C 1 -C 4 -Alkini Le, -CH 2 - Z, or any R 2 and R 3 together form a heterocyclic ring; Each Z in formula (VI) is H, -OH, F, Cl, -CH 3、 -CF 3、 -CH 2 Cl, -CH 2 F or -CH 2 Independent from OH Selected; R in formula (VI) 4 is C 1 -C 16 Straight or branched chain alkyl, C 1 -C 16 -Alkenyl, C 1 -C 16 -a Lukinir, C 3 -C 10 -Cycloalkyl, -(CH 2 ) 0-6 -Z 1、 -(CH 2 ) 0-6 -aryl, and -(CH 2 ) 0 -6 -het, wherein alkyl, cycloalkyl, and phenyl are unsubstituted. is or is replaced; R in formula (VI) 5 , H, C 1-10 -Alkyl, aryl, phenyl, C 3-7 -Cycloalkyl, -(CH 2 ) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -Alkyl-aryl, -(CH 2 ) 0-6 -C 3-7 -Cycloalkoxy Ru-(CH 2 ) 0-6 -phenyl, -(CH 2 ) 0-4 -CH[(CH 2 ) 1-4 -phenyl] 2、 Indanyl, -C(O)-C 1-10 - Alkyl, -C(O)-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -C(O)-(CH 2 ) 0-6 -phenyl, -(CH 2 ) 0- 6 -C(O)-phenyl, -(CH 2 ) 0-6 -het, -C(O)-(CH 2 ) 1-6 -het is selected independently, or is R 5 is selected from the residue of an amino acid, wherein alkyl, cycloalkyl, phenyl, and and the aryl substituents are unsubstituted or substituted; Z in formula (VI) 1 is -N(R 10 )-C(O)-C 1-10 -Alkyl, -N(R 1O )-C(O)-(CH 2 ) 0-6 -C 3-7 -Cycloa Rukill, -N(R 10 )-C(O)-(CH 2 ) 0-6 -phenyl, -N(R 10 )-C(O)(CH 2 ) 1-6 -het, -C(O)-N(R 11 )(R 12 ), -C(O)-OC 1-10 -Alkyl, -C(O)-O-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -C(O)-O-(CH 2 ) 0-6 -phenyl, -C(O)-O-(CH 2 ) 1-6 -het, -OC(O)-C 1-10 -Alkyl, -OC(O)-(CH 2 ) 1-6 -C 3- 7 -Cycloalkyl, -OC(O)-(CH 2 ) 0-6 -phenyl, -OC(O)-(CH 2 ) 1-6 -Het is selected independently wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted. Converted; In formula (VI), het is a 5- to 7-membered complex containing 1 to 4 heteroatoms selected from N, O and S. A monocyclic ring or containing 1, 2, or 3 heteroatoms selected from N, O, and S. and independently selected from 8- to 12-membered fused ring systems containing at least one 5- to 7-membered heterocyclic ring. and the heterocyclic ring or fused ring system is unsubstituted on the carbon or nitrogen atoms. , or replaced; R in formula (VI) 10 -H, -CH 3、 -CF 3 , -CH 2 OH, or -CH 2 Selected from Cl; R in formula (VI) 11 and R 12 , H, C 1-4 -Alkyl, C 3-7 -Cycloalkyl, -(CH 2 ) 1-6 -C 3-7 - Cycloalkyl, (CH 2 ) 0-6 -phenyl, wherein alkyl, cycloalkenyl, alkyl and phenyl are unsubstituted or substituted; or R 11 and R12 is nitrogen together form het, and U in formula (VI) is independently as shown in formula (VII) below:

[0093] [ka]

[0094] During the ceremony: Each n in formula (VII) is independently selected from 0 to 5; X in formula (VII) is selected from the group of -CH and N; R in formula (VII) a and R b are independently an O atom, a S atom, or a N atom, or C 0-8 -Alkyl wherein one or more of the carbon atoms in the alkyl chain is optionally selected from the group consisting of O, S or is substituted with a heteroatom selected from N, where each alkyl is independently unsubstituted. or replaced; R in formula (VII) d is Re-Q-(R f ) p (R g ) q、 and Ar 1 -D-Ar 2 selected from the group consisting of: R in formula (VII) c is selected from the group of H, or any R c and R d Both are cycloalloys. Kill or form het, R c and R d When forms a cycloalkyl or het, R 5 is bonded to the formed ring through a C atom or a N atom; In formula (VII), p and q are independently selected from 0 or 1; R in formula (VII) e is C 1-8-alkyl and alkylidene, each Re being unsubstituted. be or be replaced; Q is N, O, S, S(O) and S(O) 2 selected from the group consisting of: Ar of formula (VII) 1 and Ar 2 is independently selected from the group consisting of substituted or unsubstituted aryl and het. Selected; R in formula (VII) f and R g are independently H, -C 1-10 -Alkyl, C 1-10 -Alkylaryl, -OH , -OC 1-10 -Alkyl, -(CH 2 ) 0-6 -C 3-7 -cycloalkyl, -O-(CH 2 ) 0-6 -Aryl, Phenyl Nyl, aryl, phenyl-phenyl, -(CH 2 ) 1-6 -het, -O-(CH 2 ) 1-6 -het, -OR 13 , -C(0)- R 13、 -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -SR 13 , -S(O)-R 13 , -S(O) 2 -R 13 , -S(O) 2 - N R 13 R 14, -NR 13 -S(O) 2 -R 14 , -SC t-10 -Alkyl, Aryl-C 1-4 -Alkyl, or het-C 1 -4-alkyl, where alkyl, cycloalkyl, het and aryl are unsubstituted. Exchange or substituted -SO 2 -C 1-2 -Alkyl, -SO 2 -C 1-2 -Alkylphenyl, -OC 1-4 -Alkyl or any R g and R f are together formed into a ring selected from het or aryl. ; D in formula (VII) is -CO-, -C(O)-C 1-7 -Alkylene or arylene, -CF 2 -, -O-, -S(O) r of wherein r is 0 to 2 1,3-dioxalane, or C 1-7 -Alkyl-OH wherein the alkyl, alkylene or arylene is unsubstituted or substituted with one or more halides. Rogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -Alkyl, or -CF 3 or each D are independent, N(R h ) are selected from; Rh is H, unsubstituted or substituted C 1-7 -Alkyl, aryl, unsubstituted or substituted -O -(C 1-7 -cycloalkyl), -C(O)-C 1-10 -Alkyl, -C(O)-C 0-10 -Alkyl-aryl, -C- O.C. 01-10 -Alkyl, -COC 0-10 -Alkyl-Aryl, -SO 2 -C 1-10 -Alkyl, or -SO 2 -(C 0-10 -alkylaryl); R in formula (VII)6 , R 7 , R 8 and R 9 are independently H, -C 1-10 -Alkyl, -C 1-10 -Alkoxy , aryl-C 1-10 -Alkoxy, -OH, -OC 1-10 -Alkyl, -(CH 2 ) 0-6 -C 3-7 -Cycloalkoxy Le, -O-(CH 2 ) 0-6 -Aryl, phenyl, -(CH 2 ) 1-6 -het, -O-(CH 2 ) 1-6 -het, -OR 13、 -C(O) -R 13、 -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -SR 13、 -S(O)-R 13 , -S(O) 2 -R 13、 -S(O) 2 -NR 1 3 R 14、 or -NR 13 -S(O) 2 -R 14 wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted; and any R 6 , R 7 , R 8 and R 9 optionally together form a ring system; R in formula (VII) 13 and R 14 are independent of each other, H, C 1-10 -Alkyl, -(CH 2 ) 0-6 -C 3-7 -Cycloal Kill, -(CH 2) 0-6 -(CH) 0-1 -(aryl) 1-2、 -C(O)-C 1-10 -Alkyl, -C(O)-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -C(O)-O-(CH 2 ) 0-6 -aryl, -C(O)-(CH 2 ) 0-6 -O-Fluorenyl, -C(O) -NH-(CH 2 ) 0-6 -aryl, -C(O)-(CH 2 ) 0-6 -aryl, -C(O)-(CH 2 ) 0 . 6 -het, -C(S)-C 1-10 - Alkyl, -C(S)-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -C(S)-O-(CH 2 ) 0-6 -aryl, -C(S)-( CH 2 ) 0-6 -O-Fluorenyl, -C(S)-NH-(CH 2 ) 0-6 -aryl, -C(S)-(CH 2 ) 0-6 -aryl, or-C(S)-(CH 2 ) 1-6 -het, where each alkyl, cycloalkyl, and Aryl is unsubstituted or substituted: or any R 13 and R 14 is a nitrogen atom Also formed het; Wherein R of formula (VII) 13 and R 14 the alkyl substituents of are unsubstituted or substituted; If replaced, C 1-10-Alkyl, halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -Al Kill, and -CF 3 and R 13 and R 14 The substituted phenyl or aryl of 1-4 -Alkyl, C 1-4 -a Aroxy, Nitro, -CN, -OC(O)-C 1-4 -Alkyl, and -C(O)-OC 1-4 -Aryl The group is substituted with one or more substituents selected from the group consisting of aryl, ... and aryl.

[0095] In certain embodiments, the compound further comprises at least one additional independently selected linker. an independently selected group attached to the ILM of formula (VI) or a non-natural mimetic thereof; In one embodiment, the second ILM further comprises a derivative of formula (VI) or In certain embodiments, the at least one additional independently selected non-naturally occurring mimetic of The selected linker group comprises two additional independently selected linker groups that chemically couple the ILM to the second ILM. In one embodiment, the ILM of formula (VI) or a non-natural mimetic thereof comprises a linker group. At least one additional linker group to R 4 and R 5 Chemically combine groups selected from For example, an ILM of formula (VI) or a non-natural mimetic thereof, and an ILM of formula (VI) or A second ILM of the non-natural mimetic can be attached as shown below:

[0096] [ka]

[0097] In certain embodiments, the ILM comprises at least one additional independently selected linker group, L; and the second ILM has a structure selected from the group consisting of:

[0098] [ka]

[0099] [ka]

[0100] These are derivatives of the IAP antagonists described in WO2008 / 014236. In any of the compounds described herein, the ILM may be represented by formula (VIII), or a non- It can have a structure that mimics the natural type, as described in Ndubaku, C., et al. Antagonism of c- IAP and XIAP proteins are required for efficient induction of cell death by small -molecule IAP antagonists, ACS Chem. Biol., 557-566, 4 (7) (2009) Based on P ligands:

[0101] [ka]

[0102] wherein each of A1 and A2 in formula (VIII) is independently an optionally substituted monocyclic, fused ring, aryl and heteroaryl; and R in formula (VIII) is selected from H or Me.

[0103] In certain embodiments, the linker group L is attached to A1 of formula (VIII). , the linker group L is attached to A2 of formula (VIII).

[0104] In certain embodiments, the ILM is selected from the group consisting of:

[0105] [ka]

[0106] In any of the compounds described herein, the ILM has the following formula (IX): The IAP antagonist may have a structure that is a non-natural mimetic of the IAP antagonist described in Mannhold, R., et al. ists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210 -9 (2010) are derived from chemical species cross-referenced as follows:

[0107] [ka]

[0108] In the formula, R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, most preferably Preferred are isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl. and R of formula (IX) is selected from 2 is selected from -OPh or H.

[0109] In any of the compounds described herein, the ILM has the structure of formula (X): This is consistent with Mannhold, R., et al. IAP antagonists: promising candidates for or cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010) Derived from the chemical species:

[0110] [ka]

[0111] During the ceremony: R in formula (X) 1 -H, -CH 2 OH, --CH 2 CH 2 OH, --CH 2 NH 2、 --CH 2 CH 2 NH 2 Selected from; X in formula (X) is S or CH 2 Selected from; R in formula (X) 2 is selected from:

[0112] [ka]

[0113] R in formula (X) 3 and R 4 is independently selected from H or Me. In any of the compounds described herein, the ILM has the structure of formula (XI): This is Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010) The chemical species that are:

[0114] [ka]

[0115] In the formula (XI), R 1 is selected from H or Me, and R in formula (XI) 2 H or teeth

[0116] [ka]

[0117] is selected from. In any of the compounds described herein, the ILM has the formula (XII), which is shown in Mannhold, R., et al. IAP antagonists: Mising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010 ) are derived from chemical species cross-referenced in:

[0118] [ka]

[0119] During the ceremony: R in formula (XII) 1 is selected from:

[0120] [ka]

[0121] R in formula (XII) 2 is selected from:

[0122] [ka]

[0123] In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0124] [ka]

[0125] [ka]

[0126] In any of the compounds described herein, the ILM may be represented by formula (XIII), or a non-naturally occurring The structure of the peptide can be a natural mimetic, as described in Flygare, JA, et al. Small-molecule peptide an-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 ( 2 Based on the IAP ligands summarized in:

[0127] [ka]

[0128] During the ceremony: Z in formula (XIII) is absent or O; R in formula (XIII) 1 is selected from:

[0129] [ka]

[0130] R 10 is selected from H, alkyl, or aryl; X is CH 2 and O; and

[0131] [ka]

[0132] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM has the structure of formula (XIV): This is the result of Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent IAP ligands summarized in the review, Expert Opin. Ther. Pat., 20 (2), 251-67 ( 2010) Based on:

[0133] [ka]

[0134] During the ceremony: Z in formula (XIV) is absent or O; R in formula (XIV) 3 and R 4 is independently selected from H or Me; R in formula (XIV) 1 is selected from:

[0135] [ka]

[0136] R 10 is selected from H, alkyl, or aryl;

[0137] [ka]

[0138] X is CH 2and O; and

[0139] [ka]

[0140] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM is selected from the group consisting of: Can be:

[0141] [ka]

[0142] This is the same as the ligature disclosed in U.S. Patent Publication No. 2008 / 0269140 and U.S. Patent No. 7,244,851. It is a derivative of amide.

[0143] In any of the compounds described herein, the ILM may be represented by formula (XV), or a non-natural The structure of the IAP ligand can be a natural mimetic, such as the IAP ligand described in WO 2008 / 128171. is a derivative of:

[0144] [ka]

[0145] During the ceremony: Z in formula (XV) is absent or O; R in formula (XV) 1 is selected from:

[0146] [ka]

[0147] R 10 is selected from H, alkyl, or aryl;

[0148] [ka]

[0149] X is CH 2 and O; and

[0150] [ka]

[0151] is a nitrogen-containing heteroaryl; and R in formula (XV) 2 is selected from H, alkyl or acyl.

[0152] In certain embodiments, the ILM has the structure:

[0153] [ka]

[0154] In any of the compounds described herein, the ILM may be represented by formula (XVI), or a non-natural The structure of the IAP ligand can be a natural mimetic, such as the IAP ligand described in WO 2006 / 069063. Based on:

[0155] [ka]

[0156] During the ceremony: R in formula (XVI) 2 is selected from alkyl, cycloalkyl, and heterocycloalkyl; More preferably, isopropyl, tert-butyl, cyclohexyl and tetrahydropyridine are Preferably, the aryl is selected from aryl, and most preferably, the aryl is selected from cyclohexyl;

[0157] [ka]

[0158] The heteroaryl of formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl. is a nitrogen-containing heteroaryl, most preferably thiazole; and In formula (XVI), Ar is aryl or heteroaryl.

[0159] In any of the compounds described herein, the ILM may be represented by formula (XVII), or a non-natural The structure of the compound can be a natural mimetic, as described by Cohen, F. et al., Antagonists of inhibitors itors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem Based on the IAP ligands described in . Lett., 20(7), 2229-33 (2010):

[0160] [ka]

[0161] During the ceremony: R in formula (XVII) 1 is a halogen (e.g., fluorine), cyano,

[0162] [ka]

[0163] selected from the group consisting of: X in formula (XVII) is O or CH 2 is selected from the group:

[0164] In any of the compounds described herein, the ILM may have the structure of formula (XVIII): This is based on Cohen, F. et al., Antagonists of inhibitors of apoptosis protein s based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2 Based on the IAP ligands described in

[0165] [ka]

[0166] In the formula (XVIII), R is an alkyl, aryl, heteroaryl, arylalkyl, arylalkyl, or halogen (at variable substitution positions).

[0167] In any of the compounds described herein, the ILM has the structure of formula (XIX): This is based on Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (201 Based on the IAP ligands described in

[0168] [ka]

[0169] During the ceremony

[0170] [ka]

[0171] is a 6-membered nitrogen heteroaryl. In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0172] [ka]

[0173] In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0174] [ka]

[0175] In any of the compounds described herein, the ILM may be represented by formula (XX), or a non-natural The structure of the IAP ligand can be a natural mimetic, such as the IAP ligand described in WO 2007 / 101347. Based on:

[0176] [ka]

[0177] X in formula (XX) is CH 2 , O, NH or S. In any of the compounds described herein, the ILM may be represented by formula (XXI), or a non-natural The compounds may have the structure of a natural mimetic, as described in U.S. Pat. No. 7,345,081 and U.S. Pat. Based on the IAP ligands described in 7,419,975:

[0178] [ka]

[0179] During the ceremony: R in formula (XXI) 2 is selected from:

[0180] [ka]

[0181] R in formula (XXI) 5 is selected from:

[0182] [ka]

[0183] and W in formula (XXI) is selected from CH or N; and

[0184] [ka]

[0185] R 6 is independently a monocyclic or bicyclic fused aryl or heteroaryl. In certain embodiments, the ILM of the compound is selected from the group consisting of:

[0186] [ka]

[0187] In certain embodiments, the ILM of the compound is selected from the group consisting of:

[0188] [ka]

[0189] [ka]

[0190] These include WO2009 / 060292, U.S. Patent No. 7,517,906, WO2008 / 134679, WO2007 / 130626 and It is described in WO2008 / 128121.

[0191] In any of the compounds described herein, the ILM is represented by formula (XXII) or formula (XXI II), or a non-natural mimetic thereof, which may be any of the structures described in WO 2015 / 006524 and WO 2015 / 006524. and Perez HL, Discovery of potent heterodimeric antagonists of inhibitors of ap optosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015) and / or its pharmacologic approved derivatives. and acceptable salts, tautomers or stereoisomers of:

[0192] [ka]

[0193] During the ceremony: R of formula (XXII) or formula (XXIII) 1 is an optionally substituted alkyl, an optionally substituted silyl cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl aryl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXII) or formula (XXIII) 2 is an optionally substituted alkyl, an optionally substituted silyl cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl aryl, optionally substituted arylalkyl, or optionally substituted aryl; or R of formula (XXII) or formula (XXIII) 1 and R 2 are independently optionally substituted thioacyl groups. alkyl, where the substituent attached to the S atom of the thioalkyl is an optionally substituted alkyl. alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 R 23 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 Selected from ; -CH 2 CHR 21 COR 2 R 21 is NR 24 R 25 selected from the group consisting of: -CH 2 R 23 R 23 is an optionally substituted aryl or an optionally substituted heterocyclyl; wherein the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 2 O) m C H 3 or a polyamine chain, such as spermine or spermidine; OR 26 R 26 is selected from optionally substituted alkyl, where the optional substituents are OH, Halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXII) or formula (XXIII) 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryl alkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or wherein the substituents are selected from alkyl, halogen, is OH or OH; R of formula (XXII) or formula (XXIII) 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted or optionally substituted cycloalkyl; and X is selected from a bond or a chemical linker group.

[0194] In certain embodiments, X is a bond or is selected from the group consisting of:

[0195] [ka]

[0196] In the formula, "*" is the attachment point of a PTM, L or ULM, e.g., an ILM. In any of the compounds described herein, the ILM is represented by formula (XXIV) or formula (XXV I), or a non-natural mimetic thereof, and may have the phosphoryl group as shown below. The structures can have a chemical linker to the carbo group L, and the structures are described in WO 2015 / 006524 and P erez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or a pharma- ceutical acceptable salt, tautomer, or derivative thereof. Isomers or stereoisomers:

[0197] [ka]

[0198] During the ceremony: R of formula (XXIV), formula (XXV) or formula (XXVI) 1 is an optionally substituted alkyl, substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl Selected from; R of formula (XXIV), formula (XXV) or formula (XXVI) 2 is an optionally substituted alkyl, substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl Selected from; or, R of formula (XXIV), formula (XXV) or formula (XXVI) 1 and R 2 are independently an optionally substituted wherein the substituent attached to the S atom of the thioalkyl is optionally substituted. optionally substituted branched alkyl, optionally substituted heterocyclyl, -( CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 R 23 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 Selected from ; -CH 2 CHR 21 COR 2 R 21 is NR 24 R 25 Selected from; -CH 2 R 23 R 23 is an optionally substituted aryl or an optionally substituted heterocyclyl; wherein the optional substituents include alkyl and halogen; NR 24 R25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 2 O) m C H 3 or a polyamine chain, such as spermine or spermidine; OR 26 R 26 is selected from optionally substituted alkyl, where the optional substituents are OH, Halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXIV), formula (XXV) or formula (XXVI) 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl aryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, where the substituents are alkyl, halo, rogene or OH; R of formula (XXIV), formula (XXV) or formula (XXVI) 5 , R 6 , R 7 and R 8 are independently hydrogen, any or optionally substituted cycloalkyl.

[0199] In certain embodiments, an ILM according to formula (XXII) to formula (XXVI): R 7 and R 8 is selected from H or Me; R 5 and R 6 is selected from the group including:

[0200] [ka]

[0201] R 3 and R 4 is selected from the group including:

[0202] [ka]

[0203] In any of the compounds described herein, the ILM is represented by formula (XXVII) or formula (XX VII), or a non-natural mimetic thereof, which structure is described in WO 2014 / 055 461, and Kim, K.S., Discovery of tetrahydroisoquinoline-based bivalent heterodimers. eric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014) and / or pharma- ceutically acceptable salts, tautomers or derivatives thereof derived from an IAP ligand. Most are stereoisomers:

[0204] [ka]

[0205] During the ceremony: R 35is selected from alkyl, halogen, alkoxy, cyano, and haloalkoxy; are 1 to 2 substituents; R of formula (XXVII) and formula (XXVIII) 1 is H or optionally substituted alkyl, substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl Selected from; R of formula (XXVII) and formula (XXVIII) 2 is H or optionally substituted alkyl, substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl Selected from; or, R of formula (XXVII) and formula (XXVIII) 1 and R 2 is an optionally substituted thioalkyl-CR 60 R 6 1 S.R. 70 wherein R 60 and R 61 is selected from H or methyl; R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted heterocyclic Rocyclyl, -(CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 is selected from During the ceremony: v is an integer from 1 to 3; -(CH 2 ) vCOR 20 and -CH 2 CHR 21 COR 22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 Selected from; -CH 2 R 23 R 23 is an optionally substituted aryl or an optionally substituted heterocyclyl; wherein the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 CH 2 (OCH 2 CH 2 ) m CH 3 or -[CH 2 CH 2 (CH 2 )δNH]ψCH 2 CH 2 (CH 2 )ωNH 2 Selected from; In the formula, δ=0~2, ψ=1~3, ω=0~2; OR 26 R 26is an optionally substituted alkyl, where the optional substituents are OH, halogen, N or NH 2 and m is an integer from 1 to 8; R of formula (XXVII) and formula (XXVIII) 3 and R 4 independently optionally substituted alkyl; Optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryl arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or Optionally substituted heterocycloalkyl, where the substituents are alkyl, halo, Gen or OH; R of formula (XXVII) and formula (XXVIII) 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted substituted alkyl, or optionally substituted cycloalkyl; R of formula (XXVII) and formula (XXVIII) 31 is an optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably At least one of the following is selected from the group consisting of:

[0206] [ka]

[0207] X in formulae (XXVII) and (XXVIII) is -(CR 81 R 82 ) m -, optionally substituted heteroaryl or or heterocyclyl;

[0208] [ka]

[0209] Z in formula (XXVII) is selected from C=O, -O-, -NR, -CONH-, -NHCO-, or is absent. Very well; -(CR 81 R 82 ) m -R 81 and R 82 are independently hydrogen, halogen, alkyl or cycloalkyl. or R 81 and R 82 can together form a carbocyclic ring;

[0210] [ka]

[0211] R 10 and R 11 is independently selected from hydrogen, halogen, or alkyl;

[0212] [ka]

[0213] R 12 , R 13 , R 14 , R 15 and R 16 are independently hydrogen, halogen, or optionally substituted Alkyl, or OR 17 Selected from; R 17 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl. Selected; -(CR 21 R 22 ) m - and

[0214] [ka]

[0215] m and n are independently 0, 1, 2, 3, or 4;

[0216] [ka]

[0217] o and p are independently 0, 1, 2 or 3;

[0218] [ka]

[0219] q and t are independently 0, 1, 2, 3, or 4;

[0220] [ka]

[0221] where r is 0 or 1. In any of the compounds described herein, the ILM may be represented by formula (XXIX), formula (XXX), formula (XXXI) or formula (XXXII), or a non-natural mimetic thereof, and These can have chemical linkers to the linker group L as described in WO 2014 / 05546 1, and Kim, K.S., Discovery of tetrahydroisoquinoline-based bivalent heterodimers. ic IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014) P ligand derived from:

[0222] [ka]

[0223] [ka]

[0224] During the ceremony: R of formula (XXIX) to formula (XXXII) 2 is H, optionally substituted alkyl, optionally substituted cyclo cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl aryl, optionally substituted arylalkyl, or optionally substituted aryl; ; or, R of formula (XXVII) and formula (XXVIII) 1 and R 2 is H, optionally substituted thioalkyl-CR 6 0 R 61 S.R. 70 wherein R 60 and R 61 is selected from H or methyl; R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted hexaalkyl, Tetracyclyl, -(CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 CHR 21 COR22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 Selected from; -CH 2 R 23 R 23 is an optionally substituted aryl or an optionally substituted heterocyclyl; wherein the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 CH 2 (OCH 2 CH 2 ) m CH 3 or -[CH 2 CH 2 (CH 2 )δNH]ψCH 2 CH 2 (CH 2 )ω r NH 2 is selected from In the formula, δ=0~2, ψ=1~3, ω=0~2; OR 26 R 26 is an optionally substituted alkyl, where the optional substituents are OH, halogen, N or NH 2 and; m is an integer from 1 to 8; R of formula (XXIX) to formula (XXXII) 6 and R 8 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and R of formula (XXIX) to formula (XXXII) 31 is an optionally further substituted alkyl, aryl, and preferably selected from the group consisting of arylalkyl, heteroaryl and heteroarylalkyl. Selected from the group consisting of:

[0225] [ka]

[0226] In certain embodiments, the ILM of the compound is:

[0227] [ka]

[0228] In any of the compounds described herein, the ILM may be represented by formula (XXXIII) or a non- These may have a structure that mimics the natural type, and these are described in WO2014 / 074658 and WO 2013 / 071035 The IAP ligands are derived from those described in:

[0229] [ka]

[0230] During the ceremony: R in formula (XXXIII) 2 is H, optionally substituted alkyl, optionally substituted cycloalkyl , optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, selected from optionally substituted arylalkyl, or optionally substituted aryl; R in formula (XXXIII) 6 and R 8 are independently hydrogen, optionally substituted alkyl, or substituted cycloalkyl; R in formula (XXXIII) 32 is (C 1 -C 4 Alkylene)-R 33 wherein R 33 Optionally, selected from hydrogen, aryl, heteroaryl, or cycloalkyl substituted with; X in formula (XXXIII) is selected from:

[0231] [ka]

[0232] Z and Z′ in formula (XXXIII) are independently selected from:

[0233] [ka]

[0234] During the ceremony, each

[0235] [ka]

[0236] represents a point of attachment to the compound, and Z and Z' are both

[0237] [ka]

[0238] It cannot be; Y in formula (XXXIII) is selected from:

[0239] [ka]

[0240] In the formula (XXXIII), Z and Z' are the same, and Z is

[0241] [ka]

[0242] where each

[0243] [ka]

[0244] represents a point of attachment to the compound, and X is selected from:

[0245] [ka]

[0246] Y in formula (XXXIII) is independently selected from:

[0247] [ka]

[0248] [ka]

[0249] During the ceremony:

[0250] [ka]

[0251] represents the point of attachment to the -C=O moiety of the compound;

[0252] [ka]

[0253] represents the point of attachment to the -NH moiety of the compound;

[0254] [ka]

[0255] represents the first point of attachment to Z;

[0256] [ka]

[0257] represents the second point of attachment to Z; m is an integer from 0 to 3; n is an integer from 1 to 3; p is an integer from 0 to 4; and A is -C(O)R 3 and; R 3 is -C(O)R 3 , OH, NHCN, NHSO 2 R 10 , N.H.O.R. 11 or N(R 12 )(R 13 ) are selected from; NHSO 2 R 10 and NHOR 11 R 10 and R 11 are independently hydrogen, optionally substituted -C 1 -C 4 Alkyl, Cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocycloaryl Selected from Kill; N(R 12 )(R 13 )R 12 and R 13 are independently hydrogen, -C 1 -C 4 Alkyl, -(C 1 -C 4 )Alkylene)-N H-(C 1 -C 4 alkyl), and -(C 1 -C 4 alkylene)-O-(C 1 -C 4 Hydroxyalkyl) Selected or R 12 and R 13 are N, O and and S, forming a saturated heterocyclyl optionally containing one additional heteroatom selected from wherein the saturated heterocycle is optionally substituted with methyl.

[0258] In any of the compounds described herein, the ILM is represented by formula (XXXIV) or formula (XX XV), or a non-natural mimetic thereof, which are described in WO 2014 / 047024. and / or pharma- ceutically acceptable salts, tautomers, and / or amines thereof. isomers, or stereoisomers:

[0259] [ka]

[0260] During the ceremony: In the formula (XXXIV) or (XXXV), X is absent or -(CR 10 R 11 ) m -, optionally replaced a group selected from heteroaryl, or optionally substituted heterocyclyl;

[0261] [ka]

[0262] Y and Z in formula (XXXIV) or formula (XXXV) are each independently selected from the group consisting of C=O, -O-, -NR 9 -, -CONH-, -NHCO- may be independently selected or absent; R of formula (XXXIV) or formula (XXXV) 1 and R 2 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or R of formula (XXXIV) or formula (XXXV) 1 and R 2 are independently optionally substituted thioalkyl wherein the substituent attached to the S atom of the thioalkyl is selected from the group consisting of optionally substituted aryl, alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 where v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 CHR 21 COR 22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 Selected from; -CH 2 R 23 R 23 is an optionally substituted aryl or an optionally substituted heterocyclyl; wherein the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 20 ) m C H 3 or a polyamine chain; R 26 is optionally substituted alkyl, where the optional substituents are OH, halogen or Or NH 2 and; -(CR 10 R 11 ) m - m is an integer from 1 to 8; R of formula (XXXIV) or formula (XXXV) 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryl alkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or wherein the substituents are selected from alkyl, halogen, is OH or OH; R of formula (XXXIV) or formula (XXXV) 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted substituted alkyl, or optionally substituted cycloalkyl; -(CR 10 R 11 ) m -R 10 and R 11 are independently hydrogen, halogen, or optionally substituted alkoxy. Selected from Kill;

[0263] [ka]

[0264] R 12 and R 13 are independently selected from hydrogen, halogen, or optionally substituted alkyl. or R 12 and R 13 can together form a carbocyclic ring;

[0265] [ka]

[0266] R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, optionally substituted alkyl, LE, OR 19 Selected from; OR 19 R 19 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl Selected from; -(CR 10 R 11 ) m - m and n are independently 0, 1, 2, 3, or 4; -(CR 10 R 11 ) m - o and p are independently 0, 1, 2, or 3; -(CR 10 R 11 ) m - q is 0, 1, 2, 3, or 4; r is 0 or 1; -(CR 10 R 11 ) m -t is 1, 2, or 3.

[0267] In any of the compounds described herein, the ILM may be represented by formula (XXXVI), or a non- These may have the structure of a natural mimetic, such as the IAP ligases described in WO 2014 / 025759. and / or its pharma- ceutically acceptable salts, tautomers or stereoisomers. It is an isomer:

[0268] [ka]

[0269] During the ceremony, A in formula (XXXVI) is selected from:

[0270] [ka]

[0271] where the dotted lines represent optional double bonds; X in formula (XXXVI) is selected from the following: -(CR 21 R 22 ) m -,

[0272] [ka]

[0273] In the formula (XXXVI), Y and Z are each independently -O-, -NR 6 - independently selected from or absent; V in formula (XXXVI) is selected from -N- or -CH-; W in formula (XXXVI) is selected from -CH- or -N-; R in formula (XXXVI) 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl; R in formula (XXXVI) 3 and R 4 are independently optionally substituted alkyl, optionally substituted silyl aryl, optionally substituted aryl, optionally substituted heteroaryl, substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted hetero arylalkyl, or optionally substituted heterocycloalkyl; R of formula (XXIV), formula (XXV) or formula (XXVI) 5 , R 6 , R 7 and R 8 are independently hydrogen, any or optionally substituted cycloalkyl; Preferably it is methyl;

[0274] [ka]

[0275] R 9 and R 10are independently selected from hydrogen, halogen, or optionally substituted alkyl. or R 9 and R 10 can together form a ring;

[0276] [ka]

[0277] R 11 , R 12 , R 13 and R 14 are independently hydrogen, halogen, optionally substituted alkyl or OR 15 Selected from; OR 15 R 15 is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl Selected from; -(CR 21 R 22 ) m - and

[0278] [ka]

[0279] m and n are independently selected from 0, 1, 2, 3, or 4;

[0280] [ka]

[0281] o and p are independently selected from 0, 1, 2 or 3;

[0282] [ka]

[0283] q is selected from 0, 1, 2, 3, or 4;

[0284] [ka]

[0285] In the formula, r is selected from 0 or 1. In any of the compounds described herein, the ILM is represented by formula (XXXVII) or formula (X XXVIII), or a non-natural mimetic thereof, which is described in WO 2014 / 011712 or a pharma- ceutically acceptable salt, tautomer or the like thereof. or a stereoisomer:

[0286] [ka]

[0287] During the ceremony: X in the formula (XXXVII) and the formula (XXXVIII) is -(CR 16 R 17 ) m -or-

[0288] [ka]

[0289] or non-existent; Y and Z in formula (XXXVII) and formula (XXXVIII) are each independently -0-, C=0, NR 6 are independently selected from or absent; R of formula (XXXVII) and formula (XXXVIII) 1 and R 2 is optionally substituted alkyl, substituted cycloalkyl, optionally substituted alkylaryl, or optionally substituted aryl selected from R of formula (XXXVII) and formula (XXXVIII) 3 and R 4 are independently optionally substituted alkyl , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, selected from optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXXVII) and formula (XXXVIII) 5 and R 6 are independently optionally substituted alkyl or optionally substituted cycloalkyl; R of formula (XXXVII) and formula (XXXVIII) 7 and R 8 are independently hydrogen, optionally substituted a alkyl, or optionally substituted cycloalkyl, or preferably methyl; and;

[0290] [ka]

[0291] R 9 and R 10 is independently selected from hydrogen, optionally substituted alkyl, or R 9 and R 10 may together form a ring;

[0292] [ka]

[0293] R 11 ~R 14 are independently hydrogen, halogen, optionally substituted alkyl, or OR 15 Choose from Is; OR 15 R 15is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl Selected from; -(CR 16 R 17 ) m -R 16 and R 17 are independently hydrogen, halogen, or optionally substituted alkoxy. Selected from Kill; R of formula (XXXVII) and formula (XXXVIII) 50 And R 51 are independently optionally substituted aryl Selected from Kill or R 50 and R 51 together form a ring; -(CR 16 R 17 ) m - and

[0294] [ka]

[0295] m and n are independently an integer of 0 to 4;

[0296] [ka]

[0297] wherein o and p are independently an integer of 0 to 3;

[0298] [ka]

[0299] q is an integer from 0 to 4; and

[0300] [ka]

[0301] The r is an integer of 0 to 1. In one embodiment, R of the ILM of formula (XXXVII) or formula (XXXVIII) 1 and R 2 T-button and R of the ILM of formula (XXXVII) or formula (XXXVIII) 3 and R 4 Tetrahydronaphthalene It is phthalene.

[0302] In any of the compounds described herein, the ILM is represented by formula (XXXIX) or formula (XLIX). ), or a non-natural mimetic thereof, which are described in WO2013 / 071039. Derived from the IAP ligands listed below:

[0303] [ka]

[0304] During the ceremony: R in formula (XXXIX) and formula (XL) 43 And R 44 independently represent an optionally substituted halo. aryl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl cycloalkyl, cycloalkylalkyl, and R in formula (XXXIX) and formula (XL) 6 And R 8 are independently hydrogen, optionally substituted alkyl aryl, or optionally substituted cycloalkyl; Each X in formulas (XXXIX) and (XL) is independently selected from:

[0305] [ka]

[0306] Each Z in formula (XXXIX) and formula (XL) is

[0307] [ka]

[0308] wherein each

[0309] [ka]

[0310] represents the point of attachment of the compound; and Each Y is selected from:

[0311] [ka]

[0312] [ka]

[0313] During the ceremony:

[0314] [ka]

[0315] represents the point of attachment to the -C=O moiety of the compound;

[0316] [ka]

[0317] represents the point of attachment to the amino moiety of the compound;

[0318] [ka]

[0319] represents the first point of attachment to Z;

[0320] [ka]

[0321] represents the second point of attachment to Z; and A is -C(O)R 3 ,or

[0322] [ka]

[0323] or any of the tautomeric forms previously described, wherein: -C(O)R 3 R 3 OH, NHCN, NHS0 2 R 10 , N.H.O.R. 11 or N(R 12 )(R 13 ) are selected from; NHS0 2 R 10 and NHOR 11 R 10 And R 11 are independent, -C 1 -C 4 Alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which is selected from optionally substituted, and hydrogen; N(R 12 )(R 13 )R 12 and R 13 each independently represents hydrogen, -C 1 -C 4 Alkyl, -(C 1 -C 4 Alkire N)-NH-(C 1 -C 4 alkyl), benzyl, -(C 1 -C4 alkylene)-C(O)OH, -(C 1 -C 4 Alkylene)-C(O)CH 3 , -CH(benzyl)-COOH, -C 1 -C 4 Alkoxy, and -(C 1 -C 4 alkylene)-O-(C 1 -C 4 or N(R 12 )(R 13 )R 12 and R 13 together with the nitrogen atom to which they are commonly bonded, one selected from N, O and S forming a saturated heterocyclyl optionally containing two additional heteroatoms, The ring is optionally substituted with methyl.

[0324] In any of the compounds described herein, the ILM may have the structure of formula (XLI): These are derived from the IAP ligands described in WO2013 / 071039:

[0325] [ka]

[0326] During the ceremony: W in formula (XLI) 1 are O, S, and NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLI) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 Both neither O nor both S; R in formula (XLI) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-( Substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or Unsubstituted Heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); X 1 But, O, NR A , S, S(O), or S(O) 2 If selected from, X 2 is C( R 2a R 2b ) and; or: X in formula (XLI) 1 is CR 2c R 2d Choose from difference R, X 2 CR 2a R 2b and R 2c and R 2a Together Forming bonds; or: X in formula (XLI) 1 and X 2 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated or unsubstituted; 3-10 membered cycloalkyl rings, fused, substituted or unsubstituted, saturated or partially saturated a fused 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; or: X in formula (XLI) 1 CH 2 and X 2 is C=0, C=C(R C ) 2 or C=NR C Here In each R c are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C 1 -C 6 Alkyl, Substitutional or non-substitutional C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloar alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 a Alkyl-(substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted aryl), or -C 1 - C 6 alkyl-(substituted or unsubstituted heteroaryl); NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d and C.R. 2a R 2b R 2a , R 2b , R 2c , R2d are independently H, substituted or unsubstituted C 1 -C 6 Al Kill, Replace or Not Replace C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, Substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or Unsubstituted Heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl) and -C(=O )R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloa , substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cyclo alkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C2 -C 5 Heterocycloalkyl), -C 1 -C 6 a Aryl- (substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl - NR D R E Selected from; NR D R E R D and R E are independently H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted substitution C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl- (substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 - C 5 Heterocycloa Rukill), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl- (substituted or unsubstituted heteroaryl; m in formula (XLI) is selected from 0, 1 or 2; -U- in formula (XLI) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -NH (C=O)O-, -O(C=O)NH-, or -NHS(=O)2 Selected from: NH-; R in formula (XLI) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLI) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3, OR -OR 5 Selected from; -NHR 5 , -N(R 5 )2, -N+(R 5 )3, and -OR 5 Each R 5 are independent of each other, H, C 1 -C 3 Alkyl, C 1 -C 3 Ha Roalkyl, C 1 -C 3 Heteroalkyl, and -C 1 -C 3 Alkyl-(C 3 -C 5 Cycloalkyl) Selected; or: R in formula (XLI) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached. Form; or: R in formula (XLI) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLI) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 Heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , - (C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)- NHS(=O) 2 NHR 7 Each R 7 is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroar Kill, Replace or Not Replace C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 - C 10 Heterosi chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 - C 6 Alkyl-(substituted or unsubstituted C 3 -C 10 Cycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted substitution C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P -CH(substituted or unsubstituted aryl -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d , H, C 1 -C 6 Alkyl, C 1 -C 6 centre Luoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Heteroalkyl, and substituted or unsubstituted aryl selected from the rule; or: R 8a and R 8d is as defined above, and R 8b and R 8c form a bond together death; or: R 8a and R 8d is as defined above, and R 8b and R 8c are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted A fused 5- to 10-membered aryl ring or a heteroatom selected from S, O and N. forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having or: R 8c and R 8d is as defined above, and R 8a and R 8b They are combined and optionally substituted with 1 to 3 heteroatoms selected from S, O and N. or an unsubstituted, saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; or: R 8a and R 8b is as defined above, and R 8c and R 8d are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 Replaced by ; and R 8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C 1 -C 4 Al Kill, C. 1 -C 4 Fluoroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, -NH 2 , -N H(C 1 - C 4 alkyl), -NH(C 1 -C4 Alkyl) 2 , -C(=O)OH, -C(=0)NH 2 , -C(=O)C 1 -C 3 Alki ru, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 alkyl), -O(C 1 -C 4 Alkyl)-NH 2 ;-O(C 1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 -C 4 Alkyl)- N-(C 1 -C 4 Alkyl) 2 or two R 9 along with the atoms to which they are attached , halogen, -OH, or C 1 -C 3 Methylenediamine substituted or unsubstituted with alkyl It forms an oxy ring or an ethylenedioxy ring.

[0327] In any of the compounds described herein, the ILM has the structure of formula (XLII): These can be derived from the IAP ligands described in WO2013 / 071039:

[0328] [ka]

[0329] During the ceremony: W in formula (XLII) 1 are O, S, and NR A , or C(R8a )(R 8b ) and; W in formula (XLII) 2 are O, S, and NR A , or C(R 8c )(R 8d ) where W 1 and W 2 Both are O not or neither S; R in formula (XLII) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-( Substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLII) 1 NR A If X 2 is C=O or CR 2c R 2d And X 3 is CR 2a R 2b in can be; or: X in formula (XLII) 1 is S, S(O) or S(O) 2 If selected from, X 2 is CR 2c R 2d And X 3 is CR 2a R 2b and; or: X in formula (XLII) 1If is O, then X 2 is CR 2c R 2d and NR A and X 3 is CR 2a R 2b and; or: X in formula (XLII) 1 CH 3 If X 2 , O, NR A , S, S(O), or S(O) 2 is selected from And X 3 is CR 2a R 2b and; X in formula (XLII) 1 CR 2e R 2f and X2 is CR 2c R 2d If R 2e and R 2c Both are bonds and forming X of formula (VLII) 3 is CR 2a R 2b and; or: X in formula (XLII) 1 and X 3 Both are CH 2 and X in formula (XLII) 2 is C=0, C=C(R C ) 2 ,Also is C=NR C where each R C are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 F Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , -C 1-C 6 Alkyl-(substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or is unsubstituted C 2 - C 5 Heterocycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl- (substituted or unsubstituted heteroaryl); or: X in formula (XLI) 1 and X 2 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated or unsubstituted; 3-10 membered cycloalkyl rings, fused, substituted or unsubstituted, saturated or partially saturated a fused 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X 3 teeth , C.R. 2a R 2b and; or: X in formula (XLI) 2 and X 3 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated or unsubstituted; 3-10 membered cycloalkyl rings, fused, substituted or unsubstituted, saturated or partially saturated a fused 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and represented by the formula (V X of LII 1 CR 2e R 2f and; NR A R A , H, C1 -C 6 Alkyl, -C(=O)C 1 -C 2 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is independent, H , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl ), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted) -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C 1 -C6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloa , substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cyclo alkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 a Aryl- (substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl - NR D R E Selected from; NR D R E R D and R E are independently H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted substitution C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl- (substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloa Rukill), -C1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl- (substituted or unsubstituted heteroaryl; m in formula (XLII) is selected from 0, 1 or 2; -U- in formula (XLII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -N H(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 Selected from: NH-; R in formula (XLII) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLII) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 Selected from; -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 , and -OR 5 Each R 5 are independent of each other, H, C 1 -C 3 Alkyl, C 1 -C 3 Ha Roalkyl, C 1 -C 3 Heteroalkyl, and -C 1 -C 3 Alkyl-(C 3 -C 5 Cycloalkyl) Selected; or: R in formula (XLII)3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached. Form; or: R in formula (XLII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 Heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7, -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , - (C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)- NHS(=O) 2 NHR 7 Each R 7 is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroar Kill, Replace or Not Replace C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 - C 10 Heterosi chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 - C 6 Alkyl-(substituted or unsubstituted C 3 -C 10 Cycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted substitution C 2 -C 10Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P -CH(substituted or unsubstituted aryl -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d , H, C 1 -C 6 Alkyl, C 1 -C 6 centre Luoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Heteroalkyl, and substituted or unsubstituted aryl selected from the rule; or: R 8a and R 8d is as defined above, and R8b and R 8c form a bond together death; or: R 8a and R 8d is as defined above, and R 8b and R 8c are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted A fused 5- to 10-membered aryl ring or a heteroatom selected from S, O and N. forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having or: R 8c and R 8d is as defined above, and R 8a and R 8b They are combined and optionally substituted with 1 to 3 heteroatoms selected from S, O and N. or an unsubstituted, saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; or: R 8a and R 8b is as defined above, and R 8c and R 8d are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 Replaced by ; and R8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C 1 -C 4 Al Kill, C. 1 -C 4 Fluoroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, -NH 2 , -N H(C 1 - C 4 alkyl), -NH(C 1 -C 4 Alkyl) 2 , -C(=O)OH, -C(=0)NH 2 , -C(=O)C 1 -C 3 Alki ru, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 alkyl), -O(C 1 -C 4 Alkyl)-NH 2 ;-O(C 1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 -C 4 Alkyl)- N-(C 1 -C 4 Alkyl) 2 or two R 9 along with the atoms to which they are attached , halogen, -OH, or C 1 -C 3 Methylenediamine substituted or unsubstituted with alkyl It forms an oxy ring or an ethylenedioxy ring.

[0330] In any of the compounds described herein, the ILM has the structure of formula (XLIII): These can be derived from the IAP ligands described in WO2013 / 071039:

[0331] [ka]

[0332] During the ceremony: W in formula (XLIII) 1 are O, S, and NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLIII) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 Both neither O nor both S; R in formula (XLIII) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-( Substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIII) 1 But NR A, S, S(O), or S(O) 2 When selected from the group consisting of X in formula (XLIII), 2 is CR 2c R 2d and X of formula (XLIII) 3 is CR 2a R 2b and; or: X in formula (XLIII) 1 When is O, X in formula (XLIII) 2 , O, NR A , S, S(O), or S(O) 2 mosquito and X of formula (XLIII) 3 CR 2a R 2b and; or: X in formula (XLIII) 1 CR 2e R 2f and X in formula (XLIII) 2 CR 2c R 2d If R 2e and R 2c and form a bond, and X in formula (XLIII) 3 is CR 2a R 2b and; or: X in formula (XLIII) 1 and X 2 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated, or or partially saturated 3- to 10-membered cycloalkyl rings, fused substituted or unsubstituted saturated or partially saturated Saturated 3- to 10-membered heterocycloalkyl ring, fused substituted or unsubstituted 5- to 10-membered aryl ring or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and having the formula X of (XLIII) 3 CR 2a R 2b and; or: X in formula (XLIII) 2 and X 3 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated, or or partially saturated 3- to 10-membered cycloalkyl rings, fused substituted or unsubstituted saturated or partially saturated Saturated 3- to 10-membered heterocycloalkyl ring, fused substituted or unsubstituted 5- to 10-membered aryl ring or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and having the formula X of (VLII) 1 CR 2e R 2f and; NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is independent, H , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3- C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl ), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted) -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloa , substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cyclo alkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 a Aryl- (substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl - NR D R E and; NR D R E R D and R E are independently H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted substitution C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl- (substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 - C 5 Heterocycloa Rukill), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl- (substituted or unsubstituted heteroaryl; In formula (XLIII), m is 0, 1 or 2; -U- in formula (XLIII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, - NH(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 NH-; R in formula (XLIII) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 is a fluoroalkyl; R in formula (XLIII) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 and; -NHR 5 , -N(R 5 ) 2 , -N+(R5 ) 3 , and -OR 5 Each R 5 are independent of each other, H, C 1 -C 3 Alkyl, C 1 -C 3 Ha Roalkyl, C 1 -C 3 Heteroalkyl, and -C 1 -C 3 Alkyl-(C 3 -C 5 Cycloalkyl) Selected; or: R in formula (XLIII) 3 and R 5 are substituted or unsubstituted 5- to 7-membered rings together with the atoms to which they are attached. Forming; or: R in formula (XLIII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLIII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 Heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , - (C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)- NHS(=O) 2 NHR 7 Each R 7 is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroar Kill, Replace or Not Replace C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 - C 10 Heterosi chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 - C 6 Alkyl-(substituted or unsubstituted C 3 -C 10 Cycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted substitution C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P -CH(substituted or unsubstituted aryl -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted substituted or unsubstituted heteroaryl); R 7 p is 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R8b , R 8c , and R 8d , H, C 1 -C 6 Alkyl, C 1 -C 6 centre Luoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Heteroalkyl, and substituted or unsubstituted aryl selected from the rule; or: R 8a and R 8d is as defined above, and R 8b and R 8c form a bond together death; or: R 8a and R 8d is as defined above, and R 8b and R 8c are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted A fused 5- to 10-membered aryl ring or a heteroatom selected from S, O and N. forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having or: R 8c and R 8d is as defined above, and R 8a and R 8b are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; or: R 8a and R 8bis as defined above, and R 8c and R 8d are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 Replaced by ; and R 8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C 1 -C 4 Al Kill, C. 1 -C 4 Fluoroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy, -NH 2 , -N H(C 1 - C 4 alkyl), -NH(C 1 -C 4 Alkyl) 2 , -C(=O)OH, -C(=0)NH 2 , -C(=O)C 1 -C 3 Alki ru, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 alkyl), -O(C 1 -C 4 Alkyl)-NH 2 ;-O(C1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 -C 4 Alkyl)- N-(C 1 -C 4 Alkyl) 2 or two R 9 along with the atoms to which they are attached , halogen, -OH, or C 1 -C 3 Methylenediamine substituted or unsubstituted with alkyl It forms an oxy ring or an ethylenedioxy ring.

[0333] In any of the compounds described herein, the ILM has the structure of formula (XLIV): These are derived from the IAP ligands described in WO 2013 / 071039:

[0334] [ka]

[0335] During the ceremony: W in formula (XLIV) 1 are O, S, and NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLIV) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 Both neither O nor both S; W in formula (XLIV) 3 are O, S, and NR A , or C(R 8e )(R 8f ), where W 1 , W2 and W 3 does not contain two adjacent oxygen or sulfur atoms; R in formula (XLIV) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-( Substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIV) 1 When is O, X in formula (XLIV) 2 CR 2c R 2d and N.R. A is selected from the formula (XLIV) W 3 CR 2a R 2b and; or: X in formula (XLIV) 1 CH 2 When X in formula (XLIV) is 2 , O, NR A , S, S(O), or S(O) 2 mosquito X of formula (XLIV) is selected from 3 CR 2a R 2b and; or: X in formula (XLIV) 1 CR 2e R 2f and X in formula (XLIV) 2 CR 2c R 2dIf R 2e and R 2c teeth Together, they form a bond, and X in formula (XLIV) 3 is CR 2a R 2b and; or: X in formula (XLIV) 1 and X 3 Both are CH 2 and X in formula (XLII) 2 is C=0, C=C(R C ) 2 ,Also is C=NR C where each R C are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C 1 -C 6 , substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterothic substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 - C 5 Heterocycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl- (substituted or unsubstituted heteroaryl); or: X in formula (XLIV) 1 and X 2 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated or unsubstituted; 3-10 membered cycloalkyl rings, fused, substituted or unsubstituted, saturated or partially saturated a fused 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and represented by the formula (X LIV)'s X 3 CR 2a R 2b and; or: X in formula (XLIV) 2 and X 3 are independently selected from C and N, and may be fused, substituted or unsubstituted, saturated or unsubstituted; 3-10 membered cycloalkyl rings, fused, substituted or unsubstituted, saturated or partially saturated a fused 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a component of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and represented by the formula (V LIV)'s X 1 CR 2e R 2f and; NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is independent, H , substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl ), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted) -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloa , substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 - C 6 Cyclo alkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 a Aryl- (substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl - NR D R E Selected from; NR D R E R D and R E are independently H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted substitution C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl- (substituted or unsubstituted C 3 -C 6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 - C 5 Heterocycloa Rukill), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl- (substituted or unsubstituted heteroaryl; In formula (XLIV), m is selected from 0, 1 or 2; -U- in formula (XLIV) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -N H(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 Selected from: NH-; R in formula (XLIV) 3 is C 1 -C 3Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLIV) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 Selected from; -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 , and -OR 5 Each R 5 are independent of each other, H, C 1 -C 3 Alkyl, C 1 -C 3 Ha Roalkyl, C 1 -C 3 Heteroalkyl, and -C 1 -C 3 Alkyl-(C 3 -C 5 Cycloalkyl) Selected; or: R in formula (XLIV) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached. Form; or: R in formula (XLIII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLIII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 Heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ; -NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , - (C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ; -(C 1 -C3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)- NHS(=O) 2 NHR 7 Each R 7 is independent, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroar Kill, Replace or Not Replace C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 - C 10 Heterosi chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 - C 6 Alkyl-(substituted or unsubstituted C 3 -C 10 Cycloalkyl), -C 1 -C 6 Alkyl- (substituted or unsubstituted substitution C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P -CH(substituted or unsubstituted aryl -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f are independent of each other, H, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haeta and substituted or unsubstituted aryl; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8d , R 8e , and R 8f is as defined above. as defined, and R 8b and R 8c together form a bond; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f)R 8a , R 8b , R 8d , and R 8f is as defined above. as defined, and R 8c and R 8e together form a bond; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8d , R 8e , and R 8f is as defined above as defined above, and R 8b and R 8c are S, O and and N. Saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted fused 5- to 10-membered aryls a substituted or unsubstituted ring containing 1 to 3 heteroatoms selected from S, O and N; forming an unsubstituted fused 5- to 10-membered heteroaryl ring; or: C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8b , R 8d , and R 8f is as defined above as defined above, and R 8c and R 8e are S, O and and N. partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted fused 5- to 10-membered aryl A ring or a substituted or unsubstituted ring containing 1 to 3 heteroatoms selected from S, O and N. forming a fused 5- to 10-membered heteroaryl ring; or: C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8c , R 8d , R 8e , and R 8f is as defined above and R 8a and R 8b are selected from S, O, and N along with the atom to which they are attached Substituted or unsubstituted, saturated or partially saturated 3- to 7-membered alkyl group containing 1 to 3 heteroatoms forming a spiro or heterospiro ring; or: C(R 8a )(R 8b ) and C(R 8e )(R 8f )R 8a , R 8b , R 8e , and R 8f is as defined above and R 8c and R 8d are selected from S, O, and N along with the atom to which they are attached Substituted or unsubstituted, saturated or partially saturated 3- to 7-membered alkyl group containing 1 to 3 heteroatoms forming a spiro or heterospiro ring; or: C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d is as defined above and R 8e and R 8f are selected from S, O, and N along with the atom to which they are attached Substituted or unsubstituted, saturated or partially saturated 3- to 7-membered alkyl group containing 1 to 3 heteroatoms forming a spiro or heterospiro ring; or: Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 Replaced by ; and R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f Each R 9 are independently halogen, -OH, -SH, (C=O), C N.C. 1 -C 4 Alkyl, C 1 -C 4 Fluoroalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Fluoroalkoxy Si, -NH 2 , -NH(C 1 - C 4 alkyl), -NH(C 1 -C 4 Alkyl) 2 , -C(=O)OH, -C(=0)NH 2 , -C(=O) C 1 -C 3 Alkyl, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 Al Kill), -O(C 1 -C4 Alkyl)-NH 2 ;-O(C 1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 - C 4 Alkyl)-N-(C 1 -C 4 Alkyl) 2 or two R 9 But they are combined Atoms with halogen, -OH, or C 1 -C 3 Alkyl substituted or unsubstituted It forms a methylenedioxy ring or an ethylenedioxy ring.

[0336] In any of the compounds described herein, the ILM is of formula (XLV), formula (XLVI), or or formula (XLVII), or a non-natural mimetic thereof, which is This can be done as described in Vamos, M., et al., Expedient synthesis of highly potent antagomir. inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-I Derived from the IAP ligand described in AP, ACS Chem. Biol., 8(4), 725-32 (2013):

[0337] [ka]

[0338] During the ceremony: R in formula (XLV) 2 , R 3 and R 4 is independently selected from H or Me; X of formula (XLV) is independently selected from O or S; and R in formula (XLV) 1 is selected from:

[0339] [ka]

[0340] In certain embodiments, the ILM has a structure according to formula (XLVIII):

[0341] [ka]

[0342] R of formula (XLVIII) 3 , and R 4 is independently selected from H or ME;

[0343] [ka]

[0344] is a 5-membered heterocycle selected from:

[0345] [ka]

[0346] In certain embodiments, the compound of formula (XLVIII)

[0347] [ka]

[0348] teeth,

[0349] [ka]

[0350] It is. In certain embodiments, the ILM has the structure shown below and is attached to a linker group L: Can be:

[0351] [ka]

[0352] In certain embodiments, the ILM has a structure according to formula (XLIX), (L), or (LI):

[0353] [ka]

[0354] During the ceremony: R of formula (XLIX), formula (L) or formula (LI) 3 is independently selected from H or ME;

[0355] [ka]

[0356] is a 5-membered heterocycle selected from:

[0357] [ka]

[0358] ; and L in formula (XLIX), formula (L) or formula (LI) is selected from the following:

[0359] [ka]

[0360] In certain embodiments, L of formula (XLIX), formula (L), or formula (LI)

[0361] [ka]

[0362] In certain embodiments, the ILM has a structure according to formula (LII):

[0363] [ka]

[0364] In certain embodiments, the ILM according to formula (LII) is

[0365] [ka]

[0366] and is chemically attached to a linker group L in the region as shown below:

[0367] [ka]

[0368] In any of the compounds described herein, the ILM is represented by formula (LIII) or (LIV): or a non-natural mimetic thereof, as described in Hennessy, EJ, et al., Di discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Based on the IAP ligands described in Chem. Lett., 22(4), 1960-4 (2012):

[0369] [ka]

[0370] During the ceremony: R of formula (LIII) and formula (LIV) 1 is selected from:

[0371] [ka]

[0372] R of formula (LIII) and formula (LIV) 2 is selected from H or Me: R of formula (LIII) and formula (LIV) 3 is selected from:

[0373] [ka]

[0374] X is H, halogen, methyl, methoxy, hydroxy, nitro, or trifluoromethyl. is selected from.

[0375] In any of the compounds described herein, the ILM is represented by formula (LV) or formula (LVI): As shown in the formula (LV) or formula (LVI) or a non-natural mimetic thereof, and can be chemically attached to a linker:

[0376] [ka]

[0377] In any of the compounds described herein, the ILM may be represented by formula (LVII), or a non-natural The structure of the compound can be a natural mimetic, as described in Cohen, F, et al., Orally bioavailable e antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane sc Based on the IAP ligands described in affold, J. Med. Chem., 52(6), 1723-30 (2009):

[0378] [ka]

[0379] During the ceremony: R1 in formula (LVII) is selected from the following:

[0380] [ka]

[0381] [ka]

[0382] X is selected from H, fluoro, methyl, or methoxy. In certain embodiments, the ILM is represented by the following structure:

[0383] [ka]

[0384] In certain embodiments, the ILM is selected from the group consisting of: The chemical bonds are shown:

[0385] [ka]

[0386] ; and

[0387] [ka]

[0388] In any of the compounds described herein, the ILM is selected from the group consisting of the following structures: This was selected by Asano, M, et al., Design, sterioselective synthesis, and biology cal evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013) Derived from:

[0389] [ka]

[0390] or

[0391] [ka]

[0392] In certain embodiments, the ILM is selected from the group consisting of: The chemical bonds are shown:

[0393] [ka]

[0394] ; and

[0395] [ka]

[0396] In any of the compounds described herein, the ILM may be represented by formula (LVIII), or a non- The structure can be a mimetic of the natural type, as described in Asano, M, et al., Design, steriosele ctive synthesis, and biological evaluation of novel tri-cyclic compounds as inhi bitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725- 37 (2013) derived from the IAP ligand:

[0397] [ka]

[0398] In the formula (LVIII), X is one or more independently selected from H, halogen, or cyano. There are two substituents.

[0399] In any of the compounds described herein, the ILM is of formula (LIX) or formula (LX): As shown in the formula (LIX) or formula (LX) or a non-natural mimetic thereof, and can be chemically attached to a linker group L:

[0400] [ka]

[0401] [ka]

[0402] wherein X in formulae (LIX) and (LX) is independently selected from H, halogen, or cyano. and L in formula (LIX) and (LX) is one or two substituents, as described herein. is a linker group that is

[0403] In any of the compounds described herein, the ILM may be represented by formula (LXI), or a non-natural The structure of the compound can be a natural mimetic, as described in Ardecky, RJ, et al., Design, systems and methods. s and evaluation of inhibitor of apoptosis (IAP) antagonists that are highly sel ective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013) From the IAP ligands described:

[0404] [ka]

[0405] During the ceremony: Formula (LXI)

[0406] [ka]

[0407] is a natural or unnatural amino acid; and R in formula (LXI) 2 is selected from:

[0408] [ka]

[0409] In any of the compounds described herein, the ILM is represented by formula (LXII) or formula (LXI II), the structure of formula (LXII) or formula (LXIII) or a non-natural mimetic thereof and can be chemically attached to a linker group L:

[0410] [ka]

[0411] [ka]

[0412] Formula (LXI)

[0413] [ka]

[0414] is a natural or unnatural amino acid; and L in formula (LXI) is a linker group as described herein.

[0415] In any of the compounds described herein, the ILM is selected from the group consisting of: The structure of the nucleotide sequence of the present invention can be that of a non-natural mimetic thereof, as described in Wang, J, et al. ., Discovery of novel second mitochondrial-derived activator of caspase mimetics as selective inhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther ., 349(2): 319-29 (2014):

[0416] [ka]

[0417] In any of the compounds described herein, the ILM may be represented by formula (LXIX), or a non- The structure of the peptide is based on the natural mimic structure described by Hird, AW, et al., Structure-based design. gn and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Based on the IAP ligands described in Bioorg. Med. Chem. Lett., 24(7): 1820-4 (2014):

[0418] [ka]

[0419] wherein R of formula LIX is selected from the group consisting of:

[0420] [ka]

[0421] ;

[0422] [ka]

[0423] R 1 is selected from H or Me;

[0424] [ka]

[0425] R 2 is selected from alkyl or cycloalkyl;

[0426] [ka]

[0427] X is independently selected from halogen, hydroxy, methoxy, nitro, and trifluoromethyl. and 1 to 2 substituents selected from the group consisting of

[0428] [ka]

[0429] Z is O or NH;

[0430] [ka]

[0431] HET is a monocyclic heteroaryl or a fused bicyclic heteroaryl; and In formula (LIX), --- represents an optional double bond.

[0432] In certain embodiments, the ILM has a chemical structure represented by:

[0433] [ka]

[0434] In certain embodiments, the ILM of the compound has a chemical structure selected from the group consisting of: R:

[0435] [ka]

[0436] [ka]

[0437] As used herein, the term "independently" means that a variable that is applied independently is used to indicate that the

[0438] The term "alkyl" refers, within its context, to any fully saturated straight-chain, branched, or cyclic alkyl radical. is intended to mean a hydrocarbon radical or alkyl group, preferably 1 -C 10 , more preferably C 1 -C 6 , or C 1 -C 3 are alkyl groups of the formula: Examples of alkyl groups are in particular methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-hexane. butyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl Propyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentyl ethene In certain embodiments, aryl, cyclohexylethyl, and cyclohexyl. The alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In one embodiment, the compounds according to the present disclosure are used to covalently bind to a dehalogenase enzyme. These compounds generally have a side chain (often via a polyethylene glycol group). The side chain contains a halogen substituent (often chlorine or or bromine), thereby making it possible to distinguish compounds containing the moiety from tannic acid. Covalent bonding of proteins occurs.

[0439] The term "alkenyl" refers to straight, branched or unbranched alkyl groups containing at least one C=C bond. or cyclic C 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0440] The term "alkynyl" refers to straight-chain, branched or alkynyl groups containing at least one C≡C bond. or cyclic C 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0441] The term "alkylene," when used, refers to an optionally substituted --(CH 2 ) n - Refers to the group ( n is typically an integer from 0 to 6. When substituted, the alkylene group is At least one C 1 -C 6 Substituted with an alkyl group (including a cyclopropyl group or a t-butyl group) It is preferred that the aryl group contains one or more halo groups, preferably 1 to 3 halo groups, or one or more or two hydroxyl groups, O-(C 1 -C 6 alkyl) groups, or as otherwise specified herein The disclosed amino acid side chains may be substituted. In certain embodiments, the alkylene group is The polyalkylene oxides may be substituted with butyl or alkoxy groups (or other groups), which may further comprise Ethylene glycol chain (1 to 10, preferably 1 to 6, and often 1 to 4 ethylene glycol chains) The alkyl group is preferably, but not limited to, a chain of repeat units, The alkyl chain is substituted with one halogen group, preferably In yet another embodiment, the alkylene (often methylene The aryl group may be, for example, a natural or unnatural amino acid, such as alanine, β-alanine, arginine, Nin, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methine The side chains of onine, proline, serine, threonine, valine, tryptophan or tyrosine The aryl groups may be substituted with amino acid side chain groups such as aryl groups.

[0442] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. 0 of The range of carbon atoms included means that the carbon is not present and has been replaced with H. Hence, C 0 - C 6 The carbon atom range includes 1, 2, 3, 4, 5 and 6 carbon atoms, C 0 Regarding carbon Instead there is an H.

[0443] The terms "substituted" or "optionally substituted" refer to any one of the following on a molecule within the context: One or more substituents at a carbon (or nitrogen) position (independent on a moiety in a compound according to the present disclosure) up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents (which may include substituents which may themselves be further substituted) i.e., when there are multiple substituents, each substituent is independent of the other substituents), and The substituents are hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO 2 ) , halogen (especially alkyl, particularly preferably on methyl groups such as trifluoromethyl) is 1, 2 or 3 halogens), an alkyl group (preferably C 1 -C 10 , more preferably C 1 - 6 ) aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl); Alkoxy group (preferably C 1 -C6 Alkyl or aryl. Phenyl and substituted phenyl ), thioether (C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 Reed ester or thioester (preferably C 1 -C 6 alkyl or aryl) Alkylene esters (wherein the attachment is on the alkylene group rather than the ester functionality, preferably C 1 -C 6 substituted with alkyl or aryl groups), preferably C 1 -C 6 Alkyl or a containing aryl, halogen (preferably F or Cl), amine (5- or 6-membered cyclic alkoxy Contains xyleneamine, C 1 -C 6 Alkylamine or C 1 -C 6 Further comprising a dialkylamine, The alkyl group may be substituted with one or two hydroxyl groups, or may be optionally substituted. -N(C 0 -C 6 Alkyl)C(O)(OC 1 -C 6 alkyl) group (optionally substituted with a polyethylene glycol chain which may be further substituted with an alkyl group containing one halogen, preferably chlorine, substituent. hydrazine, amide, which preferably has one or two C 1 -C 6 Alkyl group (1 Or two C's 1 -C 6 including carboxamides optionally substituted with alkyl groups; (preferably C 1 -C 6 alkyl or aryl), or alkanoic acid (preferably C1 -C 6 a Substituents according to the present disclosure include those substituted with, for example, Ba-SiR 1 R 2 R 3 group, where R 1 and R 2 Each of the above is specifically described herein. It was published in R 3 is H or C 1 -C 6 is an alkyl group, preferably in this context R 1 , R 2 , R 3 is C 1 -C 3 Alkyl groups (including isopropyl or t-butyl groups). may be directly attached to the substituted moiety, or the substituent may be an optionally substituted (C H 2 ) m - or optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m -or-(CH 2 CH 2 O) m - The substituted moiety (preferably in the case of an aryl or heteroaryl moiety) may be linked via a group. ), which may be substituted with any one or more of the above-mentioned substituents. The alkylene group -(CH 2 ) m -or-(CH 2 ) n - groups or, for example, the ethylene glycol groups specified above. Other chains, such as recall chains, may be substituted anywhere on the chain. Preferred substituents include halogen or C 1 -C 6 (Preferably C1 -C 3 ) alkyl groups are mentioned. which optionally contains one or two hydroxyl groups, one or two ether groups (O- C 1 -C 6 groups), up to three halo groups (preferably F), or any of the a groups otherwise described herein. and optionally substituted amides (preferably as described above) with amino acid side chains. substituted carboxamide) or urethane groups (often containing one or two C 0 -C 6 In certain embodiments, the alkyl group may have an alkyl substituent, which may also be further substituted. In the formula, the alkylene group (often a single methylene group) is optionally substituted with one or two C 1 -C 6 Alkyl groups, preferably C 1 -C 4 Alkyl group, most often methyl or O-methyl In this disclosure, the aryl group is substituted with an alkyl group or an amino acid side chain as otherwise described herein. Moieties in the molecule may be optionally substituted with up to five substituents, preferably up to three substituents. In most cases, substituted moieties in this disclosure will be substituted with one or two substituents. It will be exchanged.

[0444] The term "substituted," where each substituent is independent of any other substituent, means that Within the context of the use of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, amide, carbo Sulfone, keto, carboxy, including oxamide, sulfonamide, 1 -C 6 Ester (oxy ester or carbonyl ester), C 1 -C6 Keto, urethane-OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 , nitro, cyano, and amine (especially C 1 -C 6 Alkylene-NR 1 R 2 , Monoma Orji-C 1 -C 6 Alkyl-substituted amines with one or two hydroxyl groups Each of these groups is also intended to mean the groups represented by the formula (including those which may be optionally substituted) unless otherwise indicated. Unless otherwise specified within the context, the substituents contain 1 to 6 carbon atoms. Preferred substituents depending on the context of use include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m - (wherein m and n are, in context, 1, 2, 3, 4, 5 or 6), -S- , -S(O)-, SO 2 - or -NH-C(O)-NH-, -(CH 2 ) n OH, -(CH 2 ) n SH, -(CH 2 ) n COOH, C 1 -C 6 Al Kill, -(CH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n O.C.(O)-(C 1 -C 6 alkyl), -(CH 2 ) nC(O)O-(C 1 -C 6 alkyl), -(CH 2 ) n NHC(O)-R 1 , -(CH 2 ) n C(O)-NR 1 R 2 , -( OCH 2 ) n OH, -(CH 2 O) n COOH, C 1 -C 6 Alkyl, -(OCH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 O) n C(O)-( C 1 -C 6 Alkyl), -(OCH 2 ) n NHC(O)-R 1 , -(CH 2 O) n C(O)-NR 1 R 2 , -S(O) 2 -R S , -S(O)-R S (R S teeth , C 1 -C 6 Alkyl or -(CH 2 ) m -NR 1 R 2 group), NO 2 , CN or halogens (F, Cl, Br, I , preferably F or Cl). 1 and R 2 are H or is C 1 -C 6 Alkyl group (containing one or two hydroxyl groups or up to three halogen groups) , preferably fluorine). The term "substituted" also refers to Within the chemical context of the compound specified and the substituents used, optionally substituted aryl A heteroaryl group or a heteroaryl group or an optionally substituted group as otherwise described herein. Heterocyclic groups are also intended to mean alkylene groups as otherwise disclosed herein. Optionally, optionally substituted C 1 -C 6 Alkyl groups (methyl, ethyl Preferred are ethyl, hydroxymethyl or hydroxyethyl, and the chiral center the side chain of an amino acid group as otherwise described herein; the amide group as described above; group, or urethane group, OC(O)-NR 1 R 2 A group, wherein R 1 and R 2 are described elsewhere herein. Although it may be substituted with certain groups as shown, many other groups may also be used as substitutents. The various optionally substituted moieties may have three or more substituents, preferably three or less, and In the compound, the specific part of the molecule may be substituted with one or two substituents. If a substitution is required at a position (mainly for valence reasons) but no substitution is shown, the Unless the context of the substitution indicates otherwise, the substituent is assumed or understood to be H. Please note that.

[0445] The term "aryl" or "aromatic" refers, in context, to a single ring (e.g., benzoyl) or a combination of both. phenyl, benzyl) or fused ring (e.g. naphthyl, anthracenylphenyl , phenanthrenyl, etc.) refers to a substituted monovalent aromatic radical and, in accordance with the present disclosure, any available stable ring or as otherwise specified in the chemical structure presented. Other examples of aryl groups, in context, include heteroaromatic ring systems, For example, imidazole, furyl, pyrrole, furanyl, thienyl, thiazole, pyridine, Imidine, pyrazine, triazole, oxazole, etc., with one or more nitrogen atoms in the ring, "Heteroaryl" groups containing nitrogen or sulfur atoms, or, for example, especially indole, cyclohexyl, condensed ring systems such as indolizine, azaindolizine, and benzofurazan; They may be optionally substituted as described above. Among the heteroaryl groups that may be mentioned in particular are and nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyridine ... Imidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole Indoles, indoles, isoindoles, indolizines, azaindolizines, purines, indole quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydro Isoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, Noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria azine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolidine pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazo pyrrolopyridines, pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles rings, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan; pyran, cyclopentapyran, benzofuran, and isobenzofuran; and nitrogen, Aromatic heterocycles containing two or more heteroatoms selected from among sulfur and oxygen, e.g. For example, thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole , benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine , pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxa Examples include furopyridine, furopyrimidine, furopyrimidine, thienopyrimidine, and oxazole. all of which may be optionally substituted.

[0446] The term "substituted aryl" refers to a group consisting of at least one aromatic ring or It refers to an aromatic carbocyclic ring consisting of multiple condensed rings, at least one of which is aromatic. In the present invention, the ring is substituted with one or more substituents. For example, the aryl group may be selected from the following: The substituents may include: -(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 ) alkyl, -(CH 2 ) n -O- (CH 2 ) n -(C 1 -C 6 ) alkyl, -(CH 2 ) n -C(O)(C 0 -C 6 ) alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 ) Alki le, -(CH 2 ) n -OC(O)(C 0 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6 Alkyl)amine wherein the alkyl group on the amine optionally has one or two hydroxyl groups or up to with three halo (preferably F, Cl) groups, OH, COOH, C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , or CN groups (each of which is located at the ortho, meta, and / or CN groups on the phenyl ring). or para-position, preferably para-position), an optionally substituted phenyl group (the The phenyl group itself is preferably attached to a PTM group, including a ULM group, via a linker; and / or F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 or CN group (phenyl ring ortho-, meta-, and / or para-positions, preferably para-positions Substituted, optionally substituted naphthyl, optionally substituted heteroaryl, preferred or optionally substituted isoxazoles, including methyl-substituted isoxazoles; optionally substituted oxazoles, including thiazoles; Optionally substituted isothiazoles, including methyl substituted isothiazoles. , optionally substituted pyrrole including methyl-substituted pyrrole, optionally substituted pyrrole including methylimidazole substituted imidazole, optionally substituted benzimidazole or methoxybenzene Imidazole, optionally substituted oximidazole or methyloximidazole , optionally substituted diazole groups including methyldiazole groups, methyl-substituted triazole groups optionally substituted triazole groups, halo- (preferably F) or methyl-substituted pyridines, an optionally substituted pyridine group, including an oxapyridine group, phenyl group by oxygen), optionally substituted furan, optionally substituted phenyl Optionally substituted dihydrobenzofuran, optionally substituted indole, indole Indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted and combinations thereof.

[0447] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, The generic substituents of these groups have the same meaning as the corresponding group definitions defined herein.

[0448] The terms "heteroaryl" or "hetaryl" include, but are not limited to, optionally substituted Quinoline (attached to the pharmacophore or any carbon atom within the quinoline ring) optionally substituted on the alkyl group, optionally substituted indole (including dihydroindole), optionally substituted indolizines, optionally substituted azaindolizines (2, 3, or 4-aza indolizine), optionally substituted benzimidazole, benzodiazole, benzoxazole isofuran, optionally substituted imidazole, optionally substituted isoxazole, substituted oxazoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, Substituted thiophenes, optionally substituted thiazoles (preferably methyl substituted and / or or thiol substituted), optionally substituted isothiazole, optionally substituted triazole silyl (preferably methyl, triisopropylsilyl, optionally substituted (CH 2 ) m -OC 1 -C 6 An alkyl group or an optionally substituted (CH 2 ) m -C(O)-OC 1 -C 6 Substituted with an alkyl group 1,2,3-triazole), optionally substituted pyridine (2, 3, or 4-pyridine), or It may refer to a group according to the following chemical structure:

[0449] [ka]

[0450] During the ceremony: S c is CHR SS , N.R. URE , or O; R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alki aryl (preferably one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably one or two hydroxyl groups or up to three halo groups), or Acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 Al acetylene group; R SSH, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alki aryl (preferably substituted with one or two hydroxyl groups or up to three halo groups) ), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two hydroxy or up to three halo groups), or optionally substituted -C(O)(C 1 -C 6 Al (preferably substituted with one or two hydroxyl groups or up to three halo groups) (to be) R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6 Al each group optionally containing one or two hydroxyl groups or up to three halo groups or optionally substituted heterocycles, such as pipet Lysine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pipette lysine, piperazine, etc., each of which is optionally substituted; and Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably with one or two hydroxyl groups) or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C6 Alki aryl) (preferably substituted with one or two hydroxyl groups or up to three halo groups or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 It is an acetylene group which is an alkyl group.

[0451] The terms "aralkyl" and "heteroarylalkyl" are defined as aryl, heteroaryl, or heteroarylalkyl in accordance with the above definitions. aryl or heteroaryl, respectively, and alkyl, and / or heteroalkyl; It refers to groups containing alkyl, aryl, and / or carbocyclic and / or heterocycloalkyl ring systems.

[0452] As used herein, the term "arylalkyl" refers to any of the aryl groups defined above. An arylalkyl group refers to an aryl group as defined above appended to an alkyl group. is attached to the parent moiety through an alkyl group, where the alkyl group has 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as described above.

[0453] The term "heterocycle" refers to a ring that contains at least one heteroatom, such as N, O, or S. It refers to a cyclic group containing aryl, which may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are encompassed under the definition of heterocycle, depending on the context of its use. Suitable heteroaryl groups are described herein above.

[0454] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxolyl, Xanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiazole enyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, Dioxolanyl, Ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, iso Soxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl , oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl Dinyl, piperidinyl, phthalimido, succinimido, pyrazinyl, pyrazolinyl , pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetra Hydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolidinyl Azolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio Ranil and Chiang are examples.

[0455] The heterocyclic group includes alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, ... Cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino , substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano No, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thio Aryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thio Alkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, hetero Aryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino , nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO 2 - Alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, oxo (=O), and -SO 2 -Hetero ants Such heterocyclic groups may be optionally substituted with a ring selected from the group consisting of a single ring, a ring structure, a ring unit, a ring structure ... Examples of nitrogen heterocycles and heteroaryls include Non-limiting examples include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyrimidine. amines, pyridazines, indolizines, isoindoles, indoles, indazoles, purines, Quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, Quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, Acridine, phenanthroline, isothiazole, phenazine, isoxazole, pheno Xanthazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, Indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as N-alkoxy The term "heterocyclic" also refers to any of the heterocycles. is a benzene ring or a cyclohexane ring or another heterocyclic ring (e.g., indolyl, quinolyl Also included are bicyclic groups fused to an isoquinolyl, tetrahydroquinolyl, etc.

[0456] The term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, 3-20 carbon atoms, including but not limited to cyclohexyl, cycloheptyl, etc. and monocyclic or polycyclic rings as defined herein, such as saturated monocyclic hydrocarbon groups having It means, but is not limited to, a monovalent group derived from an alkyl group or a cycloalkane. The term "substituted cycloalkyl" includes, for example, amino, halogen, alkyl, Substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or or sulfo, These generic substituents refer to, but are not limited to, the following groups: has the same meaning as the corresponding group definition "Heterocycloalkyl" means that at least one ring carbon atom in the cyclic structure is N, O, or A monocyclic or polycyclic aryl group substituted with a heteroatom selected from the group consisting of S and P. "Substituted heterocycloalkyl" refers to a heterocycloalkyl group in which at least one ring of the ring structure is substituted. A monocyclic ring in which a carbon atom is replaced with a heteroatom selected from the group consisting of N, O, S, or P. or polycyclic alkyl groups, the groups being halogen, alkyl, substituted alkyl, carbaryl, The group consisting of ruoxy, carbylmercapto, aryl, nitro, mercapto, and sulfo These generic substituents are defined in this description. has the same meaning as the corresponding group defined in

[0457] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen; They may be fully saturated, partially unsaturated, or aromatic, and may include aryl groups, alkyl groups, Includes alkenyl and alkynyl groups.

[0458] As used herein, the term "independently" means that a variable that is applied independently is used to indicate that the

[0459] The term "lower alkyl" refers to methyl, ethyl, or propyl. The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0460] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A and Rn are independently a linker, and / or one or more The PTM, ULM, ILM or ILM' group may be covalently attached to a linker which is attached to the PTM, ULM, ILM or ILM' group of the

[0461] Exemplary MLM In certain additional embodiments, two Sensuality The MLM of the reactive compound is, for example, a substituted imidazoline, a substituted Spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, Substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazolimidazolines, substituted pyrrolopyrimidines, These include chemical moieties such as pyrrolidinones, and substituted isoquinolinones.

[0462] In further embodiments, the MLMs are adjacent and positioned in a cis or trans configuration. It comprises the core structure shown above with bis-aryl substitutions.

[0463] In yet further embodiments, the MLM is RG7112, RG7388, SAR405838, AMG-232, AM-720 9, DS-5272, MK-8242, and NVP-CGM-097, and their analogs or derivatives. Such structural features include:

[0464] In certain preferred embodiments, the MLM is a substituted imidazoline represented by formula (A-1) or a derivative of thiazoloimidazoline represented by formula (A-2), or a derivative of thiazoloimidazoline represented by formula (A-3) or a pyrrolidine derivative represented by formula (A-4): or a piperidinone / morpholinone derivative represented by formula (A-5) or a derivative represented by formula (A-6) or a pyrrolopyrimidine / imine derivative represented by formula (A-7): Derivatives of dazolopyridine or pyrrolopyrrolidinone / imidazolo represented by formula (A-8) It is a derivative of pyrrolidinone.

[0465] [ka]

[0466] In the above formulas (A-1) to (A-8), X in the formulae (A-1) to (A-8) is carbon, oxygen, sulfur, sulfoxide, sulfone, or NR a mosquito selected from the group consisting of: R a are independently H or an alkyl group having 1 to 6 carbon atoms; In formulae (A-1) to (A-8), Y and Z are independently carbon or nitrogen; A, A' and A'' in formula (A-1) to formula (A-8) are independently selected from C, N, O or S. or form a fused bicyclic ring, or a 6,5- and 5,5-fused aromatic bicyclic ring may be one or two atoms forming a group; R in formula (A-1) to formula (A-8) 1 , R 2 each independently comprises an aryl group or a heteroaryl group; The heteroaryl group is selected from the group consisting of one independently selected from sulfur or nitrogen. or two heteroatoms, and the aryl or heteroaryl group is monocyclic or may be bicyclic or may be substituted with 1 to 3 substituents independently selected from the group consisting of: May be substituted or unsubstituted: Halogen, -CN, C 1 ~C 6 Alkyl group, C 3 ~C 6 Cycloalkyl, -OH, 1-6 carbon Alkoxy, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons , sulfones containing 1-6 carbons, ketones containing 2-6 carbons, and amides containing 2-6 carbons. , and dialkylamines containing 2 to 6 carbons; R in formula (A-1) to formula (A-8) 3 , R 4 are independently H, methyl and C 1 ~C 6 The group consisting of alkyl Selected from; R in formula (A-1) to formula (A-8) 5 is selected from the group consisting of an aryl group or a heteroaryl group. and the heteroaryl group is one or two heteroaryl groups independently selected from sulfur or nitrogen. The aryl or heteroaryl group has a heteroatom and is monocyclic or bicyclic. or substituted with 1 to 3 substituents independently selected from the group consisting of: Or it can be unsubstituted: Halogen, -CN, C 1 ~C 6 Alkyl group, C 3 ~C 6 Cycloalkyl, -OH, 1-6 carbon Alkoxy, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons , sulfones containing 1-6 carbons, ketones containing 2-6 carbons, and amides containing 2-6 carbons. , dialkylamines containing 2 to 6 carbons, alkyl ethers (C 2 ~C6 ), alkyl ketones (C 3 ~C 6 ), morpholinyl, alkyl ester (C 3 ~C 6 ), alkyl cyanide (C 3 ~C 6 ) ; R in formula (A-1) to formula (A-8) 6 is H or -C(=O)R b where: R in formula (A-1) to formula (A-8) b is alkyl, cycloalkyl, mono-, di- or trisubstituted; Substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piperazinyl Lysinyl, 4-NR c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl wherein R in formula (A-1) to formula (A-8) c is an alkyl, a fluorine-substituted alkyl, a cyanoalkyl, a hydrochloride, Xyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidoalkyl, alkyl Sulfone, alkyl sulfoxide, alkyl amide, aryl, heteroaryl, monosubstituted , di- and tri-substituted aryl or heteroaryl, CH 2 CH 2 R d , and C.H. 2 CH 2 CH 2 R d wherein: R in formula (A-1) to formula (A-8) d is an alkoxy, alkyl sulfone, alkyl sulfoxide, N-Substituted carboxamides, -NHC(O)-alkyl, -NH-SO 2 -Alkyl, aryl, substituted aryl , heteroaryl, and substituted heteroaryl; R in formula (A-1) to formula (A-8) 7 , H, C 1 ~C 6 Alkyl, cyclic alkyl, fluorine-substituted alkyl , cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, 5- or 6-membered 1-membered substituted heteroaryl or aryl; R in formula (A-1) to formula (A-8) 8 -R e -C(O)-R f , -R e -alkoxy, -R e -aryl, -R e -Haeta Roaryl, and -R e -C(O)-R f -C(O)-R g wherein the compound is selected from the group consisting of: R in formula (A-1) to formula (A-8) e is an alkylene containing 1 to 6 carbons, or a bond; R in formula (A-1) to formula (A-8) f is a 4-7 membered substituted heterocycle; R in formula (A-1) to formula (A-8) g is an aryl, heteroaryl, substituted aryl or substituted aryl. selected from the group consisting of heteroaryl, and 4- to 7-membered heterocycle; R in formula (A-1) to formula (A-8) 9 In formula (A-3), one substituent on the fused bicyclic aromatic ring, two or tri-substituent, wherein the substituents are independently selected from the group consisting of Cl or is the group consisting of halogen, alkene, alkyne, and alkyl, substituted or unsubstituted with F. Selected from; R in formula (A-1) to formula (A-8) 10 is selected from the group consisting of an aryl group or a heteroaryl group; wherein the heteroaryl group contains one or two heteroatoms such as sulfur or nitrogen. The aryl or heteroaryl group may be monocyclic or bicyclic. The aryl or heteroaryl group is preferably a halogen, F, Cl, -CN, an alkene, an a Lukin, C. 1 ~C 6 Alkyl group, C 1 ~C 6 Cycloalkyl, -OH, alkoxy containing 1 to 6 carbons fluorine-substituted alkoxy containing 1 to 6 carbon atoms; sulfoxide containing 1 to 6 carbon atoms; substituted with 1-3 substituents, including sulfones containing 1-3 carbons and ketones containing 2-6 carbons. may be substituted or unsubstituted; R in formula (A-1) to formula (A-8) 11 is -C(O)-N(R h )(R i ) in which R h and R i From the following Selected from the group consisting of: H, C 1 ~C 6 Alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heptane aryl, mono-, di- or trisubstituted aryl or heteroaryl, alkyl aryl carboxylic acids, heteroaryl carboxylic acids, alkyl carboxylic acids, fluorine-substituted alkyl carboxylic acids carboxylic acids, aryl substituted cycloalkyl, heteroaryl substituted cycloalkyl; R in formula (A-1) to formula (A-8) h and R i are independently H, bonded to form a ring, 4-hydroxy Cyclohexane, monohydroxy and dihydroxy substituted alkyl (C 3 ~C 6 ), 3-Hi Hydroxycyclobutane, phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acids selected from the group consisting of: R in formula (A-1) to formula (A-8) 12 and R 13 are independently H, lower alkyl (C 1 ~C 6 ), lower class Rukenil (C 2 ~C 6 ), lower alkynyl (C 2 ~C 6 ), cycloalkyl (4-, 5- and 6-membered ring), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5-membered and 6-membered R is selected from the group consisting of aryl and heteroaryl 12 and R 13 is bonded to the ring and contains substitutions may form 5- and 6-membered rings with or without R in formula (A-1) to formula (A-8) 14 is an alkyl, substituted alkyl, alkenyl, or substituted alkenyl. , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle , cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl. selected from the group consisting of: R in formula (A-1) to formula (A-8) 15 is CN; R in formula (A-1) to formula (A-8) 16 is C 1 ~C 6 Alkyl, C 1 ~C 6 Cycloalkyl, C 2 ~C 6 Arke C with one or more hydrogens replaced by fluorine 1~6 Alkyl or C 3~6 Cycloa Rukill, 1 CH 2 is S(=O), -S or -S(=O) 2Alkyl or cycloalkyl substituted with le, terminal CH 3 is S(=O) 2 N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(a Rukill)S(=O) 2 (alkyl), -C(=O) 2 (alkyl), and alkyl substituted with -O(alkyl). or cycloalkyl, C 1 ~C 6 Alkyl or ar -cycloalkyl, 3-7 membered cycloalkyl or heteroalkyl optionally containing a -(C=0)- group or 5- to 6-membered aryl or heteroaryl groups; and the heterocycloalkyl or heteroaryl group is independently selected from O, N, or S. may contain 1 to 3 heteroatoms selected arbitrarily, and the cycloalkyl group, The heterocycloalkyl group, aryl group or heteroaryl group is halogen, C 1 ~C 6 Alki Hydroxylated C 1 ~C 6 Alkyl, thioether-containing C 1 ~C 6 Alkyl, ether, s 1 to 3 independently selected from sulfone, sulfoxide, fluorine-substituted ether and cyano group may be substituted or unsubstituted; R in formula (A-1) to formula (A-8) 17 is (CH 2 ) n C(O)NR k R l wherein R k Oh BiR l are independent of each other, H, C 1 ~C 6 Alkyl, Hydroxylated C 1 ~C6 Alkyl, C 1 ~C 6 Alcoki Dialkyl, C in which one or more hydrogens are replaced by fluorine 1 ~C 6 Alkyl, one carbon is S( O) substituted C 1 ~C 6 Alkyl, S(O)(O), C with one or more hydrogens replaced by fluorine 1 ~C 6 Alkoxyalkyl, C where hydrogen is replaced by cyano group 1~6 Alkyl, 5- and 6-membered Aryl or heteroaryl, alkylaryl having an alkyl group containing 1 to 6 carbon atoms and alkylheteroaryl having an alkyl group containing 1 to 6 carbons. wherein the aryl or heteroaryl group can be further substituted; R in formula (A-1) to formula (A-8) 18 is a substituted aryl, heteroaryl, alkyl, cycloalkyl, or The substitution is preferably selected from the group consisting of -N(C 1-4 Alkyl) (cycloalky Kill), -N(C 1-4 -N(C alkyl)alkyl-cycloalkyl, and -N(C 1-4 Alkyl)[(Alkyl (aryl)-(heterocyclic-substituted)-cycloalkyl; R in formula (A-1) to formula (A-8) 19 is selected from aryl, heteroaryl, and bicyclic heteroaryl. and the aryl and heteroaryl groups are selected from the group consisting of halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Cycloalkyl, CF 3 , F, CN, alkyne, alkylsulfone may be substituted, and the halogen substitution may be mono-, di- or tri-substituted; R in formula (A-1) to formula (A-8) 20 and R 21 is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Cycloalkane Lu, C 1 ~C 6 Alkoxy, Hydroxylated C 1 ~C 6 Alkoxy and fluorine substituted C 1 ~C 6 Al koxy, wherein R 20 and R 21 are further joined to form 5-, 6-, and 7-membered rings or may form a heterocycle, which may be further substituted; R in formula (A-1) to formula (A-8) 22 , H, C 1 ~C 6 Alkyl, C 1 ~C 6 Cycloalkyl, carboxylic acid , carboxylic acid ester, amide, reverse amide, sulfonamide, Reverse sulfonamides, N-acylureas, nitrogen-containing five-membered heterocycles wherein the 5-membered heterocycle is further selected from the group consisting of C 1 ~C 6 Alkyl, alkoxy, fluorine may be substituted with substituted alkyl, CN, and alkylsulfone; R in formula (A-1) to formula (A-8) 23 is an aryl, heteroaryl, -O-aryl, -O-heteroaryl Aryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(aryl) (alkyl)-heteroaryl, the aryl or heteroaryl group being selected from halogen, N, C 1 ~C 6 Alkyl, Hydroxylated C 1 ~C 6 Alkyl, cycloalkyl, fluorine-substituted C 1 ~ C 6 Substituted with alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide May be; R in formula (A-1) to formula (A-8) 24 is -CH 2 -(C 1-6 alkyl), -CH 2 -Cycloalkyl, -CH 2 -Ali Ru, C.H. 2 -heteroaryl, Aryl and heteroaryl are not limited to halogen, alkoxy, hydroxylated alkyl, sialylated alkyl, cycloalkyl ... Optionally substituted with substituted alkyl, cycloalkyl, and substituted cycloalkyl; R in formula (A-1) to formula (A-8) 25 is C 1-6 Alkyl, C 1-6 Alkyl-cycloalkyl, alkoxy substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or or heteroaryl, 5-, 6- and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen and these saturated heterocycles are selected from the group consisting of C 1 ~C 6 Alkyl, Fluorine-substituted C 1 ~C 6 Substituted with alkyl, alkoxy, aryl and heteroaryl groups Also well; R in formula (A-1) to formula (A-8) 26 is C 1-6 Alkyl, C 3-6Selected from the group consisting of cycloalkyl The alkyl or cycloalkyl may be -OH, alkoxy, fluorine-substituted alkoxy. , fluorine-substituted alkyl, -NH 2 , -NH-alkyl, NH-C(O)alkyl, -NH-S(O) 2 -alkyl, and -S(O) 2 -optionally substituted with alkyl; R in formula (A-1) to formula (A-8) 27 is selected from aryl, heteroaryl, and bicyclic heteroaryl. The aryl or heteroaryl group is selected from the group consisting of: 1 ~C 6 Alkyl, ar Coxie, NH 2 , NH-alkyl, halogen or -CN, and the substitutions are independently and may be mono-, di- and trisubstituted; R in formula (A-1) to formula (A-8) 28 is an aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, aryl, cycloalkyl, saturated heterocycles such as piperidine, piperidinone, tetrahydrofuran, cycloalkyl, selected from the group consisting of dihydropyran, N-acyl-piperidine, Saturated heterocycle, aryl or heteroaryl is an alkyl group containing -OH, alkoxy, halogen. substituted, di- or trisubstituted, -CN, alkylsulfone, and fluorine substituted alkyl groups. may be substituted with; and R in formula (A-1) to formula (A-8) 1” is an alkyl, aryl-substituted alkyl, alkoxy-substituted alkoxy. alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl The kill signal is selected from the group consisting of:

[0467] In certain embodiments, R f and Rg The heterocycle in Lysine, substituted piperidine, substituted piperidine (piperizine).

[0468] More specifically, non-limiting examples of MLMs include those shown below, as well as those molecules The list includes "hybrid" molecules that result from one or more combinations of the different properties exhibited in Can be obtained.

[0469] Using the MLMs of formulas A-1 to A-8, the following PROTACs were used to perform the degradation of specific proteins: where "L" is a connector (i.e., linker group). where "PTM" is a ligand that binds to a target protein.

[0470] In certain embodiments, the present disclosure provides a bilayer comprising a structure selected from the group consisting of: Sensuality sex Provide the molecule:

[0471] [ka]

[0472] In the formula, X, R a , Y, Z, A, A', A'', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R b , R c , R d , R 7 , R e , R f , R g , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R16 , R 17 , R k , R l , R 18 , R 19 , R 20 , R 21 , R 2 2 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 1’’ In this specification, the formula (A-1) to the formula (A- 8) As defined in

[0473] In certain embodiments, the present disclosure provides a bifunctional or chimeric molecule having the structure providing: PTM-L-MLM, where the PTM is linked to the MLM by L; wherein L is a bond (i.e., absent) or a chemical In certain embodiments, the MLM is selected from A-1-1, A-1-2, A-1-3, and and A-1-4:

[0474] [ka]

[0475] During the ceremony: R1' and R2' in formulae A-1-1 to A-1-4 are F, Cl, Br, I, acetylene, CN, CF 3 , and NO 2 independently selected from the group consisting of: R3' is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CH 2 OCH 3, and -OCH(CH 3 ) 2 From the group consisting of Selected; R4' in formulae A-1-1 to A-1-4 is H, halogen, -CH 3 , -CF 3 , -OCH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -Cyclopropyl, -CN, -C(CH 3 ) 2 OH, -C(CH 3 ) 2 OCH 2 CH 3 , -C(CH 3 ) 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 2 CH 3 , -C(CH 3 ) 2 CH 2 OCH 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 2 CH 3 , -C(CH 3 ) 2 CN, -C(CH 3 ) 2 C(O)CH 3 , -C( CH 3 ) 2 C(O)NHCH 3 , -C(CH 3 ) 2 C(O)N(CH 3 ) 2 , -SCH 3 , -SCH 2 CH 3 , -S(O) 2 CH 3 , -S(O 2 )CH 2 CH3 , - NHC(CH 3 ) 3 , -N(CH 3 ) 2 , pyrrolidinyl, and 4-morpholinyl; R5' in formulae A-1-1 to A-1-4 is halogen, -cyclopropyl, -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 , 1- Pyrrolidinyl, -NH 2 , -N(CH 3 ) 2 , and -NHC(CH 3 ) 3 selected from the group consisting of: R6' in formula A-1-1 to formula A-1-4 is selected from the structures shown below, wherein the linker attachment point is , indicated as "*". In addition to R6' as the point of linker attachment, R4' can also serve as the linker attachment point. When R4' is the linker attachment point, the linker is attached to the terminal atom of the R4' group as shown above. will be bound to the child.

[0476] In certain embodiments, the linker attachment points of formulas A-1-1 to A-1-4 are at least one of R4' or R6'. At least one, or both.

[0477] In certain embodiments, R6' of formulas A-1-1 to A-1-4 is independently H,

[0478] [ka]

[0479] [ka]

[0480] where "*" indicates the point of attachment of the linker. In certain embodiments, the linkers of formulas A-4-1 to A-4-6 are selected from the group consisting of R1', R2', R3', R4', R5' , R6', or a combination thereof.

[0481] In certain embodiments, the present disclosure provides a bifunctional or chimeric molecule having the structure providing: PTM-L-MLM, where the PTM is linked to the MLM by L; wherein L is a bond (i.e., absent) or a chemical In certain embodiments, the MLM is selected from the group consisting of A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, A-4-6, A-4-7, A-4-8, A-4-9, A-4-10, A-4-11, A-4-12, A-4-13, A-4-14, A-4-15, A-4-16, A-4-17, A-4 -5, and A-4-6:

[0482] [ka]

[0483] During the ceremony: R7' of A-4-1 to A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6) is , one selected from the group consisting of halogen, mono-substituted, di-substituted or tri-substituted halogen be. R8' in formulae A-4-1 to A-4-6 is H, -F, -Cl, -Br, -I, -CN, -NO 2 , ethylnyl, cyclopropyl , methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -O H, other C 1-6 Alkyl, other C 1-6 Alkenyl and C 1-6 Alkynyl, monosubstituted, disubstituted substituted or trisubstituted; R9' in formulae A-4-1 to A-4-6 is an alkyl, a substituted alkyl, an alkenyl, a substituted alkenyl, an alkoxy, an aryl, an aryloxy ... Alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl From aryl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted cycloalkenyl selected from the group consisting of; Z in formulas A-4-1 to A-4-6 is H, -OCH 3 , -OCH 2 CH 3 and halogen; R10' and R11' in formulae A-4-1 to A-4-6 are each independently H, (CH 2 ) n -R', (CH 2 ) n -NR'R'', ( CH 2 ) n -NR'COR'', (CH 2 ) n -NR'SO 2 R'', (CH 2 ) n -COOH, (CH 2 ) n -COOR', (CH) n -CONR'R'', (CH 2 ) n -OR', (CH 2 ) n -SR', (CH 2 ) n -SOR', (CH 2 ) n -CH(OH)-R', (CH 2 ) n -COR', (CH 2 ) n -SO 2 R', (CH 2 ) n -SONR'R'', (CH 2 ) n -SO 2 NR'R'', (CH 2 CH 2 O) m-(CH 2 ) n -R'、(CH 2 CH 2 O) m -(CH 2 ) n -OH、( CH 2 CH 2 O) m -(CH 2 ) n -OR'、(CH 2 CH 2 O) m -(CH 2 ) n -NR'R''、(CH 2 CH 2 O) m -(CH 2 ) n -NR'COR''、(CH 2 CH 2 O) m (CH 2 ) n -NR'SO 2 R''、(CH 2 CH 2 O) m (CH 2 ) n -COOH、(CH 2 CH 2 O) m (CH 2 ) n -COOR'、(CH 2 CH 2 O) m -(CH 2 ) n -CONR'R''、(CH 2 CH 2 O) m -(CH 2 ) n -SO 2 R'、(CH 2 CH 2 O) m -(CH 2 ) n -COR'、(CH 2 CH 2 O) m -( CH 2 ) n -SONR'R''、(CH 2 CH 2 O) m -(CH 2 ) n -SO 2 NR'R''、(CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n R'、(CH 2 )p- (CH 2 CH 2 O) m -(CH 2 ) n -OH、(CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 )n-OR'、(CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -NR' R''、(CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -NR'COR''、(CH 2 ) p -(CH 2 CH 2 O)m-(CH 2 ) n -NR'SO 2 R''、(CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -COOH、(CH 2 ) p -(CH2 CH 2 O) m -(CH 2 ) n -COOR', (CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -CONR'R'', (CH 2 )p-(CH 2 CH 2 O) m -(CH 2 ) n -SO 2 R', (CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -COR', (CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -SONR'R'', (CH 2 ) p -(CH 2 CH 2 O) m -(CH 2 ) n -SO 2 NR'R'', aryl-(CH 2 ) n -COOH, and heteroaryl-alkyl-CO-alkyl-NR'R''m wherein alkyl is selected from the group consisting of OR' and heteroaryl-(CH 2 ) n - optionally substituted with a heterocycle, wherein the heterocycle is optionally substituted with alkyl, hydroxyl, COOR′ and COR′. In the formula, R' and R" are H, alkyl, halogen-substituted alkyl, hydroxyl, NH 2 , NH(alkyl), N(alkyl) 2 , oxo, carboxy, cycloalkyl and heteroaryl selected from the rule; m, n, and p are independently 0 to 6; R12' in formulae A-4-1 to A-4-6 is -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkoxy), ... alkyl), -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl) 2 , -S( O)-(alkyl), S(O) 2 -(alkyl), -C(O)-(cyclic amine), and -O-aryl-(alkyl ), -O-aryl-(alkoxy); R1″ in formulae A-4-1 to A-4-6 is alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl. , cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl. is selected from the group consisting of:

[0484] In any of the aspects or embodiments described herein, alkyl, alkoxy Or the like may be lower alkyl or lower alkoxy.

[0485] In certain embodiments, the linker attachment points of formulas A-4-1 to A-4-6 are Z, R8', R9', R10', At least one of R11'', R12'', or R1''.

[0486] The method used to design the chimeric molecules presented in A-1-1 to A-1-4, A-4-1 to A-4-6 is -2, Equation A-3, Equation A-5, Equation A-6, Equation A-7 and Equation A-8 can be used to apply to MLM. In this case, the solvent exposed region of the MDM may be attached to a linker "L", which linker is a target These molecules will then be coupled to specific protein ligands, or "PTMs," to construct PROTACs.

[0487] Examples of MDM2 binding moieties include, but are not limited to, the following: 1. Vassilev, et al., In vivo activation of the p53 pathway by small-molecule a ntagonists of MDM2, SCIENCEvol:303, pag:844-848 (2004), and Schneekloth, et al. ., Targeted intracellular protein degradation induced by a small molecule: Enro ute to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908 , the compounds Nutrin-3, Nutrin-2, and Nutrin-1 (derivatized) described below, and all derivatives and analogs thereof, HDM2 / MDM2 inhibitors:

[0488] [ka]

[0489] (derivatized, the linker group L or the -(L-MLM) group is, for example, a methoxy group; is attached as a hydroxyl group);

[0490] [ka]

[0491] (derivatized, the linker group L or the -(L-MLM) group being, for example, a methoxy group or a hydroxyl group. bonded with a hydroxyl group);

[0492] [ka]

[0493] (derivatized, e.g., via a methoxy group, the linker group L or the -(L-MLM) group or hydroxyl groups); and 2. trans-4-iodo-4'-boranyl-chalcone

[0494] [ka]

[0495] (Derivatized, the linker group L or the linker group L or the -(L-MLM) group may be, for example (attached via a hydroxy group).

[0496] Exemplary CLM Neo-imide compounds In one embodiment, the present disclosure provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures: R:

[0497] [ka]

[0498] During the ceremony: W in formula (a) to formula (f) is independently CH 2 , CHR, C=O, SO 2 , NH and N-alkyl. Selected; X in formula (a) to formula (f) is independently O, S, or H. 2 selected from the group consisting of: Y in formula (a) to formula (f) is independently CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetero selected from the group consisting of aryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (f) is independently O, S or H. 2 where X and Both Y and Z are H 2 It should not be; G and G' in formula (a) to formula (f) are independently H, alkyl (optionally substituted straight chain, branched chain), OH, R'OCOOR, R'OCONRR", CH optionally substituted with R' 2 heterocyclyl, and benzyl, optionally substituted with R'; Q1 to Q4 in formula (a) to formula (f) are groups independently selected from R, R', N, or N-oxide. represents the carbon C to be substituted; A in formula (a) to formula (f) is independently H, alkyl (optionally substituted straight or branched chain), cycloalkyl, selected from the group consisting of aryl, Cl, H and F; R in formula (a) to formula (f) includes, but is not limited to, the following: -CONR'R'', -OR', -NR'R'', -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n R″, -aryl, -hetaryl, -alkyl (straight or branched, optionally substituted), -cycloalkyl, -hetero Cyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, - Br, -I, -CF 3 , -CN, -NR'SO 2 NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN) NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO 2 )NR'R", -SO 2 NR'COR ", -NO 2 , -CO 2 R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SCIENCE FICTION 5 , and -OCF 3 R' and R" in formula (a) to formula (f) are independently a bond, H, alkyl, cycloalkyl, a are selected from aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl; each is optionally substituted; In formulas (a) to (f), n is an integer of 1 to 10 (e.g., 1 to 4);

[0499] [ka]

[0500] The formulas (a) to (f) may be stereospecific (R or S) or non-stereospecific. represents a bond; and R in formula (a) to formula (f) n contains 1 to 4 independent functional groups or atoms.

[0501] Exemplary CLM In any of the compounds described herein, the CLM has a chemical structure selected from the group consisting of: Construction includes:

[0502] [ka]

[0503] During the ceremony: W in formula (a) to formula (f) is independently CH 2 , CHR, C=O, SO2 , NH and N-alkyl. Selected; X in formula (a) to formula (f) is independently selected from the group consisting of O, S and H2; Y in formula (a) to formula (f) is independently CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetero selected from the group consisting of aryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (f) is independently selected from the group consisting of O, S, and H2, with the proviso that X and and Z cannot both be H2; G and G' in formula (a) to formula (f) are independently H, alkyl (linear or branched), OH, R'OCOO R, R'OCONRR", CH optionally replaced by R' 2 -heterocyclyl, and optionally substituted with R' benzyl; Q1 to Q4 in formula (a) to formula (f) are groups independently selected from R, R', N, or N-oxide. represents the carbon C to be substituted; A in formula (a) to formula (f) is independently H, alkyl (optionally substituted straight or branched chain), cycloalkyl, selected from the group consisting of aryl, Cl, H and F; R in formula (a) to formula (f) includes, but is not limited to, the following: -CONR'R'', -OR', -NR'R'', -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -hetaryl, - Alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)( OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF 3 , -CN, -NR'SO 2 NR'R", -NR'CONR 'R', -CONR'COR', -NR'C(=N-CN)NR'R', -C(=N-CN)NR'R', -NR'C(=N-CN)R', -NR'C(=C-NO 2 )NR'R", -SO 2 NR'COR", -NO 2 , -CO 2 R', -C(C=N-OR')R", -CR'=CR' R", -CCR', -S(C=O)(C=N-R')R", -SF 5 , and -OCF 3 R' and R" in formula (a) to formula (f) are independently a bond, H, alkyl, cycloalkyl, a are selected from aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl; each is optionally substituted; In formulas (a) to (f), n is an integer of 1 to 10 (e.g., 1 to 4);

[0504] [ka]

[0505] The formulas (a) to (f) may be stereospecific (R or S) or non-stereospecific. represents a bond; and Rn in formula (a) to formula (f) contains 1 to 4 independent functional groups or atoms, and optionally One of the modified forms may be a PTM, a chemical linker group (L), a ULM, a CLM (or CLM') or the like. is covalently bonded to these combinations.

[0506] In certain embodiments described herein, the CLM or ULM is selected from the group consisting of: Chemical structure including:

[0507] [ka]

[0508] During the ceremony: W in formula (g) is CH 2 independently selected from the group: C=O, NH and N-alkyl; R in formula (g) is independently H, methyl, alkyl (e.g., C 1 ~C 6 Alkyl (optionally substituted selected from the group consisting of straight chain, branched chain;

[0509] [ka]

[0510] In formula (g), a bond may be stereospecific ((R) or (S)) or non-stereospecific. Represents; and Rn in formula (g) contains 1 to 4 independently selected functional groups or atoms, and optionally is modified to include a PTM, a chemical linker group (L), a ULM, a CLM (or CLM') or Covalently bonded to the combination.

[0511] In any of the embodiments described herein, W, X, Y of formula (a) to formula (g) , Z, G, G', R, R', R'', Q1 to Q4, A and Rn are independently a linker, and / or a linker that is covalently attached to one or more PTM, ULM, CLM or CLM' groups. It is possible.

[0512] More specifically, non-limiting examples of CLMs include those shown below, as well as those molecules The list includes "hybrid" molecules that result from one or more combinations of the different properties exhibited in Can be obtained.

[0513] [ka]

[0514] [ka]

[0515] [ka]

[0516] [ka]

[0517] [ka]

[0518] [ka]

[0519] [ka]

[0520] In any of the compounds described herein, the CLM has a chemical structure selected from the group consisting of: Construction includes:

[0521] [ka]

[0522] [ka]

[0523] [ka]

[0524] During the ceremony: W in formula (h) to formula (ad) is independently CH 2 , CHR, C=O, SO 2 , NH and N-alkyl Re; Q in formula (h) to formula (ac) 1 , Q 2 , Q 3 , Q 4 , Q 5 is independently selected from R', N, or N-oxide. represents a carbon C substituted with a group selected from R in formula (h) to formula (ad) 1 H, CN, C 1 ~C 3 alkyl; R in formula (h) to formula (ad) 2 H, CN, C 1 ~C 3 Alkyl, CHF 2 , C.F. 3 , CHO; R in formula (h) to formula (ad) 3 is H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy. Selected from; R in formula (h) to formula (ad) 4 is selected from H, alkyl, and substituted alkyl; R in formula (h) to formula (ad) 5 is H or lower alkyl; X in formulae (h) to (ad) is C, CH or N; R' in formula (h) to formula (ad) is H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy; R in formulae (h) to (ad) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkyl, or the like. The alkyl group may be lower alkyl, lower alkoxy, or halogenated lower alkyl.

[0525] [ka]

[0526] In formulae (h) to (ad), is a single bond or a double bond; and The CLM may be a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof. is covalently bonded to

[0527] In any aspect or embodiment described herein, the CLM or CLM′ is represented by the formula (h ) to the R group of formula (ad) (e.g., R, R 1 , R 2 , R 3 , R 4 or R'), W, X, or Q groups (e.g. , Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 ) through PTM, chemical linker group (L), ULM, CLM, CLM', or a combination thereof.

[0528] In any of the embodiments described herein, CLM or CLM′ is represented by the formula (h )~W, X, R, R in formula (ad) 1 , R 2 , R 3 , R 4 , R 5 , R', Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 Via , PTM, chemical linker group (L), ULM, CLM, CLM', or combination thereof. do.

[0529] In any of the embodiments described herein, W, X, R of formula (h) to formula (ad) 1 , R 2 , R 3 , R 4 , R', Q 1 , Q 2 , Q 3, Q 4 , and Q 5 may be independently covalently attached to a linker and / or a linker bonded to one or more PTM, ULM, ULM', CLM or CLM' groups. The copolymer may be covalently attached to an anchor.

[0530] More specifically, non-limiting examples of CLMs include those shown below, as well as the following compounds: These include "hybrid" molecules or compounds that result from a combination of one or more of the following properties: Can be:

[0531] [ka]

[0532] [ka]

[0533] During the ceremony: W in formula (ae) to formula (ap) is independently CH 2 , CHR, C=O, SO 2 , NH and N-alkyl Selected; R in formula (ae) to formula (ap) 1 H, CN, C 1 ~C 3 selected from the group of alkyl; R in formula (ae) to formula (ap) 3 is H, alkyl, substituted alkyl, alkoxy, substituted alkoxy Selected from; R in formulae (ae) to (ap) is H;

[0534] [ka]

[0535] is a single or double bond; and Rn in formulae (ae) to (ap) includes a functional group or an atom.

[0536] In any of the embodiments described herein, W, R in formula (ae) to formula (ap) 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently linked to a linker, and / or or covalently linked to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups. They may be combined.

[0537] In any of the embodiments described herein, R of formula (ae) to formula (ap) 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently linked to a linker, and / or is covalently attached to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups. This may also be the case.

[0538] In any of the embodiments described herein, Q of formula (ae) to formula (ap) 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently linked to a linker and / or one or more may be covalently attached to a linker that is attached to a PTM, ULM, ULM', CLM or CLM' group on the stomach.

[0539] In any aspect or embodiment described herein, R of formula (ae) to formula (ap) n teeth and modifying the linker group (L), the PTM, the ULM, the second CLM, CLM', which has the same chemical structure as the CLM. , a second linker, or any multiple or combination thereof.

[0540] In any aspect or embodiment described herein, the CLM is selected from: R:

[0541] [ka]

[0542] [ka]

[0543] In the formula, R' is a halogen and R 1 Formula (h) to formula (ab) or formula (ac) to formula (an) As mentioned above.

[0544] In certain instances, the CLM may be an imide that binds to cereblon E3 ligase. These imide and linker attachment points may be, but are not limited to, the following structures:

[0545] [ka]

[0546] In the formula, R' is a halogen. Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM, as defined below in ULM-a The compound includes a chemical structure selected from the group consisting of:

[0547] [ka]

[0548] , during the ceremony The dashed lines indicate at least one PTM, another ULM or VLM or MLM or ILM or CLM. (i.e. ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical linker - moiety binding, and at least one PTM, ULM' or VLM' or CLM' or attaching an ILM' or MLM' to the other end of the linker; X in the formula ULM-a 1 , X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and S O 2 selected from the group consisting of: R in the formula ULM-a Y3 , R Y4 are each independently H, straight or branched chain C 1~6 Selected from the group of alkyl are selected from the group consisting of optionally one or more halo, optionally substituted C 1~6 Alkoxyl (e.g. Optional 0 to 3 R P substituted by a group; R in the formula ULM-a P are 0, 1, 2 or 3 groups, each independently H, halo, -OH, C 1-3 Alki C=O; W of formula ULM-a 3 is optionally substituted -TN(R 1a R 1b )X 3 , -TN(R 1a R 1b ), -T-aryl, optionally Substituted -T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1 -T- Aryl, optionally substituted -NR 1-T-heteroaryl, or optionally substituted -NR 1 -T-compound is selected from the group of heterocyclic rings; X in the formula ULM-a 3 is C=O, R 1 , R 1a , R 1b and; R 1 , R 1a , R 1b each independently is optionally substituted with H, one or more halo, or -OH groups; Linear or branched chain C 1 -C 6 Alkyl group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 )C=O, N(R Y3 R Y4 )C=S,N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO 2 selected from the group consisting of; T in the formula ULM-a is X 1 covalently bonded to; W of formula ULM-a 4 is an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroa Aryl group or optionally substituted -NR 1 -T-heterocycle, wherein -NR 1 X 2 Covalently bonded to And R 1 is H or CH 3 , preferably H.

[0549] In any of the embodiments described herein, T is optionally substituted alkyl. , -(CH 2 ) n- groups, wherein each one of the methylene groups is selected from the group consisting of halogen, methyl , linear or branched C optionally substituted with one or more halogen or -OH groups 1 -C 6 a or one or two substituents selected from the group consisting of an alkyl group, an optionally substituted amino acid side chain, and n is 0 to 6, often 0, 1, 2 or 3, and preferably It is usually 0 or 1.

[0550] In certain embodiments, W of formula ULM-a 4 teeth,

[0551] [ka]

[0552] where: R 14a、 R 14b、 each independently represents H, haloalkyl, or optionally substituted The alkyl group is selected from the group consisting of:

[0553] In any of the embodiments, W of formula ULM-a 5 is a phenyl or 5-10 membered heteroaryl is selected from the group R in the formula ULM-a 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a C OR 14b , S.O. 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted halo aryl, heteroaryl, cycloalkoxy; alkyl, or cycloheteroalkyl; In additional embodiments, W for use in the present disclosure 4 Substituents are further defined herein as The W present in the particular compounds disclosed herein 4 The specific disclosed compounds include (but is not limited to) 4 Each of the substituents may be any number of W 3 Used in conjunction with a substituent and are also disclosed herein.

[0554] In certain additional embodiments, ULM-a has 0-3 R in the pyrrolidine moiety. P Based on the Each R P are independently H, halo, -OH, C 1-3 Alkyl, C=O.

[0555] In any of the embodiments described herein, W of formula ULM-a 3 , W 4 is independent and The PTM group may be covalently attached to a linker that is attached to one or more PTM groups. and wherein the dashed line represents at least one PTM, another ULM (ULM'), or at least one The binding sites of the chemical linker moieties that connect the PTM or ULM' or both to ULM are shown. vinegar.

[0556] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0557] [ka]

[0558] During the ceremony: W in formula ULM-b 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0559] [ka]

[0560] selected from the group consisting of: R in the formula ULM-b 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted Cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl alkyl, haloalkyl, or R 9 , R 10 , and the carbon atoms to which they are attached forming an optionally substituted cycloalkyl; R in the formula ULM-b 11 is an optionally substituted heterocyclic, an optionally substituted alkoxy, an optionally substituted heteroaryl, optionally substituted aryl;

[0561] [ka]

[0562] selected from the group consisting of: R in the formula ULM-b 12 is selected from the group of H or optionally substituted alkyl; R in the formula ULM-b 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl , optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) (a) is selected from the group consisting of aryl, ... R in the formula ULM-b 14a、 R 14b are each independently H, haloalkyl, or optionally substituted selected from the group of alkyl; W in formula ULM-b 5 is selected from the group consisting of phenyl and 5-10 membered heteroaryl; R in the formula ULM-b 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a C OR 14b , S.O. 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted halo aryl, heteroaryl, cycloalkoxy; cycloalkyl, or cycloheteroalkyl, each of which is optionally substituted; R in the formula ULM-b 16 are independently halo, optionally substituted alkyl, optionally substituted haloal is selected from the group of alkyl, hydroxy, or optionally substituted haloalkoxy; In the formula ULM-b, o is 0, 1, 2, 3, or 4; R in the formula ULM-b 18 are independently H, halo, optionally substituted alkoxy, cyano, optionally substituted is selected from the group consisting of alkyl, haloalkyl, haloalkoxy or a linker; and Beauty p of formula ULM-b is 0, 1, 2, 3, or 4, and the dashed line represents at least one PTM , another ULM (ULM'), or at least one PTM or ULM' or both 1 shows the attachment site of the chemical linker moiety that binds to

[0563] In certain embodiments, R of formula ULM-b is 15 teeth,

[0564] [ka]

[0565] where R 17 is H, halo, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkenyl, and C 1~6 Haloalkyl and Xa is S or O.

[0566] In certain embodiments, R of formula ULM-b is 17 are methyl, ethyl, isopropyl and cyclopropyl. The fluororubic acid is selected from the group consisting of propyl.

[0567] In certain additional embodiments, R of formula ULM-b is 15 is selected from the group consisting of:

[0568] [ka]

[0569] In certain embodiments, R of formula ULM-b is 11 is selected from the group consisting of:

[0570] [ka]

[0571] In certain embodiments, ULM has a chemical structure selected from the following group:

[0572] [ka]

[0573] During the ceremony: R in formula ULM-c, formula ULM-d, and formula ULM-e 1 is H, ethyl, isopropyl, tert-butyl, sec -butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heptane aryl, or haloalkyl; R in formula ULM-c, formula ULM-d, and formula ULM-e 14a is H, haloalkyl, optionally substituted alkyl methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl. Propyl; R in formula ULM-c, formula ULM-d, and formula ULM-e 15 H, halogen, CN, OH, NO 2、 Optionally replaced optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloalkyl; heteroalkyl; X in formula ULM-c, formula ULM-d, and formula ULM-e is C or C═O. R in formula ULM-c, formula ULM-d, and formula ULM-e 3 is an absent or optionally substituted 5-membered or 6-membered heteroaryl; and wherein the dashed line represents at least one PTM, another ULM (ULM'), or at least one PTM 1 shows the attachment sites of chemical linker moieties that link ULM, ULM', or both to ULM.

[0574] In certain embodiments, ULM includes a group according to the following chemical structure:

[0575] [ka]

[0576] During the ceremony: R in the formula ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl aryl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R in the formula ULM-f 9 is H; R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl , cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 teeth,

[0577] [ka]

[0578] or optionally substituted heteroaryl; In the formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18 are independently selected from halo, optionally substituted alkoxy, cyano, is an alkyl, haloalkyl, haloalkoxy or linker; R in the formula ULM-f 12 is H, C=O; R in the formula ULM-f 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl , optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl arylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) aryl)carbonyl, or optionally substituted aralkyl; R in the formula ULM-f 15 H, halogen, Cl, CN, OH, NO 2、 Optionally substituted heteroaryl, optionally substituted aryl;

[0579] [ka]

[0580] and selected from the group consisting of wherein the dashed line in formula ULM-f represents at least one PTM, another ULM (ULM'), or at least one The binding sites of the chemical linker moieties that connect one PTM or ULM' or both to ULM are show.

[0581] In certain embodiments, ULM is selected from the following structures:

[0582] [ka]

[0583] In the formula, n is 0 or 1. In certain embodiments, ULM is selected from the following structures:

[0584] [ka]

[0585] [ka]

[0586] [ka]

[0587] [ka]

[0588] Here, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-c15 are The phenyl ring of ULM-d9 is optionally substituted with fluorine, lower alkyl, and alkoxy groups. , where the dashed lines represent at least one PTM, another ULM (ULM'), or at least one PTM or ULM-a. vinegar.

[0589] In one embodiment, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, The phenyl rings of ULM-d1 to ULM-d9 were functionalized as esters, which were then used as prodrugs. It can be part of the

[0590] In certain embodiments, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, The hydroxyl groups on the pyrrolidine rings of ULM-d1 to ULM-d9 are each linked via an ester bond. The compound includes a prodrug moiety.

[0591] In any of the aspects or embodiments described herein, ULM and In some cases, ULM', or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof. The entities are each independently a group conforming to the following chemical structure:

[0592] [ka]

[0593] During the ceremony: ULM-g R 1’ is an optionally substituted C 1 -C 6 Alkyl groups, optionally substituted -(CH 2 ) n OH, any Substituted with -(CH 2 ) n SH, optionally substituted (CH 2 ) n -O-(C 1 -C 6 ) Alkyl group, epoxide group Optionally substituted (CH 2 ) n -WCOCW-(C 0 -C 6 ) alkyl groups, Each W is independently H or C 1 -C 3 Alkyl groups, optionally substituted -(CH 2 ) n COOH, optional Substituted with -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), optionally substituted -(CH 2 ) n NHC(O)-R 1 ,any Substituted with -(CH 2 ) n C(O)-NR 1 R 2 , optionally substituted -(CH 2 ) n OC(O)-NR 1 R 2 , -(CH 2 O) n H, Ren -(CH 2 ) n O.C.(O)-(C 1 -C 6alkyl), optionally substituted -(CH 2 ) n C(O)-O-(C 1 -C 6 alkyl), optionally substituted -(CH 2 O) n COOH, optionally substituted -(OCH 2 ) n O-(C 1 -C 6 Alki -(CH 2 O) n C(O)-(C 1 -C 6 alkyl), optionally substituted -(OCH 2 ) n NHC(O )-R 1 , optionally substituted -(CH 2 O) n C(O)-NR 1 R 2 , -(CH 2 CH 2 O) n H, optionally substituted -(CH 2 CH 2 O) n COOH, optionally substituted -(OCH 2 CH 2 ) n O-(C 1 -C 6 alkyl), optionally substituted -(CH 2 CH 2 O) n C(O)-(C 1 -C 6 alkyl), optionally substituted -(OCH 2 CH 2 ) n NHC(O)-R 1 , optionally replaced by - (CH 2 CH 2 O) n C(O)-NR 1 R 2 , optionally substituted -SO 2 RS , optionally substituted S(O)R S , NO 2 , CN or halogen (F, Cl, Br, I, preferably F or Cl); ULM-g R 1 and R 2 each independently represents H, or one or two hydroxyl groups, or up to three halogen groups (preferably fluorine) 1 -C 6 Alkyl It is a base; ULM-g R S is C 1 -C 6 an alkyl group, an optionally substituted aryl group, a heteroaryl group or Heterocyclic groups, or -(CH 2 ) m NR 1 R 2 It is a base; X and X' of ULM-g are each independently C=O, C=S, -S(O), S(O). 2 (preferably X and and X' are both C=O); ULM-g R 2’ is an optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v (SO 2 ) w Alkyl groups, optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v (SO 2 ) w NR 1N R 2N group, optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v ( SO2 ) w -aryl, optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v (SO 2 ) w -heteroaryl, any Substituted with -(CH 2 ) n -(C=O) v NR 1 (SO 2 ) w -heterocycle, optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -alkyl, optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N ,any Substituted with -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , optionally substituted -NR 1 -(CH 2 ) n -(C=O) u (NR 1 ) v (SO 2 ) w -aryl, optionally substituted -NR 1 -(CH 2 ) n -(C=O) u(NR 1 ) v (SO 2 ) w -H -aryl or optionally substituted -NR 1 -(CH 2 ) n -(C=O) v NR 1 (SO 2 ) w -heterocycle, optionally substituted Converted to -X R2’ -Alkyl group; optionally substituted -X R2’ -aryl group; optionally substituted -X R2’ -heteroaryl group; optionally substituted -X R2’ - a heterocyclic group; ULM-g R 3’ is an optionally substituted alkyl 、 Optionally substituted -(CH 2 ) n -(O) u (NR 1 ) v (SO 2 ) w -alkyl, optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N , optionally replaced Ru-(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w-C(O)NR 1 R 2 , optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -aryl, optionally substituted Ru-(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w - Heteroaryl, optionally substituted -(CH 2 ) n -C(O) u (NR 1 ) v ( SO 2 ) w -heterocycle, optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -alkyl, optionally substituted Converted to -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N , optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , optionally substituted -NR 1 -(CH 2 ) n-C(O) u (NR 1 ) v (SO 2 ) w -aryl , optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -heteroaryl, optionally substituted -NR 1 -(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -heterocycle, optionally substituted -O-(CH 2 )n-(C=O) u (NR 1 ) v (SO 2 ) w -alkyl, optionally substituted -O-(CH 2 )n-(C=O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N , optionally replaced -O-(CH 2 )n-(C=O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , optionally substituted -O-(CH 2 )n-(C=O) u (NR 1 ) v (SO 2 ) w -aryl, optionally substituted -O-(CH 2 ) n -(C=O) u(NR 1 ) v (SO 2 ) w -heteroaryl or optionally substituted -O-(CH 2 ) n -(C=O) u (NR 1 ) v (SO 2 ) w -Heterocycle;-(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -alkyl group, optionally substituted -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ an aryl group, Optionally substituted -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -heteroaryl group, optionally substituted- (CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -Heterocycle ’ group, optionally substituted -(CH 2 ) n -N(R 1’ )(C=O) m’ - (V) n’ -alkyl group, optionally substituted -(CH 2 ) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl group, any -(CH 2 ) n -N(R 1’ )(C=O) m’-(V) n’ -heteroaryl group, optionally substituted- (CH 2 ) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclic group, optionally substituted -X R3’ - alkyl group; any Replaced by -X R3’ - an aryl group; optionally substituted -X R3’ - a heteroaryl group; optionally Replaced by -X R3’ - a heterocyclic group; optionally substituted; ULM-g R 1N and R 2N are each independently H, one or two hydroxyl groups, or up to three C optionally substituted with two halogen groups 1 -C 6 Alkyl, or optionally substituted -(CH 2 ) n -a Reel, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n - a heterocyclic group; V in ULM-g is O, S or NR 1 and; ULM-g R 1 is the same as above; ULM-g R 1 and R 1’ are each independently H or C 1 -C 3 is an alkyl group; ULM-g X R2’ and X R3’ each independently represents an optionally substituted -CH 2 ) n -, -CH 2 ) n -CH(X v )=CH (X v )-(cis or trans), -CH 2 )n -CH≡CH-, -(CH 2 CH 2 O) n - or C 3 -C 6 Cycloal is a alkyl group, v is H, halo, or optionally substituted C 1 -C 3 is an alkyl group; Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' in ULM-g is independently 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w of ULM-g is independently 0 or 1; and ULM-g R 1’ , R 2’ , R 3’ Any one or more of X and X' are optionally modified to form P If the TM is not a ULM', it is covalently attached to the PTM group via a linker group, and if the PTM is a ULM' In this case, R of ULM and ULM' 1’ , R 2’ , R 3’ , X and X' The above are optionally modified and covalently linked to each other directly or via a linker group.

[0594] In any of the aspects or embodiments described herein, ULM and In some cases, ULM', or a pharma- ceutically acceptable salt, enantiomer, diastereomer, or solubilizer thereof, A solvate or polymorph is, independently, a group conforming to the following chemical structure:

[0595] [ka]

[0596] During the ceremony: ULM-h R 1’ , R 2’ , and R 3’ are the same as above, and X is C=O, C=S, -S(O) group, or S(O) 2 is a group, more preferably a C=O group, and ULM-h R 1’ , R 2’ , and R 3’ Any one or more of the following may be optionally modified to form a PTM: If not M', then the PTM group is further covalently linked to a linker group, or the PTM is a ULM ', then R for each of ULM and ULM' 1’ , R 2’ , R 3’ Any one or more of are optionally modified and are covalently linked to each other directly or via a linker group.

[0597] In any of the aspects or embodiments described herein, ULM and In some cases, ULM', or a pharma- ceutically acceptable salt, enantiomer, diastereomer, or solubilizer thereof, The solvates or polymorphs each independently conform to the following chemical structure:

[0598] [ka]

[0599] During the ceremony: ULM-I R 1’ , R 2’ , and R 3’ Any one or more of the following may be optionally modified to form a PTM: If not M', then the PTM group is further covalently linked to a linker group, or the PTM is a ULM ', then R for each of ULM and ULM' 1’ , R 2’ , R 3’ Any one or more of are optionally modified and are covalently linked to each other directly or via a linker group.

[0600] In a further preferred embodiment of the present disclosure, R of ULM-g to ULM-i 1’ is a hydroxyl group, or It is preferred that the group be metabolized to a hydroxyl group or a carboxylic acid group, thereby The compound is a prodrug form of the active compound. 1’ Examples of groups include -(CH 2 ) n OH, (CH 2 ) n -O-(C 1 -C 6 ) alkyl group, -(CH 2 ) n COOH, -(CH 2 O) n H, optionally substituted -(CH 2 ) n O.C.(O)-(C 1 -C 6 alkyl), or optionally substituted -(CH 2 ) n C(O)-O-(C 1 -C 6 Alkyl) is listed. In the formula, n is 0 or 1. 1’ is a carboxylic acid group, a hydroxyl group, or or amine groups, and The amines (each of which may be optionally substituted) may be further chemically modified to provide PTM groups (ULM' groups). (including) may provide a covalent bond to a linker group attached to the X and X' of ULM-g and ULM-h, when present, are preferably C=O, C=S, -S(O) groups or is S(O) 2 group, more preferably a C=O group; ULM-g~ULM-i R 2’ is preferably an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or an optionally substituted -NR 1 -T-heterocycle, wherein R 1 is H or CH 3 , preferably H, and T is optionally substituted -(CH 2 ) n - group, Each one of the ethylene groups is preferably a halogen, an aryl group as otherwise described herein. Amino acid side chain, or C 1 -C 3 One or two substituents selected from alkyl groups, preferably is optionally substituted with one or two methyl groups which may be optionally substituted, and n is 0 ∼6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T is -(CH 2 O) n - group, -(OCH 2 ) n - group, -(CH 2 CH 2 O) n - group, -(OCH 2 CH 2 ) n - group, All of the groups are optionally substituted.

[0601] ULM-g~ULM-i R 2’ Preferred aryl groups for are optionally substituted phenyl. and naphthyl or phenyl group, preferably phenyl group. The group is optionally attached to a PTM (including a ULM' group) via a linker group and / or Gen (preferably F or Cl), amine, monoalkylamine or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 or CN groups (each of which is ortho-, meta-, and / or or para-position, preferably para-position), an optionally substituted phenyl group (which the phenyl group itself is optionally linked via a linker group to a PTM group, including a ULM' group, and / or substituted with F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , or CN groups (located at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position) a naphthyl group which may be optionally substituted, optionally substituted with at least one of Optionally substituted heteroaryl, preferably methyl substituted isoxazole. isoxazoles, optionally substituted oxazoles including methyl substituted oxazoles; , optionally substituted thiazoles, including methyl substituted thiazoles, methyl substituted iridium Optionally substituted isothiazoles, including isothiazoles, including methyl-substituted pyrroles optionally substituted pyrrole, optionally substituted imidazole including methylimidazole; Optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted containing the oximidazole, methyloximidazole, or methyldiazole group Optionally substituted diazole groups, including methyl-substituted triazole groups a triazole group, a halo- (preferably F) or methyl-substituted pyridine group or an o Optionally substituted pyridine groups, including pyridine groups linked to a phenyl group by an oxygen. optionally substituted furan, optionally substituted benzofuran, dihydrobenzofuran, optionally substituted indole, indolizine or aza Indolizines (2, 3 or 4-azaindolizines), optionally substituted quinolines, is an optionally substituted group according to the structure:

[0602] [ka]

[0603] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R a is H or C 1 -C 6 Alkyl group (preferably Preferably C1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 1 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or a phenyl group optionally substituted with up to three halo groups, preferably fluorine groups; , an optionally substituted heteroaryl group, or an optionally substituted heterocycle, such as piperidinyl; amine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, The groups include oxazole, isoxazole, thiazole, isothiazole, imidazole, Diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrazole, Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin amine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 Alkyl groups, preferably methyl groups, or halo groups, preferably F or Cl), benzofuran, indium selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group; and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1). or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothie , piperidine, piperazine or morpholine (each of which groups, when substituted, is preferably Preferably, the group is substituted with methyl or halo (F, Br, Cl), each of which is a linker group. The PTM group may be optionally linked to a PTM group (including a ULM' group) via a

[0604] In certain preferred embodiments, ULM-g to ULM-i

[0605] [ka]

[0606] teeth,

[0607] [ka]

[0608] and In the formula, R of ULM-g to ULM-i PRO is the same as above.

[0609] ULM-g~ULM-i of R 2’ Preferred heteroaryl groups for are optionally substituted aryl groups. quinoline (attached to the pharmacophore or substituted on any carbon atom within the quinoline ring) optionally substituted indole, optionally substituted indolizine, optionally substituted optionally substituted benzofurans, Zofran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted optionally substituted isothiazoles, optionally substituted thiophenes, optionally substituted pyridines (2-, 3- or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, any optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted or a group according to the following chemical structure:

[0610] [ka]

[0611] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R of ULM-g to ULM-i a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 1 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene aryl, piperidine, piperazine, and the like, each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) acetylene group Each of these groups can be optionally attached to a PTM group (including a ULM' group) via a linker group. .

[0612] ULM-g~ULM-i R 2’ Preferred heterocyclic groups for are tetrahydrofuran, tetrahydrofuran, tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine phosphorus, oxane, or thiane, each of which may be optionally substituted; or a group conforming to the following chemical structure:

[0613] [ka]

[0614] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted alkyl aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group, and Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1). and each of these groups can be optionally attached to a PTM group (including a ULM' group) via a linker group. do.

[0615] Preferred R of ULM-g to ULM-i 2' The substituents include those described in the specific compounds disclosed herein. (including the specific compounds disclosed in the specification and drawings accompanying this specification). R 2' The substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). 2' Each of the substituents may be any number of R 3’ Substituents may also be used in conjunction with the substituents described herein. is disclosed in.

[0616] ULM-g~ULM-i R 3’ is preferably optionally substituted -T-aryl, optionally substituted - T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1-T-aryl, any -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle, Here, R 1 is H or C 1 -C 3 Alkyl group, preferably H or CH 3 where T is optionally substituted -(CH 2 ) n - group, wherein each one of the methylene groups is preferably a halogen, C 1 -C 3 selected from an alkyl group, or the side chain of an amino acid as otherwise described herein Optionally substituted with one or two substituents, preferably methyl, which may be optionally substituted. and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. T is -(CH 2 O) n - group, -(OCH 2 ) n - group, -(CH 2 CH 2 O) n - group, -(OCH 2 CH 2 ) n - may be a group Each of these groups is optionally substituted.

[0617] ULM-g~ULM-i of R 3’ Preferred aryl groups for are optionally substituted phenyl group or naphthyl group, preferably a phenyl group, in which case the phenyl The group or naphthyl group may be linked to a linker group and / or an optionally substituted halogen (preferably F or Cl), amines, monoalkylamines or dialkylamines (preferably is dimethylamine), amide group (preferably teeth -(CH 2 ) m -NR 1 C(O)R 2 where m, R 1 Oh BiR 2 is the same as above), halo (often F or Cl), OH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , CN or S(O) 2 R S Group (R S is C 1 -C 6 Alkyl groups, optionally substituted aryl groups, hetero aryl or heterocyclic groups, or (CH 2 ) m NR 1 R 2 each of which is a The phenyl ring may be substituted at the ortho, meta, and / or para positions (preferably the para position). or via an aryl (preferably phenyl), heteroaryl, or heterocycle, The phenyl group of the preferred substituents is optionally bonded to a M group (including a ULM' group). Substituted phenyl groups (i.e., the phenyl group of the substituent itself is preferably F, Cl, O H, SH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , CN, or a linker group. which are attached to a PTM group (including a ULM' group), wherein the substitution is occurring at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), optionally substituted naphthyl groups, including those mentioned above; optionally substituted heteroaryl (preferably Optionally substituted isoxazoles, including methyl-substituted isoxazoles; Optionally substituted oxazoles, including methyl substituted thiazoles; optionally substituted thiazoles, including methyl-substituted pyrroles; rol, methylimidazole, benzyl imidazole or methoxybenzylimidazole Optionally substituted imidazole, oximidazole or methyloxyimidazole, Midazole, optionally substituted diazole groups including methyldiazole groups, methyl-substituted Optionally substituted triazole groups, including triazole groups, halo (preferably F) or is a methyl-substituted pyridine or oxapyridine group (pyridine is a phenyl group with oxygen). a pyridine group containing a substituted heterocycle (e.g., a tetrahydrofuran bonded to oran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydrothiophene tetrahydroquinoline, oxane, or thiane. Aryl, heteroaryl or Each heterocycle group can be optionally attached to a PTM group (including a ULM' group) with a linker group.

[0618] ULM-g~ULM-i R 3’ Preferred heteroaryl groups for are optionally substituted aryl groups. quinoline (attached to the pharmacophore or substituted on any carbon atom within the quinoline ring) optionally substituted indoles (including dihydroindoles); Indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine) , optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole azoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thio phenanthren, optionally substituted thiazoles (preferably methyl- and / or thiol-substituted) substituted), optionally substituted isothiazole, optionally substituted triazole (preferred or methyl group, triisopropylsilyl group, optionally substituted (CH 2 ) m -OC 1 -C 6 Alkyl group , or optionally substituted (CH 2 ) m -C(O)-OC 1 -C 6 1,2,3-Triazo substituted with alkyl groups pyridine, optionally substituted pyridine (2, 3, or 4-pyridine), or Groups based on:

[0619] [ka]

[0620] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R a is H or C 1 -C 6 Alkyl group (preferably Preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 Alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 1 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene aryl, piperidine, piperazine, and the like, each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where RYC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 Alkyl) acetylene group Each of the heteroaryl groups may be optionally connected to a PTM group (including a ULM' group) via a linker group. They can be combined at will.

[0621] ULM-g~ULM-i of R 3’ Preferred heterocyclic groups for Lysine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothio phene, oxane, or thiane, each of which may be optionally substituted. or a group conforming to the following chemical structure:

[0622] [ka]

[0623] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6Alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, and others of The group is oxazole, isoxazole, thiazole, isothiazole, imidazole. , Diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrazole, Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin amine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 Alkyl groups, preferably methyl groups, or halo groups, preferably F or Cl), benzofuran, indium selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group, and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). and each of said heterocyclic groups is optionally linked to a PTM group (including a ULM' group) via a linker group. It can be done.

[0624] Preferred R of ULM-g to ULM-i 3' The substituents include those described in the specific compounds disclosed herein. (including the specific compounds disclosed in the specification and drawings accompanying this specification). R 3' The substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). 3’ Each of the substituents may be any number of R 2’Substituents may also be used in conjunction with the substituents described herein. is disclosed in the book.

[0625] In certain other preferred embodiments, R of ULM-g to ULM-i 2’ is an optionally substituted -NR 1 -X R2 ’ -Alkyl group, -NR 1 -X R2’ -aryl group; optionally substituted -NR 1 -X R2’ -HET, optional Converted to -NR 1 -X R2’ -aryl-HET or optionally substituted -NR 1 -X R2’ -HET-aryl and During the ceremony: ULM-g~ULM-i R 1 is H or C 1 -C 3 is an alkyl group (preferably H); ULM-g~ULM-i X R2’ is optionally replaced by - ( CH 2 ) n -,- ( CH 2 ) n -CH(X v )=CH(X v )-(Sis is trans), -(CH 2 ) n -CH≡CH-, -(CH 2 CH 2 O) n - or C 3 -C 6 is a cycloalkyl group; and ULM-g~ULM-i X v is H, halo, or optionally one or two hydroxyl groups or C substituted with up to three halogen groups 1 -C 3is an alkyl group; Alkyl of ULM-g through ULM-i is optionally substituted C1-C 10 Alkyl (preferably C 1 -C 6 Alki (In certain preferred embodiments, the alkyl group is a halo group, often Cl or or Br terminated); Aryl of ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably or phenyl groups); and HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, Isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidinium furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahy- Dorothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole benzoyl, indolizine, azaindolizine, quinoline (when substituted, each preferably C 1 -C 3 substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl; or a group according to the structure:

[0626] [ka]

[0627] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R a is H or C 1 -C 6 Alkyl group (preferably Preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 1 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene , piperidine, piperazine, and the like, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) acetylene group ; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, and others of The group is oxazole, isoxazole, thiazole, isothiazole, imidazole. , diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, Tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine azine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 Alkyl groups, preferably teeth methyl groups, or halo groups, preferably F or Cl), benzofuran, indium selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group, and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). do.

[0628] Each of the above groups can be optionally attached to a PTM group (including a ULM' group) via a linker group. do.

[0629] In another specific preferred embodiment of the present disclosure, R of ULM-g to ULM-i 3’ is optionally replaced -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -R S3’ group, optionally substituted -(CH 2 ) n -N(R 1’ )(C=O) m’ -(V ) n’ -R S3’ Group, optionally substituted -X R3’ -alkyl group, optionally substituted -X R3’ -aryl Group; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group, or Optionally replaced by -X R3’ -HET-aryl group, During the ceremony: R S3’ is an optionally substituted alkyl group (C 1 -C 10 , preferably C 1 -C 6 alkyl), optionally substituted is a substituted aryl group or a HET group; R 1’ is H or C 1 -C 3 is an alkyl group (preferably H); V is O, S or NR 1’ and; X R3’ is -(CH 2 ) n -, -(CH 2 CH 2 O) n -,- ( CH 2 ) n -CH(X v )=CH(X v )- (cis or trans), - ( CH 2 ) n -CH≡CH-, or C 3 -C 6 cycloalkyl groups, all of which are optionally substituted; X v is H, halo, or optionally one or two hydroxyl groups or up to three halo groups. C substituted with halogen group 1 -C 3 is an alkyl group; Alkyl is an optionally substituted C 1 -C 10 Alkyl (preferably C 1 -C 6 alkyl) group ( In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br. is closed); Aryl is an optionally substituted phenyl or naphthyl group, preferably phenyl. group); and HET is an optionally substituted oxazole, isoxazole, thiazole, or isothiazole. , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, di Hydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, Lysine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine azaindolizine, quinoline (when substituted, each preferably C 1 -C 3 Alkyl groups, preferably substituted with methyl, or halo groups, preferably F or Cl), or is a radical conforming to the structure:

[0630] [ka]

[0631] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein Ra is H or C 1 -C 6 Alkyl group (preferably Preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 0 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene , piperidine, piperazine, and the like, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) acetylene group ; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, and others of The group is oxazole, isoxazole, thiazole, isothiazole, imidazole. , diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, Tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine azine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 Alkyl groups, preferably teeth methyl groups, or halo groups, preferably F or Cl), benzofuran, indium selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group; Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). the law of nature; Each m' of ULM-g to ULM-i is 0 or 1; and Each n' of ULM-g to ULM-i is 0 or 1; wherein each of the above compounds, preferably an alkyl group, an aryl group or a Het group, is optionally , is attached to a PTM group (including a ULM' group) via a linker group.

[0632] In another embodiment, R of ULM-g through ULM-i 3 ' is -(CH 2 ) n -aryl, -(CH 2 CH 2 O) n -aryl , -(CH 2 ) n -HET or -(CH 2 CH 2 O) n -HET, During the ceremony: The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents. In this case, the substituent is preferably -(CH 2 ) n OH, itself CN, halo (the most Large with three halo groups), OH, -(CH 2 ) n O(C 1 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6 a C optionally further substituted with alkylamine 1 -C 6 alkyl, wherein The alkyl group of the amine may contain one or two hydroxyl groups or up to three halo (preferably Optionally substituted with a group, preferably F, Cl), or The aryl group of ULM-g to ULM-i is —(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 ) alkyl, -(CH 2 ) n -O- (CH 2 ) n -(C 1 -C 6 ) alkyl, -(CH 2 ) n -C(O)(C 0 -C 6 ) alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 ) Alki le, -(CH 2 ) n -OC(O)(C 0 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6 (alkyl) In this case, the alkyl group of the amine has one or two hydroxyl groups, or Up to three halo (preferably F, Cl) groups, CN, NO 2 , optionally substituted -(CH 2 ) n -(V) m’ -C H 2 ) n -(V) m’ -(C 1 -C 6 ) alkyl group, -(V) m’ -(CH 2 CH 2 O) n -R PEG and optionally substituted with a group, wherein V is O, S or NR 1’and R 1’ is H or C 1 -C 3 is an alkyl group (preferably H), R PEG is H or optionally substituted C 1 -C 6 Alkyl groups (optionally substituted with carboxyl groups) (including those that The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazolyl, Azoles, imidazoles, diazoles, oximidazoles, pyrroles, pyrrolidines, Ran, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien Ene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, yne Dole, indolizine, azaindolizine (when substituted, each preferably C 1 -C 3 Al alkyl groups, preferably methyl, or halo groups, preferably F or Cl), or or a heterocycle, including heteroaryl, selected from the group consisting of groups conforming to the structure Replaced by:

[0633] [ka]

[0634] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R a is H or C 1 -C 6 Alkyl group (preferably Preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 0 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene , piperidine, piperazine, and the like, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) acetylene group ; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, The groups include oxazole, isoxazole, thiazole, isothiazole, imidazole, Diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrazole, Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin amine, piperazine, morpholine, quinoline (each preferably C 1 -C 3Alkyl groups, preferably methyl groups, or halo groups, preferably F or Cl), benzofuran, indium selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group; The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isobutanol, Thiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, Furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydro Thiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 Substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl. ), benzofuran, indole, indolizine, azaindolizine, or The following principles are followed:

[0635] [ka]

[0636] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three hydroxyl groups) B group (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably mono substituted with one or two hydroxyl groups or up to three halo groups, or The acetylene group -C≡CR substituted with a wherein R a is H or C 1 -C 6 Alkyl group (preferably Preferably C 1 -C 3 alkyl) is an acetylene group; ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O-(C 1 -C 6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C 1 -C 6 alkyl) (preferably having one or two hydroxyl groups or up to three (substituted with a halo group); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or - C(O)(C 0 -C 6 alkyl), each group optionally containing one or two hydroxyl groups or Heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene , piperidine, piperazine, and the like, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , Halo (preferred or Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably one or two aryl groups) hydroxyl group or up to three halo groups (e.g., CF 3 ), optionally replaced by O(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylene group -C≡CR a wherein , R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl) acetylene group ; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted alkyl aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 Alki or together form a keto group; Each m' of ULM-g through ULM-i is independently 0 or 1; and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). the law of nature, wherein each of said compounds, preferably said aryl group or HET group, optionally includes a linker is linked to a PTM group (including a ULM' group) via a - group.

[0637] In yet additional embodiments, preferred compounds include those according to the following chemical structure: includes pharma- ceutically acceptable salts, stereoisomers, solvates or polymorphs thereof:

[0638] [ka]

[0639] During the ceremony: ULM-i R 1’ is OH or a group that is metabolized to OH in the patient or subject; ULM-i R 2’ is -NH-CH 2 -aryl-HET- (preferably methyl substituted thiazoles) bonded phenyl); ULM-i R 3’ -CHR CR3’ -NH-C(O)-R 3P1 Group or -CHR CR3’ -R 3P2 It is a base; ULM-i R CR3’ is C 1 -C 4 An alkyl group, preferably methyl, isopropyl, or tert-butyl. Chill; ULM-i R 3P1 is C 1 -C 3 alkyl (preferably methyl), optionally substituted oxetane group ( Preferably, the methyl-substituted -(CH 2 ) n OCH 3A group in which n is 1 or 2 (preferably 2). ), or

[0640] [ka]

[0641] group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), morpholino group (attached to the carbonyl at the 2- or 3-position); ULM-i R 3P2 teeth,

[0642] [ka]

[0643] It is a base; Aryl of ULM-i is phenyl; HET of ULM-i is an optionally substituted thiazole or isothiazole; and ULM-i R HET is H or a halo group (preferably H); In this case, the compounds are each linked to a PTM group (including a ULM' group) via a linker group. are joined at will.

[0644] In certain embodiments, a bispecific antibody comprising a ubiquitin E3 ligase binding moiety (ULM) is Sensuality sexual compounds, or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof, A ULM is a group according to the following chemical structure:

[0645] [ka]

[0646] During the ceremony: Each R in ULM-j 5 and R6 is independently OH, SH, or optionally substituted alkyl; or R 5 , R 6 and form carbonyls at the carbon atoms to which they are attached; ULM-j R 7 is H or optionally substituted alkyl; E of ULM-j is a bond, C=O, or C=S; G of ULM-j is a bond, optionally substituted alkyl, —COOH, or C═J; J in ULM-j is O or NR 8 and; ULM-j R 8 is H, CN, optionally substituted alkyl, or optionally substituted alkoxy. can be; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted or

[0647] [ka]

[0648] and; ULM-j R 9 and R 10 are independently H, optionally substituted alkyl, optionally substituted cyclo optionally substituted hydroxyalkyl, optionally substituted thioalkyl, dialkyl Sulfide-linked ULM, optionally substituted heteroaryl or haloalkyl ,or R 9 , R 10 and the carbon atom to which they are attached is optionally substituted cycloalkyl. Form a loop; ULM-j R 11 is an optionally substituted heterocyclic, an optionally substituted alkoxy, an optionally substituted heteroaryl, optionally substituted aryl, or

[0649] [ka]

[0650] and; ULM-j R 12 is H or optionally substituted alkyl; ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, Optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl carbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl ) carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl ) carbamate, Each R in ULM-j 14 are independently H, haloalkyl, optionally substituted cycloalkyl, substituted alkyl, or optionally substituted heterocycloalkyl; ULM-j R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; ; Each R in ULM-j 16 are independently halo, optionally substituted alkyl, optionally substituted haloalkenyl, alkyl, CN, or optionally substituted haloalkoxy; Each R in ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 the groups may be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23is H or OH; ULM-j Z 1 , Z 2 , Z 3 and Z 4 are independently C or N; and The o of ULM-j is 0, 1, 2, 3, or 4.

[0651] In certain embodiments, G of ULM-j is C=J, J is O and R 7 is H, and each R 14 is H and o is 0.

[0652] In certain embodiments, G of ULM-j is C=J, J is O and R 7 is H, and each R 14 is H Yes, R 15 is an optionally substituted heteroaryl, and o is 0. is C=O and M is

[0653] [ka]

[0654] It is. In certain embodiments, E of ULM-j is C═O and R 11 is an optionally substituted heterocyclic or

[0655] [ka]

[0656] and M is

[0657] [ka]

[0658] It is. In certain embodiments, E of ULM-j is C=O and M is

[0659] [ka]

[0660] and R 11 teeth

[0661] [ka]

[0662] or

[0663] [ka]

[0664] And each R 18 are independently halo, optionally substituted alkoxy, cyano, and p is 0, 1, 2, 3 or 4. It is.

[0665] In certain embodiments, ULM, and, if present, ULM′, are each independently selected from the following: It is a group that conforms to the chemical structure:

[0666] [ka]

[0667] During the ceremony: G of ULM-k is C=J, J is O; ULM-k R 7 is H; Each R of ULM-k 14 is H; ULM-k's o is 0; ULM-k R 15 teeth

[0668] [ka]

[0669] and ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl , optionally substituted alkenyl, and haloalkyl.

[0670] In another example, ULM-k R 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., For example, cyclopropyl.

[0671] In other embodiments, ULM, and, if present, ULM′, are each independently selected from the group consisting of It is a group that follows the chemical structure:

[0672] [ka]

[0673] During the ceremony: G of ULM-k is C=J, J is O; ULM-k R 7 is H; Each R of ULM-k 14 is H; ULM-k's o is 0; and ULM-k R 15 is selected from the group consisting of:

[0674] [ka]

[0675] wherein R of ULM-k is 30 is H or optionally substituted alkyl. In other embodiments, ULM, and, if present, ULM′, are each independently selected from the group consisting of It is a group that follows the chemical structure:

[0676] [ka]

[0677] During the ceremony: E of ULM-k is C=O; The M in ULM-k is

[0678] [ka]

[0679] and ULM-k R 11 is selected from the group consisting of:

[0680] [ka]

[0681] In yet another embodiment, a compound of the following chemical structure:

[0682] [ka]

[0683] wherein E of ULM-k is C=O; ULM-k R 11 teeth

[0684] [ka]

[0685] and The M in ULM-k is

[0686] [ka]

[0687] and; ULM-k, q is 1 or 2; ULM-k R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, aryl substituted with, or

[0688] [ka]

[0689] and; ULM-k R 21 is H or optionally substituted alkyl; and ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or halo. It is roalkyl.

[0690] In any embodiment described herein, R of ULM-j or ULM-k 11 From the following Selected from the group consisting of:

[0691] [ka]

[0692] [ka]

[0693] In certain embodiments, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0694] [ka]

[0695] [ka]

[0696] In certain embodiments, ULM (or ULM′, if present) conforms to the following chemical structure: Based on:

[0697] [ka]

[0698] During the ceremony: X of ULM-l is O or S; Y of ULM-l is H, methyl or ethyl; ULM-l R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0699] [ka]

[0700] and; ULM-l R 9 is H; ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, Substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxya alkyl, optionally substituted thioalkyl, or cycloalkyl; ULM-l R 11 is an optionally substituted heteroaromatic, an optionally substituted heterocyclic, an optionally substituted or

[0701] [ka]

[0702] and; ULM-l R 12 is H or optionally substituted alkyl; and ULM-l R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, Optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl carbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl ) carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl ) carbamate.

[0703] In some embodiments, ULM, and, if present, ULM′, are each independently selected from the following: It is a group that conforms to the chemical structure:

[0704] [ka]

[0705] During the ceremony: Y in ULM-m is H, methyol, or ethyl. ULM-m R 9 is H; R 10 isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl le; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted substituted isoxazole, an optionally substituted heterocycle.

[0706] In another preferred embodiment of the present disclosure, ULM, and, if present, ULM', are each independently In particular, it is a group according to the following chemical structure:

[0707] [ka]

[0708] During the ceremony: ULM-n R 17 is methyl, ethyl, or cyclopropyl; and ULM-n R 9 , R 10 , and R 11 is as defined above. In other examples, R 9 is H Yes; and ULM-n R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0709] In any of the aspects or embodiments described herein, ULM (or ULM', if present) may be any of its pharma- ceutically acceptable salts, enantiomers, It may be a diastereomer, solvate, or polymorph. In any of the aspects or embodiments described herein, the ULM (or In this case, the ULM') is attached to the PTM directly via a bond or by a chemical linker. This may be done.

[0710] In certain embodiments of the disclosure, the ULM moiety is selected from the group consisting of:

[0711] [ka]

[0712]

change

[0713]

change

[0714]

change

[0715]

change

[0716]

change

[0717]

change

[0718]

change

[0719]

change

[0720]

change

[0721]

change

[0722]

change

[0723]

change

[0724]

change

[0725]

change

[0726]

change

[0727]

change

[0728]

change

[0729]

change

[0730]

change

[0731]

change

[0732]

change

[0733] [ka]

[0734] In this case, for example, aryl, heteroaryl, phenyl, or indium may be used. Any suitable location, including the phenyl of the diol group, may be used, for example, as an amine, ester, ether, or azobenzene. The aryl, aryl, or alkoxy groups described herein may be optionally substituted with any suitable functional group, such as alkyl, alkyl, or alkoxy. The VLM may be linked to the PTM via a linker such that Exemplary Linkers In certain embodiments, the compounds described herein can be linked via one or more chemical linkers (L). ULM above (e.g., at least one of CLM, VLM, MLM, ILM, or a combination thereof) In certain embodiments, the nucleic acid sequence includes one or more PTMs that are chemically linked or attached to The linker group L is a group that includes one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), in this case A 1 is a group attached to the PTM, and A q is tied to ULM It is a combined group.

[0735] In certain embodiments, the linker group L is -(A L ) q -And: (A L ) q is ULM (e.g. CLM, VLM, ILM, MLM, CLM', VLM', ILM' and / or MLM') a group attached to at least one of the following: Call The linker's q is an integer equal to or greater than 1; Each A L are independent, bond, CR L1 R L2 , O, S, SO, SO 2 , N.R. L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L 3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=N CN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , optionally 0 to 6 R L1 and / or R L2 Based on Converted C 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with group 5- 13 spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with group 3-11 F Tetracyclyl, optionally 0 to 8 R L1 and / or R L2 C substituted with group 5-13 Spirohetero Cycloalkyl, optionally 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group; 0 to 6 R L1 and / or R L2Heteroaryl substituted with a group , where R L1 or R L2 each independently optionally bonded to another group, and optionally 0 to 4 R L5 Based on forming a substituted cycloalkyl and / or heterocyclyl moiety; and R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or C 1-8 Alkyl, OC 1-8 Alkyl , S.C. 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl) 2 , C 3-11 Cycloalkyl, aryl , Heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl , N.H.C. 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl) 2 , N(C 1-8 Cycloalkyl)(C 1-8 Alki OH, NH 2 , SH, SO 2 C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl) 2 , C.C.-C. 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=CH(C 1-8 a Rukill), C(C 1-8 Alkyl)=C(C 1-8 Alkyl) 2 , Si(OH) 3 , Si(C 1-8Alkyl) 3 , Si(OH)(C 1 -8 Alkyl) 2 , COC 1-8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 Alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 Alkyl) 2 , CONH.C. 1-8 Alkyl, CON(C 1-8 Alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 Alki CON(C 1-8 Alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 Alkyl) 2 , N.H.C.O.N. 2 , N(C 1-8 Alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 Alkyl)SO 2 N(C 1-8 Alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 Alkyl) 2 , NHSO 2 NH 2 Yes do.

[0736] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1. is the integer above.

[0737] In certain embodiments, for example, when the linker q is greater than 2, (A L ) q is bound to ULM A is a group in which 1 and (A L ) q are linked via a linker (L) structural unit.

[0738] In certain embodiments, for example, when the linker q is 2, (A L ) q A L 1 and bound to ULM It is a group that is

[0739] In certain embodiments, for example when the linker has q=1, the linker group L has the structure -A L 1 and A L 1 is a group attached to the ULM and ABM moieties.

[0740] In certain embodiments, the linker (L) has a general structure selected from the group consisting of: Contains groups represented by: -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxyl)-, -NR(CH 2 ) n -(Low-level Arco Xyl)-OCH 2 -, -NR(CH 2 ) n -(lower alkoxyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -( Chloroalkyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(heterocycloalkyl)-, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heterocycloalkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -Aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -( Chloroalkyl)-O-(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-aryl ROLL-O-CH 2 -, -NR(CH 2 CH 2 O) n -(lower alkyl)-NH-aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(Low (alkyl)-O-aryl-CH 2 , -NR(CH 2 CH 2 O) n -Cycloalkyl-O-aryl-, NR(CH 2 CH 2 O ) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH 2 CH 2 )n -(cycloalkyl)-O-(heterocycle) -CH 2, -NR(CH 2 CH 2 ) n -(heterocycle)-(heterocycle)-CH 2 , -N(R1R2)-(heterocycle)-CH 2 ;where The linker's n can be 0 to 10; R of the linker can be H, lower alkyl; The linkers R1 and R2 may form a ring with the bond N.

[0741] In certain embodiments, the linker (L) has a general structure selected from the group consisting of: Contains groups represented by: -N(R)-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -OCH 2 -, -O-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -OCH 2 -, -O-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 )q -O(CH 2 ) r -O-; -N(R)-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -O-; -(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -O-; -(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -OCH 2 -;

[0742]

Chem.

[0743]

Chem.

[0744]

Chem.

[0745] ;In the formula, The linker's m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6; If the number is zero then there are no NO or OO bonds. The linker R is H, methyl and ethyl; X of the linker is H and F;

[0746] [ka]

[0747] wherein m in the linker may be 2, 3, 4, or 5;

[0748] [ka]

[0749] [ka]

[0750] [ka]

[0751] [ka]

[0752] [ka]

[0753] [ka]

[0754] [ka]

[0755] [ka]

[0756] [ka]

[0757] wherein each of m and n in the linker may independently be 0, 1, 2, 3, 4, 5, or 6. Ku; In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of: Selected from the group consisting of:

[0758] [ka]

[0759] [ka]

[0760] [ka]

[0761] [ka]

[0762] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of: Selected from the group consisting of:

[0763] [ka]

[0764] [ka]

[0765]

change

[0766]

change

[0767]

change

[0768]

change

[0769]

change

[0770]

change

[0771]

change

[0772]

change

[0773]

change

[0774]

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[0775]

change

[0776]

change

[0777]

change

[0778]

change

[0779]

change

[0780]

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[0781]

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[0782]

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[0783]

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[0784]

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[0785]

change

[0786] [ka]

[0787] [ka]

[0788] [ka]

[0789] [ka]

[0790] [ka]

[0791] [ka]

[0792] wherein each of m, n, o and p is independently 0, 1, 2, 3, 4, 5, 6, or 7. In any aspect or embodiment described herein, L is selected from the group consisting of: Selected:

[0793] [ka]

[0794] [ka]

[0795] [ka]

[0796] [ka]

[0797] [ka]

[0798] [ka]

[0799] [ka]

[0800] [ka]

[0801] [ka]

[0802] [ka]

[0803] [ka]

[0804] In additional embodiments, the linker (L) includes, but is not limited to, the structures shown below: , where the dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0805] [ka]

[0806] During the ceremony: W L1 and W L2 are each independently R Q 4 with 0-4 heteroatoms, optionally substituted with ~8-membered ring, each R Q are independently H, halo, OH, CN, CF 3 , N.H. 2 , carboxyl, C 1 -C 6 Alkyl (optionally substituted straight or branched chain), C 1 -C 6 Alkoxy (optionally substituted straight chain , branched chain) or two R Q Groups, together with the atoms to which they are attached, consist of 0 to 4 hexafluorophenyl groups. Forming a 4-8 membered ring system containing a heteroatom; Y L1 each independently represents a bond, C 1 -C 6 Alkyl (optionally substituted straight or branched chain) and optionally one or more C atoms are O, or C 1 -C 6 Alkoxy (optionally substituted straight chain , branched chain); n is 0 to 10; and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0807] In additional embodiments, the linker (L) includes, but is not limited to, the structures shown below: where the dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0808] [ka]

[0809] During the ceremony: W L1 and W L2each independently represents an aryl, heteroaryl, cyclic, heterocyclic, C 1~6 Alkyl (optionally substituted straight or branched chain), C 1 -C 6 Alkoxy (optionally substituted straight chain , branched), bicyclic, biaryl, biheteroaryl, or biheterocyclic, each of which Optionally, R Q Each R Q are independently H, halo, OH, CN, CF 3 , N.H. 2 , carboxyl, Hydroxyl, Nitro, C≡CH, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1 -C 6 Alkyl ( Optionally substituted straight or branched chain), C 1 -C 6 Alkoxy (optionally substituted straight or branched chain ), O.C. 1~3 Alkyl (optionally substituted with one or more -F), OH, NH 2 , N.R. Y1 R Y2 , C.N. or two R Q Groups, together with the atoms to which they are attached, contain 0 to 4 heteroatoms. Forming a 4-8 membered ring system containing; Y L1 are each independently a bond, NR YL1 ,O.S.,NR. YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO 2 , C 1 -C 6 Alkyl (straight or branched, optionally substituted) and optionally one or more C atoms But, O, C 1 -C 6 Substituted with alkoxy (straight or branched chain, optionally substituted); Q Lis a 3-6 membered alicyclic or arom...

Claims

1. structure: 【Chemistry 1】 or a pharma- ceutical composition comprising an effective amount of a compound having the formula: The pharmaceutical composition is formulated into a tablet. Pharmaceutical compositions.

2. The compound of claim 1, wherein the compound has the structure: 【Chemistry 2】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1.

3. The compound of claim 2, wherein the compound has the structure: 【Chemistry 3】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1.

4. The compound of claim 1, wherein the compound has the structure: 【Chemistry 4】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1.

5. The compound of claim 1, wherein the compound has the structure: 【Chemistry 5】 having The pharmaceutical composition of claim 1.

6. The compound of claim 1, wherein the compound has the structure: 【Chemistry 6】 having The pharmaceutical composition of claim 1.

7. The compound of claim 1, wherein the compound has the structure: 【Chemistry 7】 having The pharmaceutical composition of claim 1.

8. The pharmaceutical composition of claim 1, wherein the compound is administered to a patient at a dose of about 25 to about 250 mg.

9. A pharmaceutical composition described in any one of claims 1 to 8 for treating a disease or disorder (excluding breast cancer) associated with estrogen receptor accumulation and aggregation in a subject.

10. A method for treating a disease or disorder associated with estrogen receptor accumulation and aggregation in a subject (excluding breast cancer), comprising administering to said subject a therapeutically effective amount of a compound according to the present invention. structure: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound has the structure: 【Chemistry 9】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition according to claim 10.

12. The compound of claim 1, wherein the compound has the structure: 【Chemistry 10】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition according to claim 10.

13. The compound of claim 1, wherein the compound has the structure: 【Chemistry 11】 、 or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition according to claim 10.

14. The compound of claim 1, wherein the compound has the structure: 【Chemistry 12】 having The pharmaceutical composition according to claim 10.

15. The compound of claim 1, wherein the compound has the structure: 【Chemistry 13】 having The pharmaceutical composition according to claim 10.

16. The compound of claim 1, wherein the compound has the structure: 【Chemistry 14】 having The pharmaceutical composition according to claim 10.

17. The pharmaceutical composition described in any one of claims 9 to 16, wherein the disease or disorder is uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, or endometriosis.

18. The pharmaceutical composition described in claim 17, wherein the disease or disorder is uterine cancer.

19. The pharmaceutical composition described in claim 17, wherein the disease or disorder is endometriosis.

20. The pharmaceutical composition described in any one of claims 9 to 19, wherein the subject is further administered an effective amount of an additional anticancer agent.

21. The additional anticancer agent is selected from the group consisting of estramustine, docetaxel, ketoconazole, goserelin acetate, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zoledronate, everolimus, pazopanib, carboplatin, cisplatin, oxaliplatin, and epothilone B. B), fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, 21. The pharmaceutical composition of claim 20, wherein the active ingredient is vincristine, temozolomide, capecitabine, camptothecin, PD0325901, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, raloxifene, paclitaxel, abraxane, or trastuzumab.

22. The pharmaceutical composition according to claim 20, wherein the additional anticancer agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 inhibitor, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1 / 2 inhibitor, a JAK / STAT inhibitor, a checkpoint 1 inhibitor, a checkpoint 2 inhibitor, a focal adhesion kinase inhibitor, a MAP kinase inhibitor, or a VEGF trap antibody.

23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the compound and the additional anticancer agent are administered to the subject at different times.

24. The pharmaceutical composition according to any one of claims 20 to 22, wherein the additional anticancer agent is formulated as a tablet.

25. The pharmaceutical composition of any one of claims 20 to 22, wherein the compound and the additional anticancer agent are formulated as separate tablets and administered to a subject at the same time or at different times.

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