Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders

Abstract

Provided are bifunctional compounds that find utility as estrogen receptor modulators, and methods for their preparation. The present invention provides a method for producing the following compound 411 or a stereoisomer thereof, comprising the steps of: TIFF2023021211000728.tif49114 The method includes the step of performing reductive amination of a salt intermediate 1 ((3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione) or a stereoisomer thereof with intermediate 2 (1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde) and a reducing agent.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure is incorporated herein by reference in its entirety. U.S. Provisional Patent Application No. 2006 / 0100999, entitled "INOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS," filed on May 1, 2006. No. 62 / 429,041, and filed August 1, 2017, entitled "TETRAHYDRONAPHTHALENE AND TETRAHYDRO 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. 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 July 13, 2016, and U.S. patent application Ser. No. 10 / 109,497, filed July 13, 2016. 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 July 11, 2014, and U.S. Patent Application No. U.S. Patent Application 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 the Prescription of Novel Substances," and U.S. Patent Application No. No. 15 / 074,820, published as Publication No. 2016 / 0272639, and U.S. Patent Application No. 15 / 074,820, published as Publication No. 2017 / 1 U.S. Provisional Patent Application No. 62 / 452,972, filed December 31, 2016; U.S. Provisional Patent Application No. 62 / 452,972, filed December 1, 2016; Patent application No. 62 / 429,041, filed March 18, 2016, and International Patent Application Publication No. WO2016 / 14 No. PCT / US2016 / 023258, published as PCT International Patent Application No. PCT / US2016 / 023258, now U.S. Pat. No. 6,9668, all of which are incorporated herein by reference. In addition, all references cited herein are incorporated by reference in their entirety. No. 6,029,139, 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 them. The present disclosure also relates to methods for inhibiting estrogen receptor degradation, including, for example, degradation of estrogen receptors. The present invention relates to the use of compounds, compositions and medicaments as inhibitors of stromal receptor activity. and 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 and 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 closely related metabolic products. When estradiol binds to the estrogen receptor, the receptor dimerizes. This dimer then binds to the estrogen response element (ERE) on DNA. The ER-DNA complex binds to the ERE and recruits other transcription factors that transcribe the DNA downstream of the ERE into mRNA. The ER then transports the DNA to the endothelial cells, which are then translated into proteins. The function may be indirect through the mediation of other transcription factors, the most notable being fos and j Many gene expressions are regulated by estrogen receptors, and estrogen Because hormone receptors are expressed in many cell types, they are sensitive to natural hormones or synthetic ER ligands. It modulates estrogen receptors through binding to either This can have a profound effect on metabolic function.

[0004] A variety of diseases have ER-mediated etiology and / or pathogenesis. 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 thought to play a role in the maintenance of normal functioning and to have neuroprotective effects. Decreased estrogen production due to steroids and associated health problems such as osteoporosis, atherosclerosis, depression, and cognition Conversely, certain types of proliferative diseases, such as breast cancer and uterine cancer, are associated with Cancer, as well as endometriosis, are stimulated by estrogen. Therefore, anti-estrogen drugs ( i.e. estrogen antagonists) are useful 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, each with distinct functions. Both ERs are encoded by the ESR1 and ESR2 genes (ESR1 and ESR2, respectively). Although it is widely expressed, there are some clear differences in its expression pattern. It is present in the endometrium, breast cancer cells, ovarian stromal cells, and 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. The beneficial aspects of strogens may be preserved.

[0006] Breast cancer is the most common malignancy 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 advanced disease in premenopausal women. This treatment can be surgical, radiotherapeutic, or medically This can be done by removing ovarian function and, in postmenopausal women, aromatase This can be achieved by using inhibitors.

[0007] Another method for estrogen withdrawal is to antagonize estrogen using antiestrogens. Antiestrogens inhibit the production of estrogen in estrogen-responsive tissues. It is a drug that binds to and competes with the ER (endogenous receptor) receptor. Nonsteroidal antiestrogens efficiently compete for ER binding, but their effectiveness varies depending on the These agents are often limited by their partial agonism, which prevents estrogen production. It has high affinity for ER and exerts agonistic effects. 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 marketed as an anti-estrogen, similar to tamoxifen. It has partial agonist activity associated with estrogenic activity and is completely devoid of estrogenic activity.

[0008] Thus, there is a need for other methods to antagonize ER receptors. One method is to transactivate transcription factors. Selective ER downregulators or agents that decrease ER expression at either the cytosolic or protein level Or to develop ER degrading substances.

[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 number of protein contacts. Due to the large surface area and shallow grooved or flat interfaces involved E3 ubiquitin ligases, of which several hundred are known in humans, It confers substrate specificity to the catalysis, and therefore has specificity for specific protein substrates and is generalizable. This makes it a more attractive therapeutic target than conventional proteasome inhibitors. The development of new drugs inevitably disrupts 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 that remain undeveloped in this field. For example, Since the discovery of natrin, a mouse double minute 2 homolog (MDM2) inhibitor, Additional compounds targeting the human double minute 2 (HDM2) E3 ligase have been reported. (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0010] The tumor suppressor p53 mediates cell growth arrest and apoptosis in response to DNA damage or stress. It plays an important role in the cis- , 979-982), and p53 inactivation 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. % (M. Hollstein, et al. Science (1991), 233, 49-53), while in the wild Patients with type 2 p53 have a protein-protein interaction with MDM2, which is mediated by the p53-MDM2 protein-protein interaction. Downregulation of p53 by cancer cells has been frequently reported (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. 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 possesses intrinsic E3 ligase activity and binds ubiquitin to p53, resulting in ubiquitin-dependent It is degraded via the ubiquitous 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Because MDM2 functions as an E3 ligase, it is possible to identify MDM2 as a disease-causing protein. It is highly likely that the recruitment of ATP to proteins and their ubiquitination and degradation activities are essential. This is an interesting approach to drug development.

[0012] One E3 ligase with attractive therapeutic potential is the von Hippel-Lindau (VHI) ligase. VHL (Vasculitis Lindau) tumor suppressor, which is a 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 erythroid-inducing cytokines 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 was obtained, demonstrating that this compound binds to the transcription factor HIF, a major substrate of VHL. It was confirmed that it mimics the binding mode of -1α.

[0013] Cereblon is a protein encoded by the CRBN gene in humans. BN orthologues are highly conserved from plants to humans, which explains their physiological role. This clearly shows the importance of cereblon. DDB1), Cullin-4A (CUL4A), and Cullin1 regulator (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 is involved in the regulation of fibroblast growth factor 8 (FGF8) and fibroblast growth factor FGF8 then contributes to the development of, for example, limbs and otic vesicles. In the embryo, this ubiquitin ligase complex regulates many developmental processes, including 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 the proteins that regulate apoptosis. In other words, 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 E3 ligase-specific domains and backbone domains. They contain baculoviral IAP repeat (BIR) domains, IAPs recognize substrates and promote their ubiquitination. Caspases can directly bind to and inhibit caspases, which are the proteins that carry out apoptosis. proteases (e.g., caspase-3, caspase-7, and caspase-9). Moreover, through binding of caspases, IAPs inhibit cell death, but pro-apoptotic The stimulation of mitochondrial protein DIABLO (second mitochondria-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 essentially binds all the 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 the IAPs. This is thought to be essential for inhibiting the anti-apoptotic effects of IAPs.

[0016] U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322, incorporated herein by reference. Two compounds, such as those listed in SensualityThe compound binds endogenous proteins via E3 ubiquitination. In particular, the patent publication Sensuality sex or proteolysis targeting chimeric (PROTAC) The present invention describes compounds that bind to target ubiquitins of various polypeptides and other proteins. These polypeptides and other proteins have been shown to be useful as regulators of chitinization. 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 estrogen receptors. The present invention identifies compounds that can inhibit the function. Summary of the Invention

[0018] This disclosure provides 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 targeting chimeric compounds, which can be used in a variety of polypeptides and These proteins have been shown to be useful as regulators of targeted ubiquitination of other proteins. The polypeptides and other proteins described herein Sensuality Decomposition and The advantage of the compounds provided herein is that they can be used in a wide range of pharmacological applications. Potentially active targets from virtually any protein class or family Furthermore, the present disclosure relates to the use of steroids in the treatment of diseases such as cancer, e.g., breast cancer, in combination with the degradation / inhibition of polypeptides. The present invention provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of conditions. To provide.

[0019] Thus, in one aspect, the present disclosure provides two Sensuality Providing a novel compound or PROTAC compound and the compound is an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase a ligand for the enzyme, or "ULM" group), and a moiety that binds to the target protein (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 ligated to the ubiquitin ligase. In a preferred embodiment, ULM (ultra-lowering metabolites) ubiquitination ligase regulator) regulates the 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., "ILM"). For example, two Sensuality The structure of the compound can be shown as follows:

[0020] [ka]

[0021] The PTM moieties 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 is not intended to limit the compounds in any way. As will be better understood, the two methods described herein Sensuality The compounds are Sensuality sexual part can be synthesized so that the number and position of can be varied as desired.

[0022] In certain embodiments, two Sensuality The compound further comprises a chemical linker (L). Leave, two Sensuality The structure of the 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 ligases. Interleukin-1-ylmorhinolaryngeal membrane protein (ILM) or von Hippel-Lindau E3 ubiquitin ligase (VHL) binding site (VLM) or cereblon E3 ubiquitin ligase binding moiety (CLM), or mouse do ubiquitin miniute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM).

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

[0026] [ka]

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

[0028] In some embodiments, the present disclosure provides compounds of Formula (I) or Formula (II):

[0029] [ka]

[0030] During the ceremony: each X PTM are independently CH, N; ULM is ILM or VLM or CLM or MLM; L is a tetrahydronaphthalene or tetrahydroisoquinoline moiety and VLM, C A coupling portion that couples 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 carbon atoms or an aryl group can be; Each R PTM2 are independently H, halogen, CN, CF3, straight or branched chain alkyl, alkoxy (e.g., methoxy or ethoxy), where the substitution is mono- or di-substituted. Well, often; Each R PTM3 are independently H, halogen, and the substitutions 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 soluble compound is composed of the amino acids alanine (A) and 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 joined by an amide bond ( 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 linkers, and / or a combination of PTMs ... 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 contemplated VLMs include those disclosed in U.S. Patent Application Publication No. 2014 / 0302, as discussed above. No. 2523, which application 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 phthalimido group, or In certain embodiments, the CLM is thalidomide, an analog or derivative thereof. Lenalidomide, pomalidomide, their analogs, their isosteres, or their derivatives Other anticipated CLMs include those described in U.S. Patent Application Publication No. 2015 / 0291562. No. 60 / 699,999, filed on Dec. 1, 2003, 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 are those disclosed in U.S. Patent Application No. 2016 / 0100607 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 polymeric compound is, for example, a substituted imidazoline, a substituted spinel Substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted piperidinones, Substituted imidazolopyridines, substituted thiazolimidazolines, substituted pyrrolopyrrolidones These include chemical moieties such as lysinones, lysinones, and substituted isoquinolinones.

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

[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" in the connector is For example, ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxyls, These may include functional groups such as carboxylic acids, thioethers, sulfoxides, and sulfones. Linkers include, but are 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 phthalimido group, or In certain embodiments, the CLM is thalidomide, an analog or derivative thereof. Lenalidomide, pomalidomide, their analogs, their isosteres, or their derivatives Other anticipated CLMs include those described in U.S. Patent Application Publication No. 2015-0291562. In some embodiments, the CLM 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 the bond as a CN bond or a CC bond. Examples of CLMs include pomalidomide, lenalidomide, and the like. 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" in the connector is For example, ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxyls, These may include functional groups such as carboxylic acids, thioethers, sulfoxides, and sulfones. Linkers include, but are 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 a method for treating a rheumatoid arthritis, comprising administering to a subject an effective amount of a compound described herein or a salt form thereof, and and a pharmaceutically 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 in 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 can be caused in order to treat or ameliorate a disease, for example, cancer. In certain additional embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, uterine cancer, or ovarian cancer. In yet another embodiment, the present invention is directed to at least one of the following: The present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method preferably comprises: ILM and PTM, PTM and VLM, PTM and CLM, or PTM and MLM linked via a linker moiety The two described herein, including Sensualityand administering a compound to the patient, wherein the compound is a 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 tetrahydroisoquinones) The VLM, CLM, MLM, ILM, or a combination thereof is connected via a linker. and binding to at least one of the nucleotides of the nucleotide sequence of the target protein or polypeptide. 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 position that results in degradation of the target protein / effectiveness of the target protein. The present disclosure provides a method for the inhibition of ATP synthesis and the regulation of protein levels. Controlling protein levels provides a treatment for a disease state or condition, which is 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. provides a method for treating or ameliorating a disease, disorder, or its symptoms, The method comprises 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 an acceptable carrier, wherein The composition is used to treat or ameliorate a disease or disorder or a symptom thereof in a subject. It is valid.

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

[0045] The foregoing general description of utility is provided for illustrative purposes only and is not intended to be limiting of the scope 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. 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 provide additional details regarding implementation. Publications and other materials used herein for purposes of illustration are incorporated by reference. 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 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 explanation 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 specific E3 ubiquitin ligases, and PTMs bind to and recruit target proteins, bringing them into close proximity to the E3 ubiquitin ligase. Typically, E3 ubiquitin ligases, in complex with E2 ubiquitin-binding proteins, catalyze the attachment of ubiquitin to lysines on target proteins via an isopeptide bond (dark circle), either alone or via the E2 protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 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. [Figure 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 of 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. [Figure 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] to [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 INVENTION

[0048] The following detailed description is provided to aid those skilled in the art in practicing the present disclosure. Those skilled in the art will be able to readily 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 by reference in their entirety. Explicitly incorporated.

[0049] E3 ubiquitin ligase proteins (e.g., inhibitors of apoptosis (IAPs), von Hippel-Zoster (VZ) Venous ligase (VHL), cereblon E3 ubiquitin ligase, and is a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase and a target protein. 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 Thus, the present disclosure provides a method for the preparation of E-protein target binding moieties (PTMs) conjugated to E-protein target binding moieties (PTMs). 3. Compounds and compositions containing ubiquitin ligase binding moieties (ULMs) This allows for the ubiquitination of selected target proteins (e.g., estrogen receptor [ER]). This leads to the degradation of the target protein by the proteasome (see Figures 1A and 1B). The present disclosure also provides libraries of compositions and uses thereof.

[0050] In certain embodiments, the present disclosure provides methods for the preparation of, for example, small molecule ligands (i.e., 2,000, 1,000, 500 or and the like) have a molecular weight of less than 200 daltons. The ligands are E3 ubiquitins, such as IAPs, VHL, MDM2, or cereblon. The moiety can bind to a target protein (e.g., ER) and It places the protein in close proximity to an E3 ubiquitin ligase, allowing for its degradation (and / or inhibition) ) can bind to the target protein to produce a small molecule. This means that the molecule is non-peptidyl, i.e., has fewer than, for example, 4, 3, or 2 amino acids. In many cases, they are not considered peptides, as they contain amino acids that are not present 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 herein 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] Where 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 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 a 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 boundary values ​​in the specified ranges. If one or both of the boundary values ​​are included, then either or both of the included boundary values ​​must be excluded. The scope of the present disclosure also includes the above.

[0053] The following terms are used to describe this disclosure. If a term is not defined, it is assumed that the term is used in connection with its use in describing this disclosure. is given its art-recognized meaning by those of ordinary skill in the art applying the term.

[0054] As used herein, the articles "a" and "an" are used interchangeably with "a" and "an" unless the context clearly dictates otherwise. Unless otherwise indicated, one or more of the grammatical objects of the article (i.e. As an example, "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, "and / or" means The phrase "either or both" means "either or both" of the elements so combined. It should be understood that in some instances the elements are present in a conjugated fashion and in other instances they are present in a non-conjugated fashion. Multiple elements listed with "and / or" should be construed in the same manner. "and / or" means that "one or more" of the elements are so combined. The fact that other elements than those specifically identified by the "" clause are Thus, non-limiting examples include: When used in conjunction with open-ended language, such as "including," "A and / or B" In one embodiment, the reference to A refers only to A (optionally including elements other than B) and not to another. In some embodiments, it refers to only B (optionally including elements other than A), and in other embodiments, In this case, it refers to both A and B (and optionally includes other elements).

[0056] As used herein in the specification and claims, "or" means any of the above. It 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" is inclusive. i.e., any one of many elements or a list of elements. Both include one, but also include more than one, and optionally include additional items not listed. For example, "only one of," or "exactly one of," or when used in a claim. 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, "either," "one of," or "one of" Only when preceded by an exclusive term such as "only one of" or "exactly one of" Those that indicate 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" g), "involving", "holding", "composed of All transitional phrases, such as "f)" are open-ended, i.e., include but are not limited to "consisting of" and "essentially consisting of" should be understood to mean Only the transitional phrase "consisting essentially of" is definite or semi-definite, respectively. The term "patentable" is a transitional phrase, as set forth in Section 2111.03 of the United States Patent Examining Guidelines. 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. , and does not necessarily include at least one of all elements specifically listed in the element list. 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 element 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" is at least one of" (or equivalently "at least one of A or B" or equivalently "A and and / or B) may, in one embodiment, optionally be a plurality of A It refers to at least one A containing elements A and no B (optionally including elements other than B). In the embodiment, it refers to at least one B, optionally including multiple Bs, and A is absent (optionally). In yet another embodiment, at least one element optionally containing multiple A's is Both refer 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 method steps or actions may be different from the order in which the method steps or actions are recited unless the context indicates otherwise. The order in which the data 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 different times than the administration of the additional therapeutic agent(s); In certain preferred embodiments, the methods described herein refer to both administration at a time that is convenient for the patient and administration at a time that is convenient for the patient. 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 the compound of interest. It refers to any specific chemical compound disclosed in this document, including tautomers, positional isomers, geometric isomers, and the like. and, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereoisomers). stereoisomers, including phenanthrene (stereoisomers), and prodrugs and / or prodrugs thereof, where appropriate in the context. or deuterated forms thereof, and pharmaceutically acceptable salts and derivatives thereof. A small molecule is a drug in which one or more 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 of the disclosed compounds (including racemic mixtures) as well as other compounds such as specific enantiomers or mixtures enriched in specific enantiomers. The term may also be used in context to facilitate administration and delivery of the compound to the site of activity. In describing the compounds, many 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 present in the compounds shown, and 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 a specific substrate protein. This refers to a family of proteins that promotes degradation and targets their substrate proteins for degradation. ubiquitination, either alone or in conjunction with an E2 ubiquitin-conjugating enzyme, to lysines on target proteins. IA, which adds a cleavage inhibitor to the target protein substrate, subsequently targeting that 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 leads to 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 limited to monoubiquitination, in which case only one Only ubiquitin is added to the substrate molecule by the ubiquitin ligase. The proteins that are isolated are not targeted for proteasomal degradation but are instead degraded by, for example, ubiquitin. through binding to other proteins that have domains capable of binding chitin. Further complicating the issue is the ability of ubiquitin to alter the intracellular location and function of the ubiquitin. Another lysine on chitin can be targeted by E3 to form the chain. The lysine involved is Lys48 on the ubiquitin chain, which is recognized by the proteasome. It is the lysine used to generate polyubiquitin.

[0064] The terms "patient" or "subject" are used throughout this specification to refer to a patient who is receiving a composition according to the present disclosure. To describe the animal, preferably a human or livestock, to which treatment, including prophylactic treatment, is provided. For example, to treat an infection, condition, or pathology specific to a particular animal, such as a human patient. In medical treatment, the term patient refers to a domestic animal, e.g., a dog or cat, or a human, e.g., a horse. In general, in this disclosure, patients and The term "product" is used unless otherwise indicated or implied from the context in which it is used. Unless otherwise specified, the term refers to a human patient.

[0065] The word "effective" when used within the context of its intended use It 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. otherwise described or used in

[0066] Compounds and Compositions In one embodiment, the present disclosure provides IAP E3 ubiquitin ligase binding moieties (ILMs), selenium, and erythrocyte segregation proteins. 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 as a compound comprising: 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 same unless the context indicates otherwise. The term ULM is used in a comprehensive sense. For example, the term ULM includes IAP (i.e., ILM), MDM2 ( those that bind to 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 HL-binding moiety encompasses all cereblon-binding moieties, and 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 polysaccharides Sensuality The present invention provides a novel therapeutic 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 I In certain embodiments, ILM / VLM / CLM / MLM and PTM are linked or attached via a chemical linker (L). ILM binds to the IAP E3 ubiquitin ligase VLM binds to VHL, CLM binds to cereblon E3 ubiquitin ligase, and The MLM and MLM bind to the MDM2 E3 ubiquitin ligase, and the PTM recognizes the target protein. By recognizing the target protein and placing the ubiquitin ligase protein in close proximity, The interaction of the moiety with its target promotes the degradation of the target protein. Government Noh The reactive compound may be depicted 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 moiety, and CLM is the cereblon E3 ubiquitin ligase binding moiety. 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 and E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, etc.). chitin ligase, VHL, MDM2 E3 ubiquitin ligase) or binds to 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 contain multiple PTMs (same or different proteins). targeting a protein target), multiple ULMs, more than one ULM (i.e., multiple / different E3 ubiquitins), Moieties that specifically bind to ligases, e.g., VHL, IAP, cereblon, and / or MDM2 ) or combinations thereof. Therefore, the PTM and ULM (e.g., ILM, VLM, CLM, and / or MLM) may be directly or via one or more They may be attached via chemical linkers, or combinations thereof. In this state, if a compound has multiple ULMs, those 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 the protein.

[0072] In certain embodiments, when a compound comprises multiple ULMs, the ULMs are the same. In certain embodiments, the compound may be a combination of multiple ULMs (e.g., ULM, ULM'), direct or chemical phosphorus. It comprises at least one PTM linked to a ULM 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 ULMs'. In further embodiments, at least two different ULMs, multiple ULMs, and / or multiple Compounds containing ULM's can be attached directly, via chemical linkers, or both. The embodiments described herein further comprise at least one PTM linked to a 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 the same or optionally In yet a further embodiment, when the PTMs are different, each PTM is associated with the same protein. It may bind to a protein target or may specifically bind to different protein targets. In further embodiments, the PTM itself may be, for example, an ILM, VLM, CLM, MLM, ILM', VLM', CLM' , and / or a ULM (or ULM'), such as MLM'.

[0074] In additional embodiments, the present disclosure relates to enantiomers, diastereomers, solvates and and polymorphs thereof, including pharmaceutically 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 compounds of Formula (I) or Formula (II):

[0076] [ka]

[0077] During the ceremony: each X PTM are independently CH, N; ULM is ILM or VLM or CLM or MLM; L is a tetrahydronaphthalene or tetrahydroisoquinoline moiety and VLM, C A coupling portion that couples 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 TeR 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, CF3, straight or branched chain alkyl, alkoxy (e.g., methoxy or ethoxy), where the substitution is mono- or di-substituted. Well, often; Each R PTM3 are independently H, halogen, and the substitutions may be mono- or di-substituted. and RPTM4 is H, alkyl, methyl, ethyl.

[0078] A target protein (e.g., 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 allow the synthesis of a desired polypeptide. The PTM group by the method specifically binds to, for example, the estrogen receptor (binding to the target protein). The compositions described below include a series of small molecule target protein binding moieties. Examples of such small molecule target protein binding moieties include: Pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of the subject proteins These binding moieties preferably include a linker. ubiquitin ligase binding moiety via the ubiquitin ligase. target protein (to which the 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 such that the protein is deregulated and the patient is unable to degrade the protein and / or includes any disease state and / or condition that would benefit from inhibition.

[0080] In an additional aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject an effective amount of a compound described herein or a salt form thereof, and and a pharmaceutically 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 regulates the degradation and / or inhibition of proteins in the presence of a steroid hormone, and the degradation and / or inhibition of proteins is inhibited. The present invention relates to the treatment or amelioration of 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 additional embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, or a combination thereof.

[0081] In another aspect, the present disclosure provides a method for degrading a protein or polypeptide, thereby Methods for treating a condition or ameliorating the symptoms 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 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, is administered to a subject, optionally with a pharmaceutically acceptable carrier, additive, or excipient, and and optionally an additional bioactive agent, wherein the composition is administered in combination with the The disclosed method is useful for treating or ameliorating a disease or disorder or a symptom thereof in an elephant. Administration of an effective amount of at least one compound described herein may be used to treat 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, bacterium, fungus, protozoan, 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 causes the condition.

[0082] In another aspect, the present disclosure provides methods for treating cancer in biological systems using compounds according to the present disclosure. A method for identifying the degradative effect 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 proteins or polypeptides that are targets for degradation by ubiquitin ligases. Such small molecule target protein binding moieties are used to and the like, as well as suitable salts, enantiomers, solvates, and polymorphs thereof, e.g., estrogen receptors. These binding moieties also include other small molecules that can target proteins of interest, such as receptors. 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, and binds to the protein 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 exemplify 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 present invention are also disclosed. Also included are other small molecules that can target proteins of interest. The references are incorporated herein by reference in their entireties.

[0086] Exemplary ILM AVPI tetrapeptide fragment In any of the compounds described herein, the ILM may be alanine-valine-proline. The peptide may comprise an acetylcholine-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):

[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 ring or piperidin ring. 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 cyclo 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- to 8-membered rings The ring can be further optionally 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 alkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl and each of the alkyl, aryl, and heteroarylalkyl groups is selected from the group consisting of arylalkyl, heteroaryl, and heteroarylalkyl, each of which is further selected from the group consisting of arylalkyl, heteroaryl, and heteroarylalkyl, optionally halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (heteroalkyl) substituted with 1 to 3 substituents selected from (hetero)cycloalkyl, or (hetero)aryl; or R 7 is -C(O)NH-R 4 and R 4 is an alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkyl, Heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl and 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 (V) is a tetrapeptide fragment or a non-natural mimetic thereof, such as A, V, P, and 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 peptides may have the structure of natural mimetics, such as the IAP antagonists described in WO 2008 / 014236. or a pharmaceutically acceptable salt or hydrate thereof.

[0091] [ka]

[0092] During the ceremony: R1 in formula (VI) is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3- C 1O -cycloalkyl, which are unsubstituted or substituted; R2 in formula (VI) is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3- C 1O -cycloalkyl, which are unsubstituted or substituted; R3 in formula (VI) is H, -CF3, -C2H 5、 C1-C4-Alkyl, C1-C4-Alkenyl, C1-C4-Alkyny -CH2-Z, or any of R2 and R3 together form a heterocyclic ring; Each Z in formula (VI) is H, —OH, F, Cl, —CH 3、 -CF 3、 Independently of -CH2Cl, -CH2F or -CH2OH and selected; R4 in formula (VI) is C1-C16 straight or branched chain alkyl, C1-C 16 -Alkenyl, C1-C 16 -a Rukynyl, C3-C 10 -cycloalkyl, -(CH2) 0-6 -Z 1、 -(CH2) 0-6 -aryl, and -(CH2)0 -6 -het, wherein alkyl, cycloalkyl, and phenyl are unsubstituted is or is replaced by; R5 in formula (VI) is H, C 1-10 -Alkyl, aryl, phenyl, C 3-7 -cycloalkyl, -(CH 2) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -Alkyl-aryl, -(CH2) 0-6 -C 3-7 -Cycloalkane Ru-(CH2) 0-6 -phenyl, -(CH2) 0-4 -CH[(CH2) 1-4 -phenyl] 2、 Indanyl, -C(O)-C 1-10 - Alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-(CH2) 0-6 -phenyl, - (CH2) 0- 6-C(O)-phenyl, -(CH2) 0-6 -het, -C(O)-(CH2) 1-6 -het is selected independently, or and R5 is selected from the residue of an amino acid, wherein alkyl, cycloalkyl, phenyl, and and the aryl substituents are unsubstituted or substituted; Z1 in formula (VI) is —N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 1O )-C(O)-(CH2)0-6 -C 3-7 -Cycloa Rukill, -N(R 10 )-C(O)-(CH2) 0-6 -phenyl, -N(R 10 )-C(O)(CH2) 1-6 -het, -C(O)-N(R 11 )(R 12 ), -C(O)-OC 1-10 -Alkyl, -C(O)-O-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -phenyl, -C(O)-O-(CH2) 1-6 -het, -OC(O)-C 1-10 -Alkyl, -OC(O)-(CH2) 1-6 -C 3- 7-Cycloalkyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -Selected independently from het 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 heterocyclic ring or rings 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、 selected from —CF3, —CH2OH, or —CH2Cl; R in formula (VI) 11 and R 12 is H, C 1-4 -Alkyl, C 3-7-cycloalkyl, -(CH2) 1-6 -C 3-7 - Cycloalkyl, (CH2) 0-6 -phenyl, wherein alkyl, cycloalkenyl, alkyl and phenyl are unsubstituted or substituted; or R 11 and R 12 is nitrogen and 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 O, S or is substituted with a heteroatom selected from N, wherein each alkyl is independently unsubstituted. or replaced; R in formula (VII) d is Re-Q-(R f ) p (R g ) q、 and selected from the group Ar1-D-Ar2; R in formula (VII) c is selected from the group of H or any R c and R d Both are cycloalcoholic Kill or form a het, R c and R d When R5 forms a cycloalkyl or het, is bonded to the formed ring at 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 - selected from the group of alkyl and alkylidene, each Re being unsubstituted; be or be replaced; Q is selected from the group N, O, S, S(O) and S(O)2; Ar1 and Ar2 in formula (VII) are 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, - (CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl Nyl, aryl, phenyl-phenyl, -(CH2) 1-6 -het, -O-(CH2) 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-C1 -4 -alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted. Exchange or substituted -SO2-C 1-2 -Alkyl, -SO2-C 1-2 -Alkylphenyl, -OC 1-4 -Alkyl or any R g and R f together form a ring selected from het or aryl ; D in formula (VII) is -CO-, -C(O)-C 1-7 -Alkylene or arylene, -CF2-, -O-, -S(O) r of wherein r is 0 to 2 1,3-dioxalanes, or C 1-7 -Alkyl-OH wherein alkyl, alkylene or arylene is unsubstituted or substituted with one or more halides. Rogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -substituted with -alkyl, or -CF3; or each D are independent and 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, -SO2-C 1-10 -Alkyl, or -SO2 -(C 0-10 -alkylaryl); R6, R7, R8 and R9 in formula (VII) are independently H, -C 1-10 -Alkyl, -C 1-10 -alkoxy , aryl-C 1-10 -Alkoxy, -OH, -OC 1-10-Alkyl, -(CH2) 0-6 -C 3-7 -Cycloalkane Le, -O-(CH2) 0-6 -aryl, phenyl, -(CH2) 1-6 -het, -O-(CH2) 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-NR1 3R 14、 or -NR 13 -S(O)2-R 14 wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted; and any of R6, R7, R8 and R9 optionally together form a ring system; R in formula (VII) 13 and R 14 are independently H, C 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -Cycloal Kill, -(CH2) 0-6 -(CH) 0-1 -(aryl) 1-2、 -C(O)-C 1-10 -Alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -aryl, -C(O)-(CH2) 0-6 -O-Fluorenyl, -C(O) -NH-(CH2) 0-6 -aryl, -C(O)-(CH2) 0-6 -aryl, -C(O)-(CH2)0.6-het, -C(S)-C 1-10 - Alkyl, -C(S)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(S)-O-(CH2) 0-6 -aryl, -C(S)-( CH2) 0-6 -O-Fluorenyl, -C(S)-NH-(CH2) 0-6 -aryl, -C(S)-(CH2) 0-6 -aryl, or -C(S)-(CH2) 1-6 -het, wherein each alkyl, cycloalkyl, and Aryl is unsubstituted or substituted; or any R 13 and R 14 is a nitrogen atom Also formed a het; where R in formula (VII) 13 and R 14 wherein the alkyl substituents are unsubstituted or substituted; If replaced, C 1-10 -Alkyl, halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -Al substituted by one or more substituents selected from -CF3, -CF4, -CF5, -CF6, -CF7, -CF8, -CF9, -CF10, -CF11, -CF12, -CF13, -CF14, -CF15, -CF16, -CF17, -CF18, -CF19, -CF20, -CF21, -CF22, -CF23, -CF24, -CF25, -CF26, -CF27 13 and R 14 The substituted phenyl or aryl of 1-4 -Alkyl, C 1-4 -a Alkoxy, Nitro, -CN, -OC(O)-C 1-4 -Alkyl, and -C(O)-OC 1-4 -Select from aryl The group is substituted with one or more substituents selected from the group consisting of aryl, ...

[0095] In certain embodiments, the compound comprises at least one additional independently selected linker an independently selected group attached to an ILM of formula (VI) or a non-natural mimetic thereof; In one embodiment, the second ILM is a derivative of formula (VI) or a derivative thereof In certain embodiments, at least one additional independently selected non-naturally occurring mimetic of The selected linker groups chemically link the ILM and the second ILM together. In one embodiment, an ILM of formula (VI) or a non-natural mimetic thereof comprises a linker group At least one additional linker group to 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 of 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 A1 and A2 in formula (VIII) each independently represent an optionally substituted single ring, fused ring, selected from 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 may be represented by the following formula (IX): The IAP antagonist may have a structure similar to that of 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) derived from the cross-referenced chemical species:

[0107] [ka]

[0108] In the formula, R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, most preferably Preferably, 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 Mannhold, R., et al. IAP antagonists: promising candidates or cancer therapy, Drug Discovery Today, 15 (5-6), 210-9 (2010) Derived from chemical species that:

[0110] [ka]

[0111] During the ceremony: R in formula (X) 1 is H, -CH2OH, --CH2CH2OH, --CH2NH 2、 --CH2CH2NH2; X in formula (X) is selected from S or CH2; R in formula (X) 2 is selected from the following:

[0112] [ka]

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

[0114] [ka]

[0115] In the formula, R in formula (XI) 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 may be of 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 the following:

[0120] [ka]

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

[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 of formula (XIII), or a non-natural 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 the following:

[0129] [ka]

[0130] R 10 is selected from H, alkyl, or aryl; X is selected from CH2 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 4are independently selected from H or Me; R in formula (XIV) 1 is selected from the following:

[0135] [ka]

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

[0137] [ka]

[0138] X is selected from CH2 and 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 rigor 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 ligands can be a natural mimetic, such as those 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 the following:

[0146] [ka]

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

[0148] [ka]

[0149] X is selected from CH2 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 following 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 ligands may be a natural mimetic, such as those 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 is selected from aryl, most preferably 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 of formula (XVII), or a non-natural The structure of the compound can be a natural mimetic, as described in Cohen, F. et al., Antagonists of inhib 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 selected from the group of O or CH2.

[0164] In any of the compounds described herein, the ILM may have the structure of formula (XVIII): This is because 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 alkyl, aryl, heteroaryl, arylalkyl, heteroaryl, 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 due to 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 six-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 of formula (XX), or a non-natural The structure of the IAP ligands may be a natural mimetic, such as those described in WO 2007 / 101347. Based on:

[0176] [ka]

[0177] X in formula (XX) is selected from CH2, 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 the following:

[0180] [ka]

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

[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 may be represented by formula (XXII) or formula (XXI) II), or a non-natural mimetic thereof, which can be found in 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 pharmaceutically acceptable salts thereof. 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 thioacids. alkyl, wherein the substituent attached to the S atom of the thioalkyl is an optionally substituted alkyl. alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 Selected from ; -CH2CHR 21 COR2 R 21 is NR 24 R 25 selected from the group consisting of: -CH2R 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, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH2O) m C H3, 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, is a halogen or NH2; 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 optionally substituted heteroaryl; wherein the substituents are selected from alkyl, halogen, n or OH; R of formula (XXII) or formula (XXIII) 5 , R6 , R 7 and R 8 are independently hydrogen, optionally substituted alkyl, 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] where "*" is the point of attachment 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 mimic thereof, and may have a phosphoryl group as shown below. The structures may have a chemical linker to the carbo-group L, as 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 pharmaceutically acceptable salt, tautomer, or the like thereof. Isomers or stereoisomers:

[0197] [ka]

[0198] During the ceremony: R of formula (XXIV), formula (XXV) or formula (XXVI) 1 is 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 optionally substituted alkyl, substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl Selected from; or alternatively, R of formula (XXIV), formula (XXV) or formula (XXVI) 1 and R 2 are independently an optionally substituted chi wherein the substituent attached to the S atom of the thioalkyl is optionally substituted. optionally substituted branched alkyl, optionally substituted heterocyclyl, -( CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 Selected from ; -CH2CHR 21 COR 2 R 21 is NR 24 R25 Selected from; -CH2R 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, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH2O) m C H3, 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, is a halogen or NH2; 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 R8 are independently hydrogen, any is alkyl substituted with , 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 may be 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 heterodimes. eric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014) and / or pharmaceutically acceptable salts, tautomers or derivatives thereof derived from IAP ligands. Most are stereoisomers:

[0204] [ka]

[0205] During the ceremony: R 35 is 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 alternatively, R of formula (XXVII) and formula (XXVIII) 1 and R 2 is an optionally substituted thioalkyl-CR 60 R 6 1 SR 70 wherein R is independently selected from 60 and R 61 is selected from H or methyl, and R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted heterocyclic alkyl, Isocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 is selected from During the ceremony: v is an integer from 1 to 3; -(CH2) v COR 20 and -CHCHR 21 COR 22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH2CHR 21 COR 22 R 21 is NR 24 R 25 Selected from; -CH2R 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, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3, or -[CH2CH2(CH2 )δNH]ψCH2CH2(CH2)ωNH2; In the formula, δ=0~2, ψ=1~3, ω=0~2; OR 26 R 26 is optionally substituted alkyl, where the optional substituents are OH, halogen, is NH2 or NH2; and m is an integer from 1 to 8; R of formula (XXVII) and formula (XXVIII) 3and R 4 are 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 and optionally substituted heterocycloalkyl, wherein 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 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 or selected from the group consisting of:

[0206] [ka]

[0207] X in formulas (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] wherein o and p are independently 0, 1, 2, or 3;

[0218] [ka]

[0219] wherein 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, such as those 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 an alkyl group selected from an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aryl alkyl group, or an optionally substituted aryl group; ; or alternatively, R of formula (XXVII) and formula (XXVIII) 1 and R 2 is H, optionally substituted thioalkyl-CR 6 0 R 61 SR 70 wherein R is independently selected from 60 and R 61 is selected from H or methyl, and R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted hydroxyl group, Tetracyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and; During the ceremony: v is an integer from 1 to 3; -(CH2) v COR 20 and -CHCHR 21 COR 22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH2CHR 21 COR 22R 21 is NR 24 R 25 Selected from; -CH2R 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, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3, or -[CH2CH2(CH2 )δNH]ψCH2CH2(CH2)ω r NH2, In the formula, δ=0~2, ψ=1~3, ω=0~2; OR 26 R 26 is optionally substituted alkyl, where the optional substituents are OH, halogen, NH2 or NH2; 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, aryl and preferably selected from the group consisting of aryl alkyl, heteroaryl, and heteroaryl alkyl. 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 of formula (XXXIII) or a non- These may have a structure mimicking a natural type, and these are described in WO2014 / 074658 and WO 2013 / 071035 Derived from the IAP ligands 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, optionally selected from substituted arylalkyl, or optionally substituted aryl; R in formula (XXXIII) 6 and R 8 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R in formula (XXXIII) 32 is (C1-C4 alkylene)-R 33 wherein R 33 is optionally further selected from hydrogen, aryl, heteroaryl, or cycloalkyl substituted with; X in formula (XXXIII) is selected from:

[0231] [ka]

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

[0233] [ka]

[0234] During the ceremony, each

[0235] [ka]

[0236] represents the 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, NHSO2R 10 , NHOR 11 or N(R 12 )(R 13 ) are selected from; NHSO2R 10 and NHOR 11 R 10 and R 11 are independently hydrogen, optionally substituted -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocycloalkenyl Selected from kill; N(R 12 )(R 13 )R 12 and R 13 are independently hydrogen, -C1-C4 alkyl, -(C1-C4) alkylene)-N H-(C1-C4 alkyl), and -(C1-C4 alkylene)-O-(C1-C4 hydroxyalkyl) Selected or R 12 and R 13 are N, O and and S to form 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 may be of formula (XXXIV) or formula (XX XV), or a non-natural mimetic thereof, which are described in WO 2014 / 047024 and / or pharmaceutically acceptable salts, tautomers, or derivatives thereof derived from the IAP ligands described above. isomers, or stereoisomers:

[0259] [ka]

[0260] During the ceremony: X in formula (XXXIV) or (XXXV) 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 alkyl, alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and v is an integer from 1 to 3; -(CH2) v COR 20 and -CHCHR 21 COR 22 R 20 and R 22 are independently OH, NR 24 R 25 OR 26 from Selected; -CH2CHR 21 COR 22 R 21 is NR 24 R 25 Selected from; -CH2R 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, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH 20 ) m C H3, or a polyamine chain; R 26is optionally substituted alkyl, where the optional substituents are OH, halogen or or NH2; -(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 optionally substituted heteroaryl; wherein the substituents are selected from alkyl, halogen, n or OH; R of formula (XXXIV) or formula (XXXV) 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally 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 13can 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 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; and 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 of 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 a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. It is an isomer:

[0268] [ka]

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

[0270] [ka]

[0271] where the dotted line represents an optional double bond; X in formula (XXXVI) is selected from the following: -(CR 21 R 22 ) m -,

[0272] [ka]

[0273] Y and Z in formula (XXXVI) 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 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 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, or Preferably it is methyl;

[0274] [ka]

[0275] R 9 and R 10 are 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 is 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] wherein 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 may be of formula (XXXVII) or formula (X XXVIII), or a non-natural mimetic thereof, which is described in WO 2014 / 011712 or a pharmaceutically acceptable salt, tautomer thereof, derived from an IAP ligand described in or a stereoisomer:

[0286] [ka]

[0287] During the ceremony: X in formula (XXXVII) and 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 selected independently 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, optionally selected from 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 alkyl alkyl, or optionally substituted cycloalkyl, or preferably methyl; and;

[0290] [ka]

[0291] R 9 and R 10are 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 be; OR 15 R 15 is 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 alkyl groups. 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] 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 may be represented by formula (XXXIX) or formula (XL ), or a non-natural mimetic thereof, which are described in WO2013 / 071039 Derived from IAP ligands listed:

[0303] [ka]

[0304] During the ceremony: R of formula (XXXIX) and formula (XL) 43 and R 44 are independently further optionally substituted halo alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl cycloalkyl, cycloalkylalkyl, and R of formula (XXXIX) and formula (XL) 6 and R 8 are independently hydrogen, optionally substituted alkyl, cycloalkyl, 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 foregoing tautomeric forms, wherein: -C(O)R 3 R 3 OH, NHCN, NHS02R 10 , NHOR 11 or N(R 12 )(R 13 ) are selected from; NHS02R 10 and NHOR 11 R 10 and R 11are independently -C1-C4 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, —C1-C4 alkyl, —(C1-C4 alkylene -NH-(C1-C4 alkyl), benzyl, -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)CH3, -CH(benzyl)-COOH, -C1-C4 alkoxy, and -(C1-C4 alkylene)-O-(C1-C4 hydroxyalkyl); or N(R 12 )(R 13 )R 12 and R 13 together with the nitrogen atom to which they are commonly bonded, are selected from N, O and S. forming a saturated heterocyclyl optionally containing two additional heteroatoms, wherein the saturated hetero The ring is optionally methyl substituted.

[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, NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLI) 2are O, S, NR A , or C(R 8c )(R 8d ) where W 1 and W 2 is both nor O, or neither S; R in formula (XLI) 1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1 -C6 alkyl-(substituted or unsubstituted heteroaryl); X 1 But, O, NR A , S, S(O), or S(O)2, then X 2 is C( R 2a R 2b ) and; or: X in formula (XLI) 1 is CR 2c R 2d Choose from difference Re, X 2 is 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, unsubstituted, saturated, or 3- to 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 is selected from CH2, and X 2 is C=0, C=C(R C )2, or C=NR C and; here At each R c are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2 -C5 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), or -C1- C alkyl-(substituted or unsubstituted heteroaryl); NR A R A is H, C1-C6 alkyl, —C(═O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d and CR 2a R 2b R 2a , R 2b , R 2c , R 2d are independently H, substituted or unsubstituted C1-C6 alkyl alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl; substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1 -C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted C2-C5 heterocycloalkyl), or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O )R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl alkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl -C1-C6 alkyl- (substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 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)2NH-, -NHC(=O)NH-, -NH selected from (C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLI) 3 is selected from C1-C3 alkyl, or C1-C3 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 independently H, C1-C3 alkyl, C1-C3 halo -C1-C3 alkyl-(C3-C5 cycloalkyl) Selected; or: R in formula (XLI) 3 and R 5 form substituted or unsubstituted 5- to 7-membered rings 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)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,- (C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2 R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)- NHS(=O)2NHR 7 Each R 7 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl Kill, Replace or Not Replace C3-C 10 Cycloalkyl, substituted or unsubstituted C2- C 10 Heterogeneity chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted Substitution C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) 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 heteroaryl)-(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 is H, C1-C6 alkyl, C1-C6 fluorine C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl. Selected from the rules; 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 together with the atoms or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted a substituted fused 5- to 10-membered aryl ring or a heteroatom containing 1 to 3 heteroatoms selected from S, O and N; forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having the following structure; 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. or forming 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 together with the atoms forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 is replaced by ; and R 8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C1-C4 alkoxy alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -N H(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl), -O(C -O(C1-C4 alkyl)-NH2; -O(C1-C4 alkyl)-NH-(C1-C4 alkyl), and -O(C1-C4 alkyl)- N-(C1-C4 alkyl)2, or two R 9 along with the atoms to which they are bonded , halogen, —OH, or C1-C3 alkyl substituted or unsubstituted methylenedione 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, NR A , or C(R 8a )(R 8b ) and; W in formula (XLII) 2 are O, S, NR A , or C(R 8c )(R 8d ) where W 1 and W 2 are both O not or neither S; R in formula (XLII) 1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-( substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 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 When is selected from S, S(O) or S(O)2, X 2 is CR 2c R 2d and X 3 is CR 2a R 2b and; or: X in formula (XLII) 1 If 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 If is CH3, X 2 , O, NR A , S, S(O), or S(O)2; and X 3 is CR 2a R 2b and; X in formula (XLII) 1 is 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 CR2a R 2b and; or: X in formula (XLII) 1 and X 3 are both CH2, 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 C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 cycloalkyl Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or is unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 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, unsubstituted, saturated, or 3- to 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, unsubstituted, saturated, or 3- to 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 is CR 2e R 2f and; NR A R A is H, C1-C6 alkyl, —C(═O)C1-C2 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 are independent, H , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or Unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl ), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted hexamethyl -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl alkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl -C1-C6 alkyl- (substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 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)2NH-, -NHC(=O)NH-, -N selected from -H(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLII) 3 is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLII) 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 independently H, C1-C3 alkyl, C1-C3 halo -C1-C3 alkyl-(C3-C5 cycloalkyl) Selected; or: R in formula (XLII) 3 and R 5 form substituted or unsubstituted 5- to 7-membered rings 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)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,- (C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2 R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)- NHS(=O)2NHR 7 Each R 7 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl Kill, Replace or Not Replace C3-C 10 Cycloalkyl, substituted or unsubstituted C2- C 10 Heterogeneity chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted Substitution C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) 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 heteroaryl)-(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 is H, C1-C6 alkyl, C1-C6 fluorine C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl. Selected from the rules; 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 together with the atoms or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted a substituted fused 5- to 10-membered aryl ring or a heteroatom containing 1 to 3 heteroatoms selected from S, O and N; forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having the following structure; 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. or forming 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 together with the atoms forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 is replaced by ; and R 8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C1-C4 alkoxy alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -N H(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl), -O(C -O(C1-C4 alkyl)-NH2; -O(C1-C4 alkyl)-NH-(C1-C4 alkyl), and -O(C1-C4 alkyl)- N-(C1-C4 alkyl)2, or two R 9 along with the atoms to which they are bonded , halogen, —OH, or C1-C3 alkyl substituted or unsubstituted methylenedione 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, NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLIII) 2 are O, S, 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 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-( substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIII) 1 But NR A , S, S(O), or S(O)2, X in formula (XLIII) 2 is CR 2c R 2d and X of formula (XLIII) 3 is CR 2a R2b and; or: X in formula (XLIII) 1 is O, then X in formula (XLIII) 2 , O, NR A , S, S(O), or S(O)2 and X of formula (XLIII) 3 is CR 2a R 2b and; or: X in formula (XLIII) 1 is CR 2e R 2f and X in formula (XLIII) 2 is CR 2c R 2d If R 2e and R 2c together 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 partially saturated 3- to 10-membered cycloalkyl ring, fused, substituted or unsubstituted, saturated or partially 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 is 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 partially saturated 3- to 10-membered cycloalkyl ring, fused, substituted or unsubstituted, saturated or partially 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 (VLII)X 1 is CR 2e R 2f and; NR A R A is H, C1-C6 alkyl, —C(═O)C1-C2 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 are independent, H , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or Unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl ), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted hexamethyl -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl alkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl -C1-C6 alkyl- (substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 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)2NH-, -NHC(=O)NH-, - NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLIII) 3 is C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLIII) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 OR -OR 5 and; -NHR 5 , -N(R5 )2, -N+(R 5 )3, and -OR 5 Each R 5 are independently H, C1-C3 alkyl, C1-C3 halo -C1-C3 alkyl-(C3-C5 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)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C 3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,- (C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2 R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)- NHS(=O)2NHR 7 Each R 7 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl Kill, Replace or Not Replace C3-C 10 Cycloalkyl, substituted or unsubstituted C2- C 10 Heterogeneity chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted Substitution C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) 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 heteroaryl)-(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 , R 8b , R 8c , and R 8d is H, C1-C6 alkyl, C1-C6 fluorine C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl. Selected from the rules; 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 together with the atoms or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted a substituted fused 5- to 10-membered aryl ring or a heteroatom containing 1 to 3 heteroatoms selected from S, O and N; forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having the following structure; 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 together with the atoms forms 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 together with the atoms forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring; where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 is replaced by ; and R 8a , R 8b , R 8c and R 8d Each R 9 are independently halogen, -OH, -SH, (C=O), CN, C1-C4 alkoxy alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -N H(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O)C1-C3 alkyl -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl), -O(C -O(C1-C4 alkyl)-NH2; -O(C1-C4 alkyl)-NH-(C1-C4 alkyl), and -O(C1-C4 alkyl)- N-(C1-C4 alkyl)2, or two R 9 along with the atoms to which they are bonded , halogen, —OH, or C1-C3 alkyl substituted or unsubstituted methylenedione 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 can be derived from the IAP ligands described in WO 2013 / 071039:

[0334] [ka]

[0335] During the ceremony: W in formula (XLIV) 1 are O, S, NR A , or C(R 8a )(R 8b ) are selected from; W in formula (XLIV) 2 are O, S, 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, NR A , or C(R 8e )(R 8f ), where W 1 , W 2 and W 3 does not contain two adjacent oxygen or sulfur atoms; R in formula (XLIV) 1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-( substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or is unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIV) 1 When is O, X in formula (XLIV)2 is CR 2c R 2d and N.R. A is selected from the formula (XLIV) W 3 is CR 2a R 2b and; or: X in formula (XLIV) 1 is CH2, X in formula (XLIV) 2 , O, NR A , S, S(O), or S(O)2 X of formula (XLIV) is selected from 3 is CR 2a R 2b and; or: X in formula (XLIV) 1 is CR 2e R 2f and X in formula (XLIV) 2 is CR 2c R 2d If 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 are both CH2, 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 C1-C6, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 Alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 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, unsubstituted, saturated, or 3- to 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 having the formula (X LIV)'s X 3 is 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, unsubstituted, saturated, or 3- to 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 is CR 2e R 2f and; NR A R A is H, C1-C6 alkyl, —C(═O)C1-C2 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 R2a , R 2b , R 2c , R 2d , R 2e , and R 2f are independent, H , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or Unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl ), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted hexamethyl -C(=O)R B Selected from; -C(=O)R B R B is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl alkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl -C1-C6 alkyl- (substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted Substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or is unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl- (substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl- (substituted or unsubstituted heteroaryl); m in formula (XLIV) is selected from 0, 1 or 2; -U- in formula (XLIV) is -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -N selected from -H(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLIV) 3 is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLIV) 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 independently H, C1-C3 alkyl, C1-C3 halo -C1-C3 alkyl-(C3-C5 cycloalkyl) Selected; or: R in formula (XLIV) 3 and R 5 form substituted or unsubstituted 5- to 7-membered rings 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)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C 3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 -NHC(=O)NHR 7 , -NHS(=O)2NHR 7 ,- (C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2 R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)- NHS(=O)2NHR 7 Each R 7 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl Kill, Replace or Not Replace C3-C 10 Cycloalkyl, substituted or unsubstituted C2- C 10 Heterogeneity chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted Substitution C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl) 2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) 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 heteroaryl)-(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 independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 hetero selected from substituted or unsubstituted alkyl, 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, and R 8b and R 8c along with the atoms to which they are attached, 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, and R 8c and R 8e along with the atoms to which they are attached, S, O and and N. saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted fused 5- to 10-membered aryl ring or substituted or unsubstituted rings 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 atoms to which they are attached Substituted or unsubstituted saturated or partially saturated 3- to 7-membered alkyl acrylates containing 1 to 3 heteroatoms forming a spiro or heterospiro ring; or: C(R 8a )(R 8b ) and C(R 8e )(R 8f )R8a , 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 atoms to which they are attached Substituted or unsubstituted saturated or partially saturated 3- to 7-membered alkyl acrylates 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 atoms to which they are attached Substituted or unsubstituted saturated or partially saturated 3- to 7-membered alkyl acrylates containing 1 to 3 heteroatoms forming a spiro or heterospiro ring; or: where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloa alkyl, heterocycloalkyl, aryl or heteroaryl has 1 to 3 R 9 is 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, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=0)NH2, -C(=O) C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl) alkyl), -O(C1-C4 alkyl)-NH2; -O(C1-C4 alkyl)-NH-(C1-C4 alkyl), and -O(C1- C4 alkyl)-N-(C1-C4 alkyl)2, or two R 9 But they are combined substituted or unsubstituted with halogen, —OH, or C1-C3 alkyl, along with the atom It forms a methylenedioxy ring or an ethylenedioxy ring.

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

[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 the following:

[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 are 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] 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 are 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, an 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 the following:

[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 the following:

[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 may be of formula (LV) or formula (LVI): As shown in Figure 1, the compound has the structure of 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 is of 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:

[0380] [ka]

[0381] [ka]

[0382] wherein 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 bond is shown:

[0385] [ka]

[0386] ; and

[0387] [ka]

[0388] In any of the compounds described herein, the ILM may be selected from the group consisting of the following structures: This is 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 bond is shown:

[0393] [ka]

[0394] ; and

[0395] [ka]

[0396] In any of the compounds described herein, the ILM may be of formula (LVIII), or a non- It can have a structure that mimics 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] wherein X in formula (LVIII) 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 may be 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 formulas (LIX) and (LX) is independently selected from H, halogen, or cyano. and L in formulas (LIX) and (LX) is one or two substituents, and L is any of the groups 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) Derived 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 may be 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 compound 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 of formula (LXIX), or a non- It has a structure that conforms to natural mimics, as 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 2is 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 a straight, branched, or cyclic, fully saturated alkyl group. It is understood that the term "hydrocarbon radical" refers to a hydrocarbon radical or alkyl group, preferably C-C 10 More preferably, it is a C1-C6 or C1-C3 alkyl group, which may be optionally substituted. Examples of alkyl groups are, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-hexyl, Butyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl Propyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentyl ethene cyclohexyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, The alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In some embodiments, compounds according to the present disclosure are used to covalently bind to dehalogenase enzymes. 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 allowing the compound containing that moiety to be easily bonded to tannic acid. Covalent bonding of proteins occurs.

[0439] The term "alkenyl" refers to straight, branched or alkyl groups containing at least one C=C bond. or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon radicals.

[0440] The term "alkynyl" refers to straight, branched or alkyl groups containing at least one C≡C bond. or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon radicals.

[0441] The term "alkylene," when used, refers to an optionally substituted -(CH) n -refers to the group ( (n is generally an integer from 0 to 6). When substituted, the alkylene group may be a methylene group. substituted with one or more C1-C6 alkyl groups (including cyclopropyl or t-butyl groups); It is preferred that the aryl group contains one or more halo groups, preferably 1 to 3 halo groups, or one or more halo groups. or two hydroxyl groups, an O—(C1-C6 alkyl) group, or as otherwise specified herein The disclosed amino acid side chains may be substituted. In certain embodiments, the alkylene group is They may be substituted with butyl or alkoxy groups (or other groups), which may further Ethylene glycol chain (1 to 10, preferably 1 to 6, and in most cases 1 to 4 ethylene glycol chains) The alkyl group is preferably substituted with a chain of alkyl groups (but not limited to, a chain of alkyl groups). The alkyl chain is substituted with one halogen group, preferably In yet other embodiments, alkylene (often methylene) is substituted with a chlorine group. The ) group can be, for example, a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, Nin, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine leucine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methyl The side chains of onine, proline, serine, threonine, valine, tryptophan, or tyrosine The amino acid may be substituted with an amino acid side chain group such as a group.

[0442] The term "unsubstituted" shall mean substituted only with hydrogen atoms. The range of carbon atoms included means that carbon is not present and has been replaced with H. Hence, C0- The carbon atom range for C6 includes 1, 2, 3, 4, 5 and 6 carbon atoms, and for C0, Instead there is an H.

[0443] The terms "substituted" or "optionally substituted" refer to any one of the groups 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 five substituents, preferably up to three substituents, often one or two substituents (which may include substituents that may themselves be further substituted) that is, when there are multiple substituents, each substituent is independent of the other substituents), and Substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), and nitro (NO2) , halogen (especially alkyl, especially preferred on methyl groups such as trifluoromethyl) is 1, 2, or 3 halogens), alkyl group (preferably C1-C 10 , more preferably C1-6) aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), Alkoxy groups (preferably C1-C6 alkyl or aryl; phenyl and substituted phenyl including thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl alkyl), ester or thioester (preferably C1-C6 alkyl or aryl), alkylene esters (the attachment is on the alkylene group rather than the ester functionality, and is preferred) or substituted with a C1-C6 alkyl or aryl group), preferably a C1-C6 alkyl or aryl group. containing aryl, halogen (preferably F or Cl), amine (5- or 6-membered cyclic alkyl an alkylamine, further comprising a C1-C6 alkylamine or a C1-C6 dialkylamine; The alkyl group may be substituted with one or two hydroxyl groups, or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (optionally substituted with polyethylene glycol chain) may be substituted with an alkyl group containing one halogen, preferably chlorine, substituent. hydrazine, amide, which preferably has one or two C1-C6 alkyl groups (1 or carboxamido optionally substituted with two C1-C6 alkyl groups), alkano an alkanoic acid (preferably C1-C6 alkyl or aryl), or an alkanoic acid (preferably C1-C6 aryl) Substituents according to the present disclosure include those substituted with, for example, For example, it may include a -SiR1R2R3 group, where each of R1 and R2 is as otherwise defined herein. and R3 is H or a C1-C6 alkyl group, preferably R1, R2, R3 is a C1-C3 alkyl group (including an isopropyl or t-butyl group). Each may be directly attached to the substituted moiety, or the substituent may be an optionally substituted (C H2) m - or optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) m - The substituted moiety (preferably in the case of an aryl or heteroaryl moiety) is and the like), which may be substituted with any one or more of the substituents described above. The alkylene group -(CH2) m -or-(CH2) n -group or, for example, the ethylene group specified above. Other chains, such as alkyl chains, may be substituted anywhere on the chain. Preferred substituents include halogen or C1-C6 (preferably C1-C3) alkyl groups. which optionally contains one or two hydroxyl groups, one or two ether groups (O- C1-C6 groups), up to three halo groups (preferably F), or any of the groups otherwise described herein. and optionally substituted amides (preferably as described above) with amino acid side chains. substituted carboxamide) or urethane groups (often one or two C0-C6 In certain embodiments, the alkyl groups may be further substituted. In the formula, the alkylene group (often a single methylene group) is optionally substituted with one or two C1-C6 alkyl groups, preferably C1-C4 alkyl groups, in most cases methyl or O-methyl The amino acid is substituted with a methyl 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 C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carbo Sulfone, including oxamide, sulfonamide, keto, carboxy, C1-C6 ester (oxy) ester or carbonyl ester), C1-C6 keto, urethane -OC(O)-NR1R2 or -N(R 1) -C(O)-O-R1, nitro, cyano, and amine (especially C1-C6 alkylene -NR1R2, mono or or di-C1-C6 alkyl substituted amines with one or two hydroxyl groups Each of these groups is also intended to mean a group, including groups which may be optionally substituted, unless otherwise indicated. Unless otherwise specified within 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 ) m - (wherein m and n are 1, 2, 3, 4, 5 or 6, depending on the context), -S- , -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 Al Kill, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -( OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-( C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S, -S(O)-R S (R S teeth , C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogens (F, Cl, Br, I R1 and R2 may each be H or Cl depending on the context. is a C1-C6 alkyl group (containing one or two hydroxyl groups, or up to three halogen groups) , preferably fluorine). The term "substituted" also refers to Optionally substituted aryl within the chemical context of the compound specified and the substituents used A group or heteroaryl group or an optionally substituted group as otherwise described herein. Alkylene groups are also intended to mean heterocyclic groups, as otherwise disclosed herein. and preferably an optionally substituted C1-C6 alkyl group (methyl, ethyl, Preferred are methyl or hydroxymethyl or hydroxyethyl, and accordingly the chiral center the side chains of amino acid groups as otherwise described herein, the amides described above, a group, or a urethane group, an OC(O)-NR1R2 group, where R1 and R2 are as otherwise defined herein. Although it may be substituted with certain groups as shown, many other groups may also be used as substituents. The various optionally substituted moieties may have three or more substituents, preferably three or fewer substituents, 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 due to valence) but no substitution is indicated, 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., benzoate). anthracenyl, phenyl, benzyl) or fused ring (e.g., naphthyl, anthracenylphenyl) substituted (as otherwise described herein) or non-substituted with aryl, ... refers to a substituted monovalent aromatic radical and, in accordance with the present disclosure, may be any available stable ring on the Attached to the compound at the position indicated or as otherwise specified in the chemical structure presented. Other examples of aryl groups, when taken in context, include heteroaromatic ring systems, For example, imidazole, furyl, pyrrole, furanyl, thienyl, thiazole, pyridine, One or more nitrogen atoms in the ring of imidine, pyrazine, triazole, oxazole, etc. "Heteroaryl" groups containing nitrogen or sulfur atoms, or, for example, especially indole, chiral 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, pyrimidine, pyrimidine-containing heteroaryl groups. Imidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole Indoles, indoles, isoindoles, indolizines, azaindolizines, purines, indole quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroquinoline Isoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, Noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria azine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolidine pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazoline 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 furopyridine, furopyridine, 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 formula (I), the ring is substituted with one or more substituents. For example, the aryl group may be selected from the following: The substituents may include: -(CH2) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O- (CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl Le, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine wherein the alkyl group on the amine optionally has one or two hydroxyl groups or up to and three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3 , OMe, OCF3, NO2, or CN groups (each of which is in the ortho, meta, and / or phenyl ring positions) or para-position, preferably para-position), optionally substituted phenyl group (the Preferably, the phenyl group itself is attached to a PTM group, including a ULM group, via a linker; and and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN groups (on the 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 thiazole; optionally substituted thiazoles, including methyl-substituted thiazoles; Optionally substituted isothiazoles, including methyl-substituted isothiazoles , optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted pyrroles including methylimidazole substituted imidazole, optionally substituted benzimidazole or methoxybenzo Imidazole, optionally substituted oximidazole or methyloximidazole , optionally substituted diazole groups including methyldiazole groups, methyl-substituted triazole groups optionally substituted triazole groups, including halo- (preferably F) or methyl-substituted pyrazoles; an optionally substituted pyridine group, including an oxapyridine group, (bonded to a phenyl group by an oxygen atom), optionally substituted furan, optionally substituted phenyl benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, Indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinolines, and combinations thereof.

[0447] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, These generic substituents 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 heteroaryls. Quinoline (attached to the pharmacophore or any carbon atom within the quinoline ring) 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, optionally substituted substituted oxazoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, optionally Substituted thiophenes, optionally substituted thiazoles (preferably methyl-substituted and / or or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole silyl (preferably methyl group, triisopropylsilyl group, optionally substituted (CH2) m -OC 1-C6 alkyl group, or optionally substituted (CH2) m -C(O)-O-C1-C6 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 is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl aryl (preferably one or two hydroxyl groups or up to three halo groups (e.g., CF3 )), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three halo groups), or optionally substituted alkyl groups Acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group) acetylene group; R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl aryl (preferably substituted with one or two hydroxyl groups or up to three halo groups) optionally substituted O—(C1-C6 alkyl) (preferably one or two hydroxy groups) or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) (to be) R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl) each group optionally containing one or two hydroxyl groups or up to three halo groups groups, preferably fluorine 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 is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups or or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl hydroxyl) (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 C1-C 6 alkyl group (preferably C1-C3 alkyl) and an acetylene group.

[0451] The terms "aralkyl" and "heteroarylalkyl" refer to aralkyl and heteroarylalkyl groups according to the definitions above. aryl or heteroaryl, respectively, and alkyl, and / or heteroalkoxy; 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 substituted as described above.

[0453] The term "heterocycle" refers to a ring containing 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-benzodioxol, Xanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiazolyl enyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, Dioxolanil, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoquinolinyl 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, -SO-aryl, -SO-heteroaryl, -SO2- Alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl Such heterocyclic groups may be optionally substituted with a group selected from the group consisting of a single Examples of nitrogen heterocycles and heteroaryls include: Non-limiting examples include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine Indoles, pyridazines, indolizines, isoindoles, indoles, indazoles, purines, Quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, Quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, Acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenon Xanthan gum, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, Indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as N-alkanoic acid 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 a ring such as quinolyl, isoquinolyl, tetrahydroquinolyl, etc.

[0456] The term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, 3 to 20 carbon atoms, including but not limited to cyclohexyl, cycloheptyl, etc. and monocyclic or polycyclic groups as defined herein, such as saturated monocyclic hydrocarbon groups having in the ring It means, but is not limited to, a monovalent group derived from an alkyl group or a cycloalkane. The term "substituted cycloalkyl" refers to groups such as, for example, amino, halogen, alkyl, Substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or or sulfo, and These generic substituents refer to, but are not limited to, groups, and are intended to be construed as equivalents as defined in this description. has the same meaning as the definition of the corresponding group "Heterocycloalkyl" means that at least one ring carbon atom in the ring structure is N, O, or monocyclic or polycyclic alkyl substituted with a heteroatom selected from the group consisting of S or P; "Substituted heterocycloalkyl" refers to a group in which at least one ring of the ring structure is substituted with a substituted heterocycloalkyl. 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, and the group is not a halogen, alkyl, substituted alkyl, carbaryl, The group consisting of ruoxy, carbylmercapto, aryl, nitro, mercapto, and sulfo Although these generic substituents are not intended to be limiting in any way, they may contain one or more substituents selected from the group consisting of: has the same meaning as the definition of 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 contain 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 that is attached to the PTM, ULM, ILM, or ILM' group.

[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 thiazoloimidazolines, substituted pyrrolo These include chemical moieties such as pyrrolidinones, and substituted isoquinolinones.

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

[0463] In yet additional 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. It includes structural features such as:

[0464] In certain preferred embodiments, the MLM is a substituted imidazoline represented by formula (A-1): 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 formulas (A-1) to (A-8) is carbon, oxygen, sulfur, sulfoxide, sulfone, and NR a mosquito selected from the group consisting of: R a are independently H or an alkyl group having 1 to 6 carbon atoms; Y and Z in formulas (A-1) to (A-8) 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 of; R1 and R2 in formulas (A-1) to (A-8) are independently 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 have 1 to 3 substituents independently selected from the group consisting of: May be substituted or unsubstituted: Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkyl group containing 1-6 carbon atoms Alkoxy, fluorine-substituted alkoxy containing 1 to 6 carbon atoms, sulfoxide containing 1 to 6 carbon atoms , sulfones containing 1 to 6 carbons, ketones containing 2 to 6 carbons, and amides containing 2 to 6 carbons , and dialkylamines containing 2 to 6 carbons; R3 and R4 in formulae (A-1) to (A-8) are independently selected from the group consisting of H, methyl, and C1 to C6 alkyl. Selected from; R5 in formulas (A-1) to (A-8) is selected from the group consisting of aryl groups and heteroaryl groups. 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, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkyl group containing 1-6 carbon atoms Alkoxy, fluorine-substituted alkoxy containing 1 to 6 carbon atoms, sulfoxide containing 1 to 6 carbon atoms , sulfones containing 1 to 6 carbons, ketones containing 2 to 6 carbons, and amides containing 2 to 6 carbons , dialkylamines containing 2 to 6 carbon atoms, alkyl ethers (C2 to C6), alkyl ketones (C3-C6), morpholinyl, alkyl ester (C3-C6), alkyl cyanide (C3-C6) ; R6 in formulas (A-1) to (A-8) is H or -C(=O)R b wherein: R in formulas (A-1) to (A-8) b is alkyl, cycloalkyl, mono-, di- or trisubstituted Substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperazunyl Lysinyl, 4-NR c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl and wherein: R in formulas (A-1) to (A-8) c is alkyl, fluorine-substituted alkyl, cyanoalkyl, hydro Xyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidoalkyl, alkyl Sulfone, alkyl sulfoxide, alkylamide, aryl, heteroaryl, monosubstituted , di- and tri-substituted aryl or heteroaryl, CH2CH2R d , and CH2CH2CH2R d wherein: R in formulas (A-1) to (A-8) d is an alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl; R7 in formulas (A-1) to (A-8) is H, C1 to C6 alkyl, cyclic alkyl, fluorine-substituted alkyl , cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, 5- or 6-membered substituted heteroaryl or aryl; R8 in formulas (A-1) to (A-8) is -R e -C(O)-R f , -R e -alkoxy, -R e -aryl, -R e -Haitai -aryl, and -R e -C(O)-R f -C(O)-R g wherein the compound is selected from the group consisting of: R in formulas (A-1) to (A-8) e is an alkylene containing 1 to 6 carbons, or a bond; R in formulas (A-1) to (A-8) f is a 4- to 7-membered substituted heterocycle; R in formulas (A-1) to (A-8) g is an aryl, heteroaryl, substituted aryl or substituted heteroaryl. selected from the group consisting of heteroaryl, and 4- to 7-membered heterocycle; R9 in formula (A-1) to formula (A-8) is one substituent on the fused bicyclic aromatic ring in formula (A-3), or three substituents, wherein the substituents are independently selected from the group consisting of Cl or is a group consisting of halogen, alkene, alkyne, and alkyl, substituted or unsubstituted with F. Selected from; R in formulas (A-1) to (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 alkyl group, or a heteroaryl group. alkyl, C1-C6 alkyl, C1-C6 cycloalkyl, -OH, alkoxy containing 1-6 carbon atoms fluorine-substituted alkoxy containing 1 to 6 carbon atoms, sulfoxide containing 1 to 6 carbon atoms, substituted with 1 to 3 substituents, including sulfones containing 1 to 3 carbons, and ketones containing 2 to 6 carbons. may be substituted or unsubstituted; R in formulas (A-1) to (A-8) 11 is -C(O)-N(R h )(R i ) where R h and R i is from below Selected from the group consisting of: H, C1-C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heptane aryl, mono-, di- or tri-substituted 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 formulas (A-1) to (A-8) h and R i are independently H, bonded to form a ring, 4-hydroxy Cyclohexane, monohydroxy and dihydroxy substituted alkyl (C3-C6), 3-hydroxy Hydroxycyclobutane, phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acids selected from the group consisting of: R in formulas (A-1) to (A-8) 12 and R 13 are independently H, lower alkyl (C1-C6), lower alkyl Alkenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4-, 5- and 6-membered) ring), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5-membered and 6-membered R is selected from aryl and heteroaryl of 12 and R 13 is bonded to the ring and contains substitutions may form 5- and 6-membered rings with or without R in formulas (A-1) to (A-8) 14 is alkyl, substituted alkyl, alkenyl, 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 formulas (A-1) to (A-8) 15 is CN; R in formulas (A-1) to (A-8) 16 is C1-C6 alkyl, C1-C6 cycloalkyl, C2-C6 alkene C, where one or more hydrogens are replaced by fluorine 1~6 Alkyl or C 3~6 Cycloa alkyl or cycloalkyl in which one CH2 is replaced by S(=O), -S or -S(=O)2 terminal CH3 is S(=O)2N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl) -S(=O)2(alkyl), -C(=O)2(alkyl), and alkyl substituted with -O(alkyl) or cycloalkyl, C1-C6 alkyl or alkoxy in which hydrogen is replaced by a hydroxyl group alkyl-cycloalkyl, 3- to 7-membered cycloalkyl or heteroalkyl optionally containing a -(C=0)- group; from the group consisting of cycloalkyl, 5- to 6-membered aryl or heteroaryl groups; and the heterocycloalkyl or heteroaryl group is independently selected from O, N, or S. and the cycloalkyl group may contain 1 to 3 heteroatoms selected arbitrarily, The heterocycloalkyl group, aryl group or heteroaryl group is selected from halogen, C1-C6 alkyl, alkyl groups, hydroxylated C1-C6 alkyl, thioether-containing C1-C6 alkyl, ether, sulfur 1 to 3 independently selected from sulfone, sulfoxide, fluorine-substituted ether, and cyano group may be substituted or unsubstituted; R in formulas (A-1) to (A-8) 17 is (CH2) n C(O)NR k R l wherein R k Oh BiR l are independently H, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxy alkyl, C1-C6 alkyl in which one or more hydrogen atoms are replaced by fluorine, one carbon atom is S( C1-C6 alkyl substituted with S(O)(O), C1 in which one or more hydrogen atoms are replaced by fluorine atoms ~C6 alkoxyalkyl, C in which hydrogen is replaced by cyano group 1~6 Alkyl, 5- and 6-membered aryl or heteroaryl, alkylaryl with alkyl groups containing 1 to 6 carbon atoms; and alkylheteroaryl having an alkyl group containing 1 to 6 carbon atoms. wherein the aryl or heteroaryl group may be further substituted; R in formulas (A-1) to (A-8) 18 is a substituted aryl, heteroaryl, alkyl, cycloalkane, The substitution is preferably selected from the group consisting of -N(C 1-4 Alkyl)(cycloalkenyl) Kill), -N(C 1-4alkyl)alkyl-cycloalkyl, and -N(C 1-4 Alkyl)[(Alkyl (aryl)-(heterocyclic-substituted)-cycloalkyl; R in formulas (A-1) to (A-8) 19 is selected from aryl, heteroaryl, and bicyclic heteroaryl and these aryl and heteroaryl groups are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 cycloalkyl, CF3, F, CN, alkyne, alkylsulfone may be substituted, and the halogen substitution may be mono-, di-, or tri-substituted; R in formulas (A-1) to (A-8) 20 and R 21 are independently C1-C6 alkyl, C1-C6 cycloalkyl Alkyl, C1-C6 alkoxy, hydroxylated C1-C6 alkoxy, and fluorine-substituted C1-C6 alkoxy. 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 formulas (A-1) to (A-8) 22 is H, C1-C6 alkyl, C1-C6 cycloalkyl, carboxylic acid , carboxylic acid ester, amide, reverse amide, sulfonamide, Reverse sulfonamides, N-acylureas, nitrogen-containing five-membered heterocycles The 5-membered heterocyclic ring is further selected from the group consisting of C1-C6 alkyl, alkoxy, fluorine may be substituted with substituted alkyl, CN, and alkylsulfone; R in formulas (A-1) to (A-8) 23 is an aryl, heteroaryl, -O-aryl, or -O-heteroaryl group. Aryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(aryl) and the aryl or heteroaryl group is selected from halogenated alkyl-heteroaryl. C1-C6 alkyl, hydroxylated C1-C6 alkyl, cycloalkyl, fluorine-substituted C1- Substituted with C6 alkyl, CN, alkoxy, alkyl sulfone, amide, and sulfonamide May be; R in formulas (A-1) to (A-8) 24 is -CH2-(C 1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl and CH2-heteroaryl, wherein the alkyl, cycloalkyl, aryl Aryl and heteroaryl are substituted with halogen, alkoxy, hydroxylated alkyl, cyano, optionally substituted with substituted alkyl, cycloalkyl, and substituted cycloalkyl; R in formulas (A-1) to (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 saturated heterocycles containing C1-C6 alkyl, Fluorine-substituted C1-C6 alkyl, alkoxy, aryl and heteroaryl groups Also well; R in formulas (A-1) to (A-8) 26 is C 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyl The alkyl or cycloalkyl may be selected from the group consisting of -OH, alkoxy, fluorine-substituted alkoxy, and the like. , fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl, and optionally substituted with -S(O)2-alkyl; R in formulas (A-1) to (A-8) 27 is selected from aryl, heteroaryl, and bicyclic heteroaryl The aryl or heteroaryl group is selected from the group consisting of C1-C6 alkyl, alkoxy, methyl ... may be substituted with -oxy, NH, NH-alkyl, halogen or -CN, and the substitutions may be independently and may be mono-, di-, and trisubstituted; R in formulas (A-1) to (A-8) 28 is an aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, aryl, cycloalkyl, saturated heterocycles such as piperidine, piperidinone, tetrahydrofuran, and N-acyl-piperidines, 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 formulas (A-1) to (A-8) 1” is alkyl, aryl-substituted alkyl, alkoxy-substituted alkoxy alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl Kill is selected from the group consisting of.

[0467] In certain embodiments, R in Formula (A-1) to Formula (A-8) f and R g 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 These include "hybrid" molecules resulting from the combination of one or more of the different properties exhibited in It 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). and "PTM" is a ligand that binds to a target protein.

[0470] In certain embodiments, the present disclosure provides a diamine 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'', R1, R2, R3, R4, R5, R6, R b , R c , R d , R7, R e , R f , R g , R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R k , R l , R 18 , R 19 , R 20 , R 21 , R2 2. R 23 , R 24 , R 25 , R 26 , R27 , 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 PTM-L-MLM, wherein the PTM is linked to the MLM by L. a protein target binding moiety, wherein L is a bond (i.e., absent) or a chemical In certain embodiments, MLM is a linker. and A-1-4:

[0474] [ka]

[0475] During the ceremony: R1' and R2' in Formula A-1-1 to Formula A-1-4 are F, Cl, Br, I, acetylene, CN, CF3, and NO2. independently selected from the group consisting of: R3' is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, and -OCH(CH3)2. Selected; R4' in formulae A-1-1 to A-1-4 is H, halogen, -CH3, -CF3, -OCH3, -C(CH3)3, -CH(CH3)2, -Cyclopropyl, -CN, -C(CH3)2OH, -C(CH3)2OCH2CH3, -C(CH3)2CH2OH, -C(CH3)2CH2OCH 2CH3, -C(CH3)2CH2OCH2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C( CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O2)CH2CH3, - selected from the group consisting of NHC(CH3)3, -N(CH3)2, pyrrolidinyl, and 4-morpholinyl; R5' in Formulae A-1-1 to A-1-4 is halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1- selected from the group consisting of pyrrolidinyl, -NH2, -N(CH3)2, and -NHC(CH3)3; and R6' in formulas A-1-1 to A-1-4 is selected from the structures shown below, wherein the linker attachment point is , indicated as "*". Apart from 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 point of Formulas A-1-1 to A-1-4 is 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 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 PTM-L-MLM, wherein the PTM is linked to the MLM by L. a protein target binding moiety, wherein L is a bond (i.e., absent) or a chemical In certain embodiments, the MLM is any of the following: 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- A-4-6, A-4-7, A-4-8, A-4-9, A-5-10, A-5-11, A-5-12, A-5-13, A-5-14, A-5-15, A-5-16, A-5-17, A-5-18, A-5-19, A-6-20, A-6-21, A-6-22, A-6-23, A-6-2

[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, -NO2, ethylnyl, cyclopropyl methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -O H, other C 1-6 Alkyl and 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 alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy ... Alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl cycloalkyl, substituted cycloalkyl, alkenyl and substituted cycloalkenyl selected from the group consisting of: Z in formulae A-4-1 to A-4-6 is selected from the group consisting of 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, (CH2) n -R', (CH2) n -NR'R'', ( CH2) n -NR'COR'', (CH2) n -NR'SO2R'', (CH2) n -COOH, (CH2) n -COOR', (CH) n -CONR'R'', (CH 2) n -OR', (CH2) n -SR', (CH2) n -SOR', (CH2) n -CH(OH)-R', (CH2) n -COR', (CH2) n -SO2R', (CH2) n -SONR'R'', (CH2) n -SO2NR'R'', (CH2CH2O) m -(CH2) n -R', (CH2CH2O) m -(CH2) n -OH, ( CH2CH2O) m -(CH2) n -OR', (CH2CH2O) m -(CH2) n -NR'R'', (CH2CH2O) m -(CH2) n -NR'COR'', (CH2 CH2O) m (CH2) n -NR'SO2R'', (CH2CH2O) m (CH2)n -COOH、(CH2CH2O) m (CH2) n -COOR'、(CH2CH2O) m -(CH2) n -CONR'R''、(CH2CH2O) m -(CH2) n -SO2R'、(CH2CH2O) m -(CH2) n -COR'、(CH2CH2O) m -( CH2) n -SONR'R''、(CH2CH2O) m -(CH2) n -SO2NR'R''、(CH2) p -(CH2CH2O) m -(CH2) n R'、(CH2)p- (CH2CH2O) m -(CH2) n -OH、(CH2) p -(CH2CH2O) m -(CH2)n-OR'、(CH2) p -(CH2CH2O) m -(CH2) n -NR' R''、(CH2) p -(CH2CH2O) m -(CH2) n -NR'COR''、(CH2) p -(CH2CH2O)m-(CH2) n -NR'SO2R''、(CH2 ) p -(CH2CH2O) m -(CH2) n -COOH、(CH2) p -(CH2CH2O) m -(CH2) n -COOR'、(CH2) p -(CH2CH2O) m -(CH 2) n -CONR'R''、(CH2)p-(CH2CH2O) m -(CH2)n -SO2R', (CH2) p -(CH2CH2O) m -(CH2) n -COR', (CH 2) p -(CH2CH2O) m -(CH2) n -SONR'R'', (CH2) p -(CH2CH2O) m -(CH2) n -SO2NR'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-(CH2) n - optionally substituted with a heterocycle, wherein the heterocycle may be optionally substituted with alkyl, hydroxyl, COOR′ and COR′. where R' and R" are H, alkyl, halogen-substituted alkyl, hydroxyl, NH2 , NH(alkyl), N(alkyl)2, oxo, carboxy, cycloalkyl and heteroaryl Selected from the rules; 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), -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 applied to MLM, In this case, the solvent exposed region of the MDM may be attached to a linker "L", which is These molecules will be coupled to specific protein ligands (PTMs) to construct PROTACs.

[0487] Examples of MDM2 binding moieties include, but are not limited to: 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), as described below; and all derivatives and analogs thereof, HDM2 / MDM2 inhibitors:

[0488] [ka]

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

[0490] [ka]

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

[0492] [ka]

[0493] (derivatized, the linker group L or -(L-MLM) group may be attached, for example, via a methoxy group , or attached as a hydroxyl group); and 2. trans-4-iodo-4'-boranyl-chalcone

[0494] [ka]

[0495] (derivatized, the linker group L or the linker group L or -(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 selected from the group consisting of CH2, 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 CH2, -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 (optionally substituted straight chain, branched CH2-heterocyclyl optionally substituted with OH, R'OCOOR, R'OCONRR", R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) are groups independently selected from R, R', N, and N-oxide. represents the carbon C to be substituted; A in formula (a) to formula (f) is independently H, alkyl (optionally substituted straight chain, branched chain), cyclohexyl, selected from the group consisting of alkyl, 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', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n R”, ​​-aryl, -hetaryl, -alkyl (optionally substituted straight or branched chain), -cycloalkyl, -hetero Cyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, - Br, -I, -CF3, -CN, -NR'SO2NR'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-NO2)NR'R", -SO2NR'COR ", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, and -OCF3 R' and R" in formula (a) to formula (f) are independently a bond, H, alkyl, cycloalkyl, and selected from aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl. each optionally substituted; In formulas (a) to (f), n is an integer of 1 to 10 (e.g., 1 to 4);

[0499] [ka]

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

[0501] Exemplary CLM In any of the compounds described herein, the CLM may have 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 selected from the group consisting of CH2, 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 CH2, -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", CH2-heterocyclyl optionally substituted with R', and benzyl; Q1 to Q4 in formulas (a) to (f) are groups independently selected from R, R', N, and N-oxide. represents the carbon C to be substituted; A in formula (a) to formula (f) is independently H, alkyl (optionally substituted straight chain, branched chain), cyclohexyl, selected from the group consisting of alkyl, 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', -SO2R', -SO2NR'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, -CF3, -CN, -NR'SO2NR'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-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR' R”, ​​-CCR', -S(C=O)(C=N-R')R”, -SF5, and -OCF3 R' and R" in formula (a) to formula (f) are independently a bond, H, alkyl, cycloalkyl, and selected from aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl. each optionally substituted; In formulas (a) to (f), n is an integer of 1 to 10 (e.g., 1 to 4);

[0504] [ka]

[0505] 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 PTMs is a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or 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 independently selected from the group of CH2, C=O, NH and N-alkyl; R in formula (g) is independently H, methyl, alkyl (e.g., C1-C6 alkyl (optionally substituted) selected from the group consisting of straight chain, branched chain;

[0509] [ka]

[0510] In formula (g), the 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 and / or covalently attached to a linker that is 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 These include "hybrid" molecules resulting from the combination of one or more of the different properties exhibited in It 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 may have a chemical structure selected from the group consisting of: Construction includes:

[0521] [ka]

[0522] [ka]

[0523] [ka]

[0524] During the ceremony: W in formulas (h) to (ad) is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl. Re; Q1, Q2, Q3, Q4, and Q5 in formula (h) to formula (ac) are independently selected from R', N, and N-oxide. represents a carbon C substituted with a group selected from the group R in formula (h) to formula (ad) 1 is selected from H, CN, C1-C3 alkyl; R in formula (h) to formula (ad) 2 is selected from the group consisting of H, CN, C1-C3 alkyl, CHF2, CF3, 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 formulas (h) to (ad) is C, CH, or N; R' in formulas (h) to (ad) is H, halogen, alkyl, substituted alkyl, alkoxy, substituted selected from alkoxy; R in formulas (h) to (ad) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower The alkyl group is preferably lower alkyl, lower alkoxy, or halogenated lower alkyl.

[0525] [ka]

[0526] In formulas (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, CLM or CLM′ may be 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. , Q1, Q2, Q3, Q4, or Q5), a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof.

[0528] In any of the embodiments described herein, CLM or CLM′ is a group represented by the formula (h )~W, X, R, R in formula (ad) 1 , R 2 , R 3 , R 4 , R 5 , R', through Q1, Q2, Q3, Q4, and Q5 , PTM, chemical linker group (L), ULM, CLM, CLM', or a 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', Q1, Q2, Q3, Q4, and Q5 may independently be covalently attached to a linker. and / or a linker bonded to one or more PTM, ULM, ULM', CLM or CLM' groups. The hydroxyl group may be covalently attached to the anchor.

[0530] More specifically, non-limiting examples of CLMs include the following compounds: These include "hybrid" molecules or compounds resulting from the combination of one or more properties of Can be:

[0531] [ka]

[0532] [ka]

[0533] During the ceremony: W in formula (ae) to formula (ap) is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl. Selected; R in formula (ae) to formula (ap) 1 is selected from the group consisting of H, CN, and C1-C3 alkyl; R in formula (ae) to formula (ap) 3 is H, alkyl, substituted alkyl, alkoxy, substituted alkoxy Selected from; R in formula (ae) to formula (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 , Q1, Q2, Q3, Q4, and Rn may independently be covalently linked to a linker, and / or or covalently attached 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 , Q1 Q2, Q3, Q4, and Rn may independently be covalently bonded 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 done.

[0538] In any of the embodiments described herein, Q1, Q2, Q3 of formula (ae) to formula (ap) Q4, and Rn may independently be covalently bonded 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 above. stomach.

[0539] In any aspect or embodiment described herein, R of formula (ae) to formula (ap) n teeth and a second CLM, CLM', having the same chemical structure as the linker group (L), PTM, ULM, or 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] where R' is a halogen and R 1 is related to 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] wherein R' is a halogen. Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM, as defined below: 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 bond, 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 Selected from the group of O2; 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 groups, optionally substituted C1~6 Alkoxyl (e.g. Optionally, 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 Archi C=O; Formula ULM-a W 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 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 optionally substituted with H, one or more halo or -OH groups; a straight or branched C1-C6 alkyl group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO2, 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 )SO2; T in the formula ULM-a is X 1covalently bonded to; Formula ULM-a W 4 is an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroa an aryl group, or an optionally substituted -NR 1 -T-heterocycle, wherein -NR 1 is X 2 Covalently bonded to and R 1 is H or CH3, preferably H.

[0549] In any of the embodiments described herein, T is optionally substituted alkyl , -(CH2) n - groups, wherein each one of the methylene groups is selected from the group consisting of halogen, methyl, , straight or branched C1-C6 alkyl groups optionally substituted with one or more halogen or -OH groups an alkyl group, or one or two substituents selected from the group consisting of an optionally substituted amino acid side chain; and n is 0 to 6, often 0, 1, 2, or 3, and is preferably It is usually 0 or 1.

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

[0551] [ka]

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

[0553] In any of the embodiments, W of formula ULM-a 5 is phenyl or 5-10 membered heteroaryl is selected from the group R in the formula ULM-a 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a C OR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 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 4 The specific disclosed compounds include (Not limited to these) 4 Each of the substituents may be any number of W 3 Used in conjunction with a substituent are also disclosed herein.

[0554] In certain additional embodiments, ULM-a has 0-3 R in the pyrrolidine moiety. P Assigned by the basis 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, The PTM group may be covalently attached to a linker that is attached to one or more PTM groups. and wherein the dashed line indicates 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: R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl alkyl, or haloalkyl, or R 9. R 10 , and the carbon atoms to which they are attached , forming an optionally substituted cycloalkyl; R in 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 formula ULM-b12 is selected from the group of H or optionally substituted alkyl; R in 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) (I) carbonyl, or optionally substituted aralkyl; R in 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 of phenyl or 5-10 membered heteroaryl; R in formula ULM-b 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a C OR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted halo aryl, heteroaryl, cycloalkoxy; cycloalkyl, or cycloheteroalkyl (each optionally substituted); R in formula ULM-b 16 are independently halo, optionally substituted alkyl, optionally substituted haloal 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 formula ULM-b 18are independently H, halo, optionally substituted alkoxy, cyano, optionally substituted is selected from the group of alkyl, haloalkyl, haloalkoxy or linker; and Beauty p of formula ULM-b is 0, 1, 2, 3, or 4, and wherein the dashed line represents at least one PTM , another ULM (ULM'), or at least one PTM or ULM', or both, The binding site of the chemical linker moiety attached to

[0563] In certain embodiments, R of formula ULM-b 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 17 are methyl, ethyl, isopropyl and cyclopropyl The fluororubic acid is selected from the group consisting of propyl phosphate and propyl phosphate.

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

[0568] [ka]

[0569] In certain embodiments, R of formula ULM-b11 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: R1 in formula ULM-c, formula ULM-d, and formula ULM-e is H, ethyl, isopropyl, tert-butyl, sec -butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted hetero haloaryl, or haloalkyl; R of formula ULM-c, formula ULM-d, and formula ULM-e 14a is H, haloalkyl, optionally substituted alkyl methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclomethyl Propyl; R of 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 cycloalkoxy; heteroalkyl; X in formula ULM-c, formula ULM-d, and formula ULM-e is C or C═O. R3 of formula ULM-c, formula ULM-d, and formula ULM-e is absent or an optionally substituted 5-membered or 6-membered heteroaryl; and wherein the dashed line indicates the presence of at least one PTM, another ULM (ULM′), or at least one PTM. 1 shows the attachment site of a chemical linker moiety that connects ULM, ULM′, or both to ULM.

[0574] In certain embodiments, a ULM comprises 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 hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f 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, optionally substituted 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, halogens, 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-d2 The phenyl ring of ULM-d9 is optionally substituted with fluorine, lower alkyl, and alkoxy groups. , where the dashed line indicates at least one PTM, another ULM (ULM'), or at least one PTM or ULM', or both, to 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 ester-linked. The compound includes a prodrug moiety.

[0591] In any of the aspects or embodiments described herein, ULM and present ULM', if any, or a pharmaceutically 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 C1-C6 alkyl group, optionally substituted -(CH2) n OH, any Substituted with -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6) alkyl group, epoxide moiety Optionally substituted (CH2) containing WCOCW n -WCOCW-(C0-C6) alkyl group, wherein Each W is independently H or a C1-C3 alkyl group, optionally substituted -(CH2) n COOH, optional Substituted with -(CH2) n C(O)—(C1-C6 alkyl), optionally substituted —(CH2) n NHC(O)-R1, optional Substituted with -(CH2) n C(O)-NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2, -(CHO) n H, Ren optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), optionally substituted —(CH2) n C(O)-O-(C1-C6 alkyl), optionally substituted -(CHO) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl -(CH2O) optionally substituted -(CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O )-R1, optionally substituted -(CHO) n C(O)-NR1R2, -(CH2CH2O) n H, optionally substituted -(CH2CH2 O) n COOH, optionally substituted -(OCH2CH2) n O—(C1-C6 alkyl), optionally substituted —(CH2CH2 O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) n NHC(O)-R1, optionally substituted- (CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 of ULM-g are each independently H, or one or two hydroxyl groups. or C1-C6 alkyl optionally substituted with up to three halogen groups (preferably fluorine). It is a base; ULM-g R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl group or Heterocyclic group, or -(CH2) m is an NR1R2 group; X and X' of ULM-g are each independently C=O, C=S, -S(O), or S(O)2 (preferably X and and X' are both C=O); ULM-g R 2’ is an optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) walkyl group, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N group, optionally substituted -(CH2) n -(C=O) u (NR1) v ( SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, any Substituted with -(CH2) n -(C=O) v NR1(SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR 1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N ,any -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w-He aryl, or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) 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 -(CH2) n -(O) u (NR1) v (SO2) w -alkyl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted Ru-(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted Ru-(CH2) n -C(O) u (NR1) v (SO2) w - Heteroaryl, optionally substituted -(CH2) n -C(O)u (NR1) v ( SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted Converted to -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2 ) w -Alkyl, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N , optionally replaced -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted —O—(CH2)n—(C═O) u (NR 1) v (SO2) w -aryl, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl or optionally substituted —O—(CH2) n -(C=O) u (NR1) v (SO2) w -heterocycle;-(CH2) n -(V) n’ -(CH2 ) n -(V) n’ -alkyl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ an aryl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted- (CH2) n -(V) n’ -(CH2) n -(V) n’ -heterocycle ’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ - (V) n’ -alkyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl group, any optionally substituted -(CH2) n-N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl group, optionally substituted- (CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclic group, optionally substituted -X R3’ - alkyl group; any -X replaced by 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 C1-C6 alkyl optionally substituted with two halogen groups, or optionally substituted -(CH2) n -a Reel, -(CH2) n -heteroaryl, or -(CH2) n - a heterocyclic group; V of ULM-g is O, S, or NR1; R1 of ULM-g is the same as above; ULM-g R 1 and R 1’ are each independently H or a C1-C3 alkyl group; ULM-g X R2’ and X R3’ each independently represents an optionally substituted —CH2) n -, -CH2) n -CH(X v )=CH (X v )-(cis or trans), -CH2) n -CH≡CH-, -(CHCHO) n - or C3-C6 cycloalkenyl is an alkyl group, wherein X v is H, halo, or an optionally substituted C1-C3 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 in 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 linked to the PTM group via a linker group; if the PTM is a ULM', it is covalently linked to the PTM group via a linker group. In this case, R of each of ULM and ULM' 1’ , R 2’ , R 3’ , any one of X and X' The above are optionally modified and covalently linked to each other either directly or via a linker group.

[0594] In any of the aspects or embodiments described herein, ULM and present In some cases, ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvent 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) or an S(O) group, more preferably a C=O group, and ULM-h R 1’ , R 2’ , and R 3’ Any one or more of the PTMs may be optionally modified to form a UL If not M', then a linker group is attached that is further covalently attached to the PTM group, or the PTM is a ULM 'If 'ULM and 'ULM', then 1’ , R 2’ , R 3’ One or more of the following: 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 present In some cases, ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvent 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 PTMs may be optionally modified to form a UL If not M', then a linker group is attached that is further covalently attached to the PTM group, or the PTM is a ULM 'If 'ULM and 'ULM', then 1’ , R 2’ , R 3’ One or more of the following: 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-i1’ is a hydroxyl group, or It is preferable that the group be a group that can 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, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2 ) n OC(O)—(C1-C6 alkyl), or optionally substituted —(CH2) n C(O)-O-(C1-C6 alkyl) In the formula, n is 0 or 1. 1’ is a carboxylic acid group, a hydroxyl group, or or amine groups, and the hydroxyl, carboxylic acid or The amines (each of which may be optionally substituted) may be further chemically modified to provide PTM groups (ULM' groups). ) can 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 an 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 optionally substituted -NR 1 -T-heterocycle, wherein R 1 is H or CH, preferably H, and T is optionally substituted -(CH) n - group, wherein Each one of the ethylene groups is preferably a halogen, an alkyl group as otherwise described herein, or an alkyl group as otherwise described herein. amino acid side chain, or one or two substituents selected from C1-C3 alkyl groups, preferably is optionally substituted with one or two methyl groups which may be optionally substituted, and n is 0 1 to 6, and is often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - group, All of the groups are optionally substituted.

[0601] ULM-g~ULM-i R 2’ Preferred aryl groups for the and naphthyl or phenyl groups, preferably phenyl groups. The group is optionally attached to a PTM (including a ULM′ group) via a linker group and / or a halo gen (preferably F or Cl), amine, mono- or di-alkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3 , OMe, OCF3, NO2 or CN groups (each of which is ortho-, meta-, and / or CN-) of the phenyl ring or para-position, preferably para-position), 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, CH3, CF3, OMe, OCF3, NO2, or CN groups (located at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position) a naphthyl group 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 pyrroles, optionally substituted imidazoles including methylimidazole; optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted containing oximidazole, methyloximidazole, or methyldiazole groups 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 containing benzoxapyridine groups (pyridine groups linked to phenyl groups by oxygen) optionally substituted benzofuran; optionally substituted pyridine; 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 HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most 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 piperidin amine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 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, tetrahydrofuran Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl 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 amine, 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 groups is linked to a linker group. The PTM group may optionally be attached 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 (which may be attached to the pharmacophore or placed on any carbon atom within the quinoline ring) optionally substituted indole, optionally substituted indolizine, optionally substituted optionally substituted benzofurans, including optionally substituted azaindolizines, 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R of ULM-g to ULM-i a is H or C1-C6 an acetylene group, which is an alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene benzophenone, piperidine, piperazine, etc., each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where R YCH, OH, CN, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); , each of which 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 Tetrahydrothien, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine phosphorus, oxane, or thiane, each of which groups may be optionally substituted; or a group according to the following chemical structure:

[0613] [ka]

[0614] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted a an aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl 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' 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’ may be used in conjunction with substituents, which are also 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 optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle, where R 1 is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted Reru-(CH2) n - group, wherein each one of the methylene groups is preferably a halogen, C-C 3 alkyl groups, or the side chains of amino acids as otherwise described herein Optionally substituted with one or two substituents, preferably optionally substituted methyl. and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - may be a base 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 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, mono- or dialkylamines (preferably is dimethylamine), amide group (preferably teeth -(CH2) m -NR1C(O)R2, wherein m, R1 and and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3 , NO2, CN or S(O)2R S Group(R S is a C1-C6 alkyl group, an optionally substituted aryl, a hetero an aryl or heterocyclic group, or (CH2) m NR1R2 groups), 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 an M group (including a ULM' group). The substituted phenyl group (i.e., the phenyl group of the substituent itself is preferably substituted with F, Cl, O At least one of H, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or a linker group and which groups are attached to a PTM group (including a ULM′ group), wherein the substitution is occurring in the ortho, meta, and / or para positions of the phenyl ring, preferably 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; methylimidazole, benzyl imidazole or methoxybenzylimidazoline optionally substituted imidazole, oximidazole or methyloxyimidazoline, including methyloxyimidazoline; 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 heterocycle (e.g., a tetrahydrofuran bonded to a ring) or an optionally substituted heterocycle (e.g., a tetrahydrofuran bonded to a ring) Lanthanum, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydrothiophene aryl, heteroaryl or Each heterocyclic group can be optionally connected 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 indole (including dihydroindole), optionally substituted Indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine) , optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally 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 (preferably or methyl group, triisopropylsilyl group, optionally substituted (CH2) m -O-C1-C6 alkyl group , or optionally substituted (CH2) m 1,2,3-Triazo substituted with -C(O)-O-C1-C6 alkyl group pyridine (2-, 3-, or 4-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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene benzophenone, piperidine, piperazine, etc., each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group, which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl). 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 according to the following chemical structure:

[0622] [ka]

[0623] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 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 Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl 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). wherein 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' 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 is revealed in the book.

[0625] In certain other preferred embodiments, R of ULM-g to ULM-i 2’ is an optionally substituted -NR1-X R2 ’ -Alkyl group, -NR1-X R2’ -aryl group; optionally substituted -NR1- XR2’ -HET, optionally placed Converted to -NR1-X R2’ -aryl-HET or optionally substituted -NR1- X R2’ -HET-aryl and During the ceremony: R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H); ULM-g~ULM-i X R2’ is optionally replaced by - ( CH2) n -,- ( CH2) n -CH(X v )=CH(X v )-(Sis is trans), -(CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group; and ULM-g~ULM-i X v is H, halo, or optionally one or two hydroxyl groups or a C1-C3 alkyl group substituted with up to three halogen groups; The alkyl of ULM-g to ULM-i is optionally substituted C1-C 10 Alkyl (preferably C1-C6 alkyl) (In certain preferred embodiments, the alkyl group is a halo group, often Cl or or Br-terminated); Aryl in 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, pyrrolidine furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahy- drogen Dolothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole Indolizine, azaindolizine, quinoline (when substituted, each preferably C1-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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene amine, 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, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 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 having a C1-C3 alkyl group, preferably teeth methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl 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 foregoing 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 -(CH2) n -(V) n’ -(CH2) n -(V) n’ -R S3’ group, optionally substituted -(CH2) 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 -X R3’ -HET-aryl group, During the ceremony: R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), optionally substituted is a substituted aryl group or a HET group; R 1’ is H or a C1-C3 alkyl group (preferably H); V is O, S or NR 1’ and; X R3’ is -(CH2) n -, -(CH2CH2O) n -,- ( CH2) n -CH(X v )=CH(X v )- (cis or trans), - ( CH2) n -CH≡CH-, or a C3-C6 cycloalkyl group, all of which are optionally substituted; X v is H, halo, or optionally one or two hydroxyl groups or up to three halo groups a C1-C3 alkyl group substituted with an halogen group; Alkyl is an optionally substituted C-C 10 an alkyl (preferably C1-C6 alkyl) group ( In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br. closed); Aryl is an optionally substituted phenyl or naphthyl group (preferably phenyl). groups); and HET is an optionally substituted oxazole, isoxazole, thiazole, or isothiazole. , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, di Hydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pi Lysine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine azaindolizine, quinoline (each preferably with a C1-C3 alkyl group when substituted), preferably substituted with methyl, or halo groups, preferably F or Cl), or is a group that conforms 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C0-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene amine, 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, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 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 having a C1-C3 alkyl group, preferably teeth methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl 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' in ULM-g through ULM-i is 0 or 1; and Each n' in 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 to ULM-i 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl , -(CH2) n -HET or -(CH2CH2O) 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) n OH, itself CN, Halo (the most (large with three halo groups), OH, -(CH2) n O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) C1-C6 alkyl optionally further substituted with alkyl)amine, The alkyl group of the amine may contain one or two hydroxyl groups or up to three halo (preferably optionally substituted with groups (preferably F, Cl), or The aryl group of ULM-g to ULM-i is —(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O- (CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl Le, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) substituted In this case, the alkyl group of the amine may have one or two hydroxyl groups, or Up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m’ -C H2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG optionally substituted with a group, wherein V is O, S or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), R PEG is H or an optionally substituted C1-C6 alkyl group (optionally substituted with a carboxyl group) (including those that The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazoline, Azoles, imidazoles, diazoles, oximidazoles, pyrroles, pyrrolidines, Ran, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien Ene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, yne dolizine, indolizine, azaindolizine (when substituted, each preferably C1-C3 alkyl alkyl groups, preferably methyl, or halo groups, preferably F or Cl), or or a heterocycle, including heteroaryl, selected from the group consisting of groups according 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C0-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene amine, 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, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 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, tetrahydrofuran Trihydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidin piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group; The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isobutanol, or thiazole. Thiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, Furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydro Thiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C1 -C3 alkyl group, preferably methyl, or halo group, preferably F or Cl, ), benzofuran, indole, indolizine, azaindolizine, or The following is the basis:

[0635] [ka]

[0636] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably one or two hydroxyl groups or up to three hydroxyl groups) O(C1-C6 alkyl) (preferably substituted with a CF3 group), substituted with one or two hydroxyl groups or up to three halo groups), or optionally Acetylenic group substituted with -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C -C6 alkyl (preferably containing one or two hydroxyl groups or up to three halo groups) group), optionally substituted O—(C1-C6 alkyl) (preferably one or two or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C0-C6 alkyl), each group optionally containing one or two hydroxyl groups or at most heterocycles substituted with up to three halo groups, preferably fluorine groups, or optionally substituted, e.g. For example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene amine, 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, NO2, halo (preferred or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted a an aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group; Each m' in 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 preferably each of said compounds of said aryl group or HET group optionally comprises 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: and pharmaceutically 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’ directly to -NH-CH-aryl-HET- (preferably methyl substituted thiazoles) (a bonded phenyl); ULM-i R 3’ is -CHR CR3’ -NH-C(O)-R 3P1 group or -CHR CR3’ -R 3P2 It is a base; ULM-i R CR3’ is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl Chill; ULM-i R 3P1 is a C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group ( Preferably methyl-substituted -(CH2) n OCH3 group, where 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 R3P2 teeth,

[0642] [ka]

[0643] It is a base; The 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 connected to any PTM group (including a ULM' group) via a linker group. are joined at will.

[0644] In certain embodiments, a ubiquitin E3 ligase binding moiety (ULM) is Sensuality sexual compounds, or a pharmaceutically 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 R5 and R6 of ULM-j is independently OH, SH, or optionally substituted alkyl; or R5, R6 and the carbon atom to which they are attached form a carbonyl; R7 of ULM-j 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 of ULM-j is O or N-R8; R8 of ULM-j 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 heterocyclic, or

[0647] [ka]

[0648] and; R9 and R of ULM-j 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. Forming a le; 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 of ULM-j 14 are independently H, haloalkyl, optionally substituted cycloalkyl, is a substituted alkyl or an 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 of ULM-j 16 are independently halo, optionally substituted alkyl, optionally substituted haloal alkyl, CN, or optionally substituted haloalkoxy; Each R of 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 23 is H or OH; Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; and The o in ULM-j is 0, 1, 2, 3, or 4.

[0651] In certain embodiments, G of ULM-j is C=J, J is O, R7 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, R7 is H, and each R 14 is H Yes, R 15is optionally substituted heteroaryl, and o is 0. In other examples, E is C=O and M is

[0653] [ka]

[0654] 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] 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, optionally substituted and p is 0, 1, 2, 3, or 4. is.

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

[0666] [ka]

[0667] During the ceremony: The G of ULM-k is C=J, where J is O; R7 of ULM-k 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, the 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: The G of ULM-k is C=J, where J is O; R7 of ULM-k is H; Each R of ULM-k 14 is H; o of ULM-k is 0; and ULM-k R 15 is selected from the group consisting of:

[0674] [ka]

[0675] wherein R of ULM-k 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, optionally aryl substituted with, or

[0688] [ka]

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

[0690] In any embodiment described herein, R of ULM-j or ULM-k 11 is from below 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: The base is:

[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 17is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0699] [ka]

[0700] and; R9 of ULM-l is H; ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally 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 aryl, 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 according to the chemical structure:

[0704] [ka]

[0705] During the ceremony: Y in ULM-m is H, methyol, or ethyl R9 of ULM-m is H; R 10 isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl It is; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted substituted isoxazole, optionally substituted heterocycle.

[0706] In another preferred embodiment of the present disclosure, the ULM, and, if present, the ULM′, are each independently In other words, 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 R9, R 10 , and R 11 is as defined above. In other examples, R9 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 pharmaceutically acceptable salts, enantiomers, It may be a diastereomer, solvate, or polymorph. In any of the aspects or embodiments described herein, the ULM (or any of the entities described herein) may be present. When the PTM is attached to a PTM, the ULM') is attached to the PTM either 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] [ka]

[0713] [ka]

[0714] [ka]

[0715] [ka]

[0716] [ka]

[0717]

change

[0718]

change

[0719]

change

[0720]

change

[0721]

change

[0722]

change

[0723]

change

[0724]

change

[0725]

change

[0726]

change

[0727]

change

[0728] [ka]

[0729] [ka]

[0730] [ka]

[0731] [ka]

[0732] [ka]

[0733] [ka]

[0734] In this case, for example, aryl, heteroaryl, phenyl, or indium The diol group may be used in any suitable location, including the phenyl, such as an amine, ester, ether, or alkyl group. and optionally via any suitable functional group, such as alkyl, alkyl, or alkoxy, as described herein. 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). Above ULM (e.g., at least one of CLM, VLM, MLM, ILM, or a combination thereof) In certain embodiments, the PTM comprises one or more PTMs 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 which A 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 moieties, a PTM moiety, or a combination thereof; and Call q of the linker is an integer of 1 or greater; Each A L are independent, bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L 3 CONR L4 , N.R. L3 SO2NR 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(=CNO2)NRL4 , 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 a group 5- 13 spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with a 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 L2 heteroaryl substituted with a group , where R L1 or R L2 are each independently optionally bonded to other groups, 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 , SC 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 Archi OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 a Lukil), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C1 -8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2 NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 Archi ru)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl) SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8alkyl), NH SO2N(C 1-8 alkyl)2, NH SO2 NH2 do.

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

[0737] In certain embodiments, for example, when the linker q is greater than 2, (A L ) q is bound to ULM A1 and (A L ) q are linked via a structural unit of a linker (L).

[0738] In certain embodiments, for example, when q of the linker is 2, (A L ) q is A L Binds to 1 and 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: This includes groups represented by: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(Low-level Arco -OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -( (chloroalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n-(heterocycloalkyl)-, -NR(CHCH 2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2 CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -( Chloroalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl -O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(Low (Aryl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, NR(CH2CH2O ) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocycle) -CH 2, -NR(CH2CH2) n -(heterocycle)-(heterocycle)-CH2, -N(R1R2)-(heterocycle)-CH2; where n in the linker may 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: This includes groups represented by: -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p-O(CH2) q -O(CH2) r -OCH2-、 -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-、 -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2)<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0745] ;In the formula, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6; If the number is zero, there are no NO or OO bonds. R of the linker 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) may be one 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) may be one of: Selected from the group consisting of:

[0763] [ka]

[0764]

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[0765]

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[0766]

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[0767]

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[0768]

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[0769]

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[0770]

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[0771]

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[0772]

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[0773]

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[0774]

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[0775]

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[0776]

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[0777]

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[0778]

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[0779]

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[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] [ka]

[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 line indicates the point of attachment to the PTM or ULM moiety.

[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, and each R Q are independently H, halo, OH, CN, CF3, NH2, carboxyl, C1-C6 Alkyl (optionally substituted straight chain, branched chain), C1-C6 alkoxy (optionally substituted straight chain , branched) or two R Q Groups, together with the atoms to which they are attached, consist of 0 to 4 helical groups. Forming a 4-8 membered ring system containing a heteroatom; Y L1 are each independently a bond, C1-C6 alkyl (optionally substituted straight or branched chain), and optionally one or more C atoms are substituted with O or C1-C6 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 line indicates the point of attachment to the PTM or ULM moiety.

[0808] [ka]

[0809] During the ceremony: W L1 and W L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1~6 Alkyl (optionally substituted straight chain, branched chain), C1-C6 alkoxy (optionally substituted straight chain , branched), bicyclic, biaryl, biheteroaryl, or biheterocyclic, each Optionally, R Q Each R is replaced by Q are independently H, halo, OH, CN, CF3, NH2, carboxyl, Hydroxyl, Nitro, C≡CH, C 2~6 Alkenyl, C 2~6 Alkynyl, C1-C6 alkyl ( optionally substituted straight chain, branched chain), C1-C6 alkoxy (optionally substituted straight chain, branched chain ), O.C. 1~3 Alkyl (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , C.N. or two R Q The 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, SO2, C 1-C6 alkyl (straight or branched chain, optionally substituted) and optionally one or more C atoms is substituted with O, C1-C6 alkoxy (optionally substituted straight chain, branched chain); Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, or a biheterocyclic or bicyclic, optionally bridged, and optionally containing 0 to 6 R Q Each R is replaced by Q is independent H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 Alkoxy-substituted or two R QThe groups, together with the atoms to which they are attached, may contain 0 to 2 heteroatoms. forming a 3- to 8-membered ring system containing aryl groups; R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight or branched chain, optionally with one or more Upper halo, C 1-6 substituted with alkoxyl) or R 1 , R 2 is where they combine together with the atom form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0 to 10; and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0810] In additional embodiments, the linker group comprises from about 1 to about 100 ethylene glycol units, from about 1 to about 100 ethylene glycol units, About 50 ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units Glycol units, optionally substituted (poly) having about 2 to 4 ethylene glycol units Ethylene glycol or interspersed with optionally substituted O, N, S, P or Si atoms In certain embodiments, the linker is an optionally substituted alkyl group such as aryl, fluoro, or cyclohexane. The alkyl group may be substituted with a phenyl, benzyl, alkyl, alkylene, or heterocyclic group. The linker may be asymmetric or symmetric in configuration.

[0811] In any of the embodiments of the compounds described herein, the linker group may be any of the groups described herein. In one embodiment, the linker is from about 1 to about 1 2 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to 6 ethylene glycol units units, approximately 2 to 5 ethylene glycol units, and approximately 2 to 4 ethylene glycol units. It is a substituted or unsubstituted polyethylene glycol group.

[0812] In another embodiment, the present disclosure provides a compound comprising the PTM group described above, The group binds to a target protein (e.g., ER) or polypeptide and is cleaved by a ubiquitin ligase. and chemically conjugated to a ULM group either directly or via a linker moiety, L. Alternatively, the PTM may be a ULM' group, which also binds to the E3 ubiquitin ligand. a gauze binding moiety, which may be the same as or different from the ULM group described above, and a linker moiety and L is a linker moiety as described above, and is attached to the ULM group via a bond or directly. ULM and PTM, or pharmaceutically acceptable salts or enantiomers thereof, may be present or absent. , stereoisomers, solvates, or polymorphs are chemically (covalently) bound to each other.

[0813] In certain embodiments, the linker group L is one or more independently selected from the group consisting of: is a group containing the above covalently bonded structural units:

[0814] [ka]

[0815] X is selected from the group consisting of O, N, S, S(O), and SO2; n is an integer from 1 to 5; R L1 teeth, is hydrogen or alkyl,

[0816] [ka]

[0817] is selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano Monocyclic or bicyclic aryl or heterocyclic rings optionally substituted with 1 to 3 substituents as defined above. is aryl;

[0818] [ka]

[0819] is selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano monocyclic or bicyclic cycloalkyl optionally substituted with 1 to 3 substituents as defined above; and the phenyl ring fragment is an alkyl, halogen, haloalkenyl, or heterocycloalkyl. one, two or more selected from the group consisting of alkyl, hydroxy, alkoxy and cyano; In certain embodiments, the linker group L may be optionally substituted with up to three substituents, as described above. It contains 10 covalently bonded structural units.

[0820] The ULM and PTM groups can be attached via any group that is appropriate and stable for the linker chemistry. In a preferred embodiment of the present disclosure, the linker is independently and the...

Claims

1. The following formula: 【Chemistry 1】 or a salt thereof.

2. The following formula: 【Chemistry 2】 or a salt thereof.

3. The following formula: 【Chemistry 3】 or a salt thereof.

4. The following formula: 【Chemistry 4】 or a salt thereof.

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