Tetrahydronaphthalene derivatives and tetrahydroisoquinoline derivatives as estrogen receptor degrading substances

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This disclosure claims priority to U.S. Provisional Patent Application No. 62 / 429,041, filed on December 1, 2016, entitled "TETRAHYDRONAPHTHALENE AND TETRAHYDROISOQU INOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS", and U.S. Provisional Patent Application No. 62 / 540,049, filed on August 1, 2017, entitled "TETRAHYDRONAPHTHALENE AND TETRAHYDRO ISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS", the contents of which are hereby incorporated by reference in their entirety for all purposes. Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed on August 5, 2016, U.S. Patent Application No. 15 / 206,497, filed on July 11, 2016, U.S. Patent Application No. 1 5 / 209,648, filed on July 13, 2016, U.S. Patent Application No. 15 / 730,728, filed on October 11, 2017, and U.S. Patent Application No. 14 / 686,640, filed on April 14, 2015, and published as U.S. Patent Application Publication No. 2015 / 0291562, U.S. Patent Application No. 14 / 792,414, filed on July 6, 2015, and published as U.S. Patent Application Publication No. 2016 / 0058872 No., U.S. Patent Application No. 14 / 371,956, filed on July 11, 2014, and published as U.S. Patent Application Publication No. 2014 / 0356322, and are hereby incorporated by reference in their entirety for all purposes. No., and U.S. Patent Application No. 14 / 792,414, filed on July 6, 2015, and published as U.S. Patent Application Publication No. 2016 / 0058872 No., and U.S. Patent Application No. 14 / 371,956, filed on July 11, 2014, and published as U.S. Patent Application Publication No. 2014 / 0356322, and are hereby incorporated by reference in their entirety for all purposes. U.S. Patent Application No. 62 / 395,228 entitled "INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS" filed on September 15, 2016, and U.S. Patent Application No. 15 / 074,820 filed on March 18, 2016 and published as U.S. Patent Application Publication No. 2016 / 0272639, and U.S. Provisional Patent Application No. 62 / 452,972 filed on January 31, 2017, U.S. Provisional Patent Application No. 62 / 429,041 filed on December 1, 2016, and International Patent Application No. PCT / US2016 / 023258 filed on March 18, 2016 and published as International Patent Application Publication WO2016 / 149668. All of these are hereby incorporated by reference in their entirety herein. Further, all reference documents cited herein are hereby incorporated by reference in their entirety herein. This disclosure relates to compounds, compositions and medicaments containing such compounds, and methods of making them. The disclosure also relates to the use of compounds, compositions and medicaments as inhibitors of estrogen receptor activity, including, for example, degradation of estrogen receptors, and to the treatment of diseases and conditions regulated by estrogen receptors, such as, for example, the treatment of breast cancer.

BACKGROUND ART

[0002]

[0003] ​​​​​​​​​​​​​It is a substance. When estradiol binds to the estrogen receptor, dimerization of the receptor occurs. , and then this dimer binds to the estrogen response element (ERE) on DNA. The ER-DNA complex recruits other transcription factors that transcribe the DNA downstream of the ERE into mRNA, which is ultimately translated into protein. Alternatively, the interaction between ER and DNA may be indirect through the mediation of other transcription factors, the most well-known of which are fos and jun. Many gene expressions are regulated by the estrogen receptor, and since the estrogen receptor is expressed in many cell types, regulating the estrogen receptor through the binding of either natural hormones or synthetic ER ligands can have a great impact on the physiology and pathophysiology of the organism.

[0004] Various diseases have etiologies and / or pathologies mediated by ER. Collectively, these diseases are called estrogen-dependent diseases. Estrogen is important for female sexual development. Furthermore, estrogen plays an important role in maintaining the regulation of bone density and blood lipid levels and is also thought to have a neuroprotective effect. As a result, decreased estrogen production in postmenopausal women is associated with many diseases such as osteoporosis, atherosclerosis, depression, and cognitive impairment. Conversely, certain types of proliferative diseases, such as breast cancer and uterine cancer, as well as endometriosis, are stimulated by estrogen. Therefore, anti-estrogen agents i.e., estrogen antagonists) have utility in the prevention and treatment of these types of disorders.

[0005] Estrogen receptors typically come in two different types, called α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Both ERs are widely expressed in different tissue types but there are some clear differences in their expression patterns. ERα is present in the uterine endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In males, the ERα protein is present in the epithelial tissue of the efferent ducts. The expression of the ERβ protein has been reported in the kidney, brain, bone, heart, lung, intestinal mucosa, prostate, and endothelial cells. Therefore, the development of selective ligands may

[0006] maintain the beneficial aspects of estrogen.

[0006] Breast cancer is the most common malignancy affecting women, and the disease incidence is increasing worldwide. In particular, estrogen acts as an endocrine growth factor for at least one-third of breast cancers. Depriving the tumor of this stimulus is considered a treatment for advanced disease in pre-menopausal women. This treatment can be achieved surgically, by radiotherapy, or by medically removing ovarian function, and in post-menopausal women by using aromatase inhibitors.

[0007] Another way to achieve estrogen withdrawal is to antagonize estrogen using anti-estrogen agents. Anti-estrogen agents are drugs that bind to estrogen receptors (ERs) present in estrogen-responsive tissues and compete with them. Conventional non-steroidal anti-estrogen agents, such as tamoxifen, efficiently compete with ER binding, but their effectiveness is often limited by the partial agonism they exhibit, and for this reason estrogen The inhibition of ER-mediated activity becomes incomplete. It has a high affinity for ER and no agonist effect Specific, i.e., "pure", anti-estrogen agents that do not have an agonist effect have advantages over conventional non-steroidal anti-estrogen agents in the treatment of estrogen-dependent diseases would. Fulvestrant is the first drug of a new class of potent and pure anti-estrogen agents and has no partial agonist activity or estrogen-like activity associated with currently marketed anti-estrogen agents such as tamoxifen Thus, there is a need for other ways to antagonize the ER receptor. One approach is to develop selective ER downregulators or ER degraders that reduce ER expression either at the transcriptional level or the protein level

[0008]

[0009] Most small molecule drugs bind closely and specifically to enzymes or receptors in well-defined pockets. On the other hand, it is well known that it is difficult to target protein-protein interactions using small molecule compounds because the contact surface of proteins is large and the interfaces involved are shallow grooves or flat interfaces E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity on ubiquitination. Therefore, they are more attractive therapeutic targets than general proteasome inhibitors because they have specificity for specific protein substrates The development of E3 ligase ligands has been found to be partially difficult because of the fact that protein-protein interactions have to be disrupted However, recent developments have shown that ​​​​​​​​​​Certain ligands that bind to these ligases have been provided. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, additional compounds targeting E3 ligases have been reported, but the field remains largely undeveloped. For example, since the discovery of nutlin, the first small molecule mouse double minute 2 homolog (MDM2) inhibitor, additional compounds targeting the MDM2 (i.e., human double minute 2 or HDM2) E3 ligase have been reported (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994). However, the field remains largely undeveloped. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, additional compounds targeting E3 ligases have been reported However, the field remains largely undeveloped. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, additional compounds targeting E3 ligases have been reported However, the field remains largely undeveloped. For example, since the discovery of nutlin, the first small molecule mouse double minute 2 homolog (MDM2) inhibitor, additional compounds targeting the MDM2 (i.e., human double minute 2 or HDM2) E3 ligase have been reported However, the field remains largely undeveloped. For example, since the discovery of nutlin, the first small molecule mouse double minute 2 homolog (MDM2) inhibitor, additional compounds targeting the MDM2 (i.e., human double minute 2 or HDM2) E3 ligase have been reported (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0010] The tumor suppressor p53 plays an important role in the arrest of cell proliferation and apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7 , 979-982), and the inactivation of p53 has been proposed as one of the important pathways for tumor cell survival (A. J . Levine, et al. Nature (2000), 408, 307-310). Mutations in p53 are found in approximately 50 % of cancer patients (M. Hollstein, et al. Science (1991), 233, 49-53), while patients with wild type p53 often show downregulation of p53 by MDM2 through protein-protein interactions between p53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). In the normal cell state without oncogenic stress signals, MDM2 keeps p53 at low concentrations In the normal cell state without oncogenic stress signals, MDM2 keeps p53 at low concentrations In the normal cell state without oncogenic stress signals, MDM2 keeps p53 at low concentrations is maintained. In response to DNA damage or cellular stress, the level of p53 increases, and furthermore, an increase in MDM2 also occurs due to the feedback loop from the p53 / MDM 2 autoregulatory system. In other words, p53 controls MDM2 at the transcriptional level, and MDM2 controls p53 at its activity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

[0011] The downregulation of p53 by MDM2 can be explained by several mechanisms. First, MDM2 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). Second, MDM2 shuttles p53 back and forth from the nucleus to the cytoplasm and promotes its proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 has intrinsic E3 ligase activity and binds ubiquitin to p53, causing it to be degraded via the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Since MDM2 functions as an E3 ligase, recruiting MDM2 to disease-causing proteins and enabling it to exert its ubiquitination and degradation activities is a very interesting drug development approach. One of the E3 ligases with attractive therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB. This complex further consists of elongin B and C, Cul2, and Rbx1.

[0012] ​ It becomes. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), which is at a low level In response to oxygen, for example, VEGF of vascular endothelial growth factor, and erythropoietin of erythrocyte-inducible cytokine It is a transcription factor that upregulates genes such as. The first small molecule ligand of von Hippel-Lindau (VHL) for the substrate recognition subunit of E3 ligase Was prepared, the crystal structure was obtained, and it was confirmed that this compound mimics the binding mode of the transcription factor HIF -1α, which is the main substrate of VHL.

[0013] Cereblon is a protein encoded by the CRBN gene in humans. The ortholog of CR BN is highly conserved from plants to humans, indicating its physiological Importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 ( DDB1), cullin-4A (CUL4A), and cullin 1 (Cullins1) regulator of 1 (RO C1). This complex ubiquitinates many other proteins . Through a mechanism that has not been fully elucidated, the Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates a number of developmental processes such as, for example, the formation of limbs and otic vesicles . This ubiquitin ligase complex has finally been concluded to be important for limb Growth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

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

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

[0016] Nos. 2015-0291562 and 2014-0356322, which are incorporated herein by reference. (including compounds described in FunctionalityThe sex compound recruits the endogenous protein to the E3 ubiquitin ligase and functions to degrade it. In particular, the patent publication Functionality describes bispecific or proteolytically degradable targeted chimeric (PROTAC: proteolysis targeting chimeric) compounds that have been found useful as regulators of the targeted ubiquitination of various polypeptides and other proteins, and those polypeptides and other proteins are degraded and / or inhibited by other means by the bispecific compounds. Functionality

[0017] The present disclosure identifies compounds capable of inhibiting estrogen receptor function, including compounds that degrade the estrogen receptor. SUMMARY OF THE INVENTION

[0018] The present disclosure describes bispecific Functionality compounds and methods of using them, which compounds recruit the endogenous protein to the E3 ubiquitin ligase and function to degrade it. In particular, the present disclosure provides bispecific or proteolytically degradable targeted chimeric (PROTAC: proteolysis ta Functionality rgeting chimeric) compounds that have been found useful as regulators of the targeted ubiquitination of various polypeptides and other proteins, and those poly peptides and other proteins are degraded and / or inhibited by other means by the bispecific compounds described herein. The advantages of the compounds provided herein are that they may have a wide range of pharmacological activities and, in fact, target from virtually any protein species or family Functionality and / or inhibited by other means. activities and can potentially target virtually any protein species or family. ​​​It is compatible with the degradation / inhibition of polypeptides. Furthermore, this specification provides a method of using an effective amount of the compounds described herein for the treatment or amelioration of conditions such as cancers, for example breast cancer. In one aspect, the present disclosure provides a bivalent compound or a PROTAC compound, which compound comprises an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase, or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand, or "PTM" group), whereby the target protein / polypeptide is positioned in proximity to the ubiquitin ligase and the degradation (and inhibition) of the protein is effected. Accordingly, in one aspect, the present disclosure provides a bivalent compound or a PROTAC compound, which compound comprises an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase, or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand, or "PTM" group), whereby the target protein / polypeptide is positioned in proximity to the ubiquitin ligase and the degradation (and inhibition) of the protein is effected.

[0019] In a preferred embodiment, the ULM (ubiquitin ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). Functionality For example, the structure of the bivalent compound can be shown as follows: The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. In a preferred embodiment, the ULM (ubiquitin ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of the bivalent compound can be shown as follows: The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. In a preferred embodiment, the ULM (ubiquitin ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of the bivalent compound can be shown as follows: The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. In a preferred embodiment, the ULM (ubiquitin ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of the bivalent compound can be shown as follows: The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. Functionality The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only.

[0020]

Chemical formula

[0021] The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. The positions of the PTM moieties and CLM moieties (e.g., VLM, CLM, MLM, ILM, or combinations thereof) exemplified herein, as well as the number thereof, are provided by way of example only. has been made and it is not intended to limit the compound in any way. As will be understood by those skilled in the art As will be understood by those skilled in the art, the bifunctional compounds described herein Functionality can be synthesized so that the number and position of each Functionality functional moiety can be varied as desired.

[0022] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this example Functionality the structure of the bifunctional compound can be shown as follows: In this example Functionality the structure of the bifunctional compound can be shown as follows:

[0023]

Chemical formula

[0024] wherein PTM is a protein / polypeptide targeting moiety, L is a linker, for example a bond or chemical group that binds PTM and ULM and ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) or von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM) or cereblon E3 ubiquitin ligase binding moiety (CLM), or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM). (VLM) or cereblon E3 ubiquitin ligase binding moiety (CLM), or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM). For example, the structure of the bifunctional compound can be shown as follows:

[0025] For example, the structure of the bifunctional compound can be shown as follows: Functionality For example, the structure of the bifunctional compound can be shown as follows:

[0026]

Chemical formula

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

[0028] In certain embodiments, the present disclosure provides compounds of formula (I) or formula (II) below:

[0029]

Chemical formula

[0030] Wherein: Each X PTM is independently CH, N; ULM is ILM or VLM or CLM or MLM; L is a tetrahydronaphthalene moiety or a tetrahydroisoquinoline moiety, and a binding moiety that binds at least one of VLM, CLM, ILM, VLM, or a combination thereof or a linker moiety; Each R PTM1 is independently OH, halogen, alkoxy (e.g., methoxy or ethoxy) , O(CO)R PTM wherein the substitution may be mono-substituted, di-substituted or tri-substituted, and thus R PTM is an alkyl or cycloalkyl group or aryl group with 1 to 6 carbons ; Each R PTM2 is independently H, halogen, CN, CF3, linear or branched alkyl, alkoxy is -Si-(for example, methoxy or ethoxy), wherein the substitution may be mono - or di - substitution and; each R PTM3 is independently H, halogen, and the substitution may be mono - or di - substitution; and and R PTM4 is H, alkyl, methyl, or ethyl.

[0031] In certain preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. Thus in certain additional embodiments, the ILM of the bivalent compound Functionality comprises the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or non - natural mimics thereof, respectively. In additional embodiments, the amino acids of the AVPI tetrapeptide fragment are joined to each other via an amide bond (i.e., -C(O)NH - or -NHC(O)-).

[0032] In certain embodiments, the compounds described herein comprise a plurality independently selected from ULM, a plurality of PTM, a plurality of chemical linkers, or combinations thereof.

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

[0034] In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Further more, other expected VLMs include those in U.S. Patent Application Publication No. 2014 / 0302 2523, as discussed above, the entire disclosure of which is incorporated herein by reference.

[0035] In certain embodiments, the CLM is selected from imide, thioimide, amide, or thioamide. ​​​Includes an induced chemical group. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof is. Other expected CLMs include the CLMs in US Patent Application Publication No. 2015 / 0291562, which application is incorporated herein by reference in its entirety.

[0036] In certain embodiments, the MLM can be natrin or a derivative thereof. Further, other expected MLMs include the MLMs in US Patent Application No. 15 / 206,497 filed on July 11, 2016 as discussed above, which application is incorporated herein by reference in its entirety. In certain additional embodiments, the Functionality MLM of the binary compound includes chemical moieties such as substituted imidazoline, substituted spi ro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted substituted morpholinone, substituted pi rolopyrimidine, substituted imidazolopyridine, substituted thiazoloimidazoline, substituted pyrrolopyro lidinone, and substituted isoquinolinone.

[0037] In additional embodiments, the MLM includes the above-described core structure with adjacent bis-aryl substitution positioned in a cis configuration or a trans configuration.

[0038] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a connector having a linear number of non-hydrogen atoms in the range of 1 to 20. The connector "L" is, for example, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, car It may contain functional groups such as boronic acid, thioether, sulfoxide, and sulfone, but is not limited to these. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Substitution with halogens such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitution, single or multiple fluorines may be included. These are not limited. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Substitution with halogens such as Cl, F, Br, and I may be included in the linker. This is okay. In the case of fluorine substitution, single or multiple fluorines may be included.

[0039] In certain embodiments, VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and carboxylic acid in trans-3-hydroxyproline are functional as amides. Here, both the nitrogen and carboxylic acid in trans-3-hydroxyproline are functional as amides. This is okay.

[0040] In certain embodiments, CLM contains a chemical group derived from imide, thioimide, amide, or thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other expected CLMs include those in US Patent Application Publication No. 2015-0291562, which application is incorporated herein by reference in its entirety. In some embodiments, CLM is a derivative of piperidine-2,6-dione, where piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic compound with a bond as a C-N bond or a C-C bond. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their derivatives. In certain embodiments, the chemical group is derived from imide, thioimide, amide, or thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. In certain embodiments, CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other expected CLMs include those in US Patent Application Publication No. 2015-0291562, which application is incorporated herein by reference in its entirety. In some embodiments, CLM is a derivative of piperidine-2,6-dione, where piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic compound with a bond as a C-N bond or a C-C bond. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their derivatives. In certain embodiments, CLM is a derivative of piperidine-2,6-dione, where piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic compound with a bond as a C-N bond or a C-C bond. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their derivatives. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their derivatives. In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is 1

[0041] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is 1 It is a connector having a linear non-hydrogen atom number in the range of ~20. The "L" of the connector is For example, it may contain functional groups such as ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, car boxylic acid, thioether, sulfoxide, and sulfone, but is not limited thereto. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Substitution with halogens such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitution, single or multiple fluorines may be included.

[0042] In additional embodiments, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition regulates protein degradation and / or inhibition in a patient or subject, such as an animal like a human, and is used for the treatment or improvement of a pathological condition or state regulated via the degraded protein. In certain embodiments, the therapeutic composition described herein is used to cause degradation of a target protein for the purpose of treating or improving a disease, such as cancer. In certain additional embodiments, the disease is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof. In yet another aspect, 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, or PTM and CLM, or PTM and MLM coupled via a linker moiety as described herein. ... a dimer described herein Functionalityadministering a sex compound, wherein VLM / ILM / CLM / MLM is linked to the PTM via a linker, targeting and degrading a protein that binds to the PTM . Similarly, a PTM (e.g., a tetrahydronaphthalene moiety, or a tetrahydroisoquinoline moiety) binds via a linker to at least one of VLM, CLM, MLM, ILM, or a combination thereof to target and degrade a protein or polypeptide . Degradation of the target protein occurs when the target protein is placed in proximity to an E3 ubiquitin ligase, resulting in degradation of the target protein / inhibition of the effect of the target protein , and control of the protein level. The protein level control provided by the present disclosure provides treatment of a disease state or condition, which is regulated via the target protein by reducing the level of that protein in patient cells . In yet another aspect, the present specification provides a method of treating or ameliorating a disease, disorder or symptom thereof in a subject or patient, such as an animal such as a human , the method comprising administering to the subject in need thereof a composition comprising an effective amount, such as a therapeutically effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate a disease or disorder or symptom thereof in the subject .

[0044]

[0045] In yet another aspect, the present specification provides a method of identifying the effect of degrading a target protein in a biological system using a compound according to the present disclosure .

[0045] The foregoing general description of the utility is presented for illustrative purposes only and is not intended to limit the disclosure and the appended claims. Additional objects and advantages related to the compositions, methods, and processes of the disclosure will be apparent to those of ordinary skill in the art upon review of the claims, detailed description, and examples. For example, the various aspects and embodiments of the disclosure can be used in many combinations, all of which are explicitly contemplated herein. These additional aspects and embodiments are explicitly included within the scope of the disclosure. Publications and other materials used herein to explain the background of the disclosure and, in certain cases, to provide additional details regarding its implementation are incorporated by reference. The appended drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are provided for the purpose of illustration only and are not to be construed as limiting the disclosure. Further objects, features, and advantages of the disclosure will become apparent from the following detailed description in conjunction with the appended drawings that illustrate exemplary embodiments of the disclosure.

[0046]

Brief Description of the Drawings

[0047]

FIG. 1A

FIG. 1B

FIG. 2

FIG. 3

FIG. 4

FIG. 5

FIG. 6

FIG. 7

DETAILED DESCRIPTION OF THE INVENTION

[0048] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. This is the case. Those skilled in the art can make modifications and changes to the embodiments described in this specification without departing from the spirit or scope of the present disclosure. All published documents, patent applications, patents, drawings, and other references mentioned in this specification are hereby incorporated by reference in their entirety. explicitly incorporated.

[0049] E3 ubiquitin ligase proteins (such as apoptosis inhibitor (IAP), von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon E3 ubiquitin ligase, or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) and a target protein are bound to a target protein by a bifunctional construct or a chimeric construct. When the E3 ubiquitin ligase protein and the target protein are placed in proximity, the E3 ubiquitin ligase protein ubiquitinates the target protein. Compositions and methods related to this surprising and unexpected discovery. Functionality ubiquitinates the target protein, which is a surprising and unexpected discovery. Compositions and methods related to this discovery are provided. The present disclosure thus provides a method for the preparation of a protein target binding moiety (PTM)-linked E. coli. 3. Compounds and compositions comprising ubiquitin ligase binding moieties (ULM) This allows ubiquitination of selected target proteins (e.g., the estrogen receptor [ER]). This leads to the degradation of the target protein by the proteasome (see Figures 1A and 1B). The disclosure also provides libraries of compositions and uses thereof.

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

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

[0052] When ranges of values are provided, and unless otherwise specified explicitly by the context (for example, in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), each intervening value between the upper and lower limits of that range and any other specified range, down to one tenth of the lower unit, , or the intervening values within that specified range, is to be understood as being included within the scope of the present disclosure. It should be understood that the upper and lower limits of these smaller ranges may independently be included within a smaller range, and this is also included within the present disclosure and forms any specifically excluded boundary values within the specified range. If the specified range includes one or both of the boundary values, ranges excluding either, both of those included boundary values are also included within the present disclosure.

[0053] The following terms are used to describe the present disclosure. Unless a term is specifically defined in this specification, the term is given the meaning recognized in the art by those skilled in the art in connection with its use in the description of the present disclosure.

[0054] As used herein, the articles "a" and "an" are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or a plurality of elements.

[0055] As used in this specification and the claims of this specification, the phrase "and / or" is to be understood to mean "either, or both" of the elements so joined. That is, in some instances the elements are joined and in other instances the elements are not joined. ​​​​is the case. Multiple elements listed using "and / or" should be interpreted in the same way. That is, "one or more" of the elements are combined in that way. Other elements other than the elements specifically specified by the "and / or" clause may exist arbitrarily regardless of their relevance to those specifically specified elements. Therefore, as a non-limiting example, when used in conjunction with a non-limiting phrase such as "including", for example, the reference to "A and / or B" in one embodiment refers only to A (optionally including elements other than B), and in another embodiment refers only to B (optionally including elements other than A), and in yet another embodiment refers to both A and B (optionally including other elements).

[0056] When used in this specification and the claims, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive. That is, it includes at least one of many elements, or a list of elements, but also includes a plurality, and optionally additional items not listed. For example, terms such as "only one of ~", or "exactly one of ~", or when used in a claim, "consisting of ~", which clearly implies the opposite, only refer to the inclusion of exactly one element among many elements, or a list of elements. Generally, when used in this specification, the term "or" is only used when an exclusive term such as "either", "one of ~", "only one of ~", or "exactly one of ~" precedes it. refers to the inclusion of exactly one element among many elements, or a list of elements. Generally, when used in this specification, the term "or", for example, terms such as "either", "one of ~", "only one of ~", or "exactly one of ~" precede it. ​​​​​should be construed as indicating an exclusive alternative (i.e., "one or the other, but not both") and should be interpreted accordingly.

[0057] In the claims, as well as in the above description, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "composed of", etc. are to be construed as non-limiting, that is, to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are to be construed as limiting or semi-limiting transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Examination Guidelines. including)"," carrying"," having"," containing g)"," involving"," holding"," composed of f)", etc. are to be construed as non-limiting, that is, to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are to be construed as limiting or semi-limiting transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Examination Guidelines. are to be construed as limiting or semi-limiting transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Examination Guidelines. are to be construed as limiting or semi-limiting transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Examination Guidelines. This is set forth in section 2111.03 of the United States Patent Examination Guidelines. This is set forth in section 2111.03 of the United States Patent Examination Guidelines.

[0058] As used herein, in the specification and claims, with respect to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more of the elements in the list, but not necessarily including at least one of all of the elements specifically recited in the list of elements, nor excluding any combinations of elements in the list. Further, this definition allows for the possibility of elements existing arbitrarily, whether or not specifically identified, in addition to the specifically identified elements in the list to which the phrase "at least one" refers, regardless of the presence or absence of a relationship between those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" should be understood to mean at least one element selected from any one or more of the elements in the list, but not necessarily including at least one of all of the elements specifically recited in the list of elements, nor excluding any combinations of elements in the list. Further, this definition allows for the possibility of elements existing arbitrarily, whether or not specifically identified, in addition to the specifically identified elements in the list to which the phrase "at least one" refers, regardless of the presence or absence of a relationship between those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" but not necessarily including at least one of all of the elements specifically recited in the list of elements, nor excluding any combinations of elements in the list. Further, this definition allows for the possibility of elements existing arbitrarily, whether or not specifically identified, in addition to the specifically identified elements in the list to which the phrase "at least one" refers, regardless of the presence or absence of a relationship between those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" should be understood to mean at least one element selected from any one or more of the elements in the list, but not necessarily including at least one of all of the elements specifically recited in the list of elements, nor excluding any combinations of elements in the list. Further, this definition allows for the possibility of elements existing arbitrarily, whether or not specifically identified, in addition to the specifically identified elements in the list to which the phrase "at least one" refers, regardless of the presence or absence of a relationship between those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" should be understood to mean at least one element selected from any one or more of the elements in the list, "at least one" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") refers, in one embodiment, to at least one A that optionally includes a plurality of A and where B is absent (optionally including elements other than B). In another embodiment, it refers to at least one B that optionally includes a plurality of B and where A is absent (optionally including elements other than A). In yet another embodiment, it refers to at least one A that optionally includes a plurality of A and at least one B that optionally includes a plurality of B (optionally including other elements).

[0059] In a particular method described herein that includes a plurality of steps or operations, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are recited, unless otherwise indicated by the context.

[0060] The terms "co-administration" and "co-administering" or "combination therapy" refer to both co-administration (simultaneous administration of two or more therapeutic agents) and administering the therapeutic agents at different times while they are present in the patient's body to some extent, preferably with an effective amount present simultaneously (administering one or more therapeutic agents at a time different from the time of administration of an additional therapeutic agent). In a particular preferred embodiment, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly including an anti-cancer agent. In a particularly preferred embodiment, co-administration of the

[0061] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed in this specification, including tautomers, positional isomers, geometric isomers, and, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or deuterated forms where appropriate. A deuterated small molecule is a small molecule in which one or more of the hydrogen atoms contained in the drug molecule are replaced by deuterium.

[0062] Within the context of its use herein, the term "compound" generally refers to a single compound, but may also include, for example, stereoisomers, positional isomers and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as other compounds such as specific enantiomers or mixtures enriched in specific enantiomers. The term also refers, within the context, to prodrug forms of the compound modified to facilitate administration and delivery of the compound to the active site. Note that in the description of the present compounds, many substituents, and in particular variables associated therewith, are described. It will be understood by those skilled in the art that the molecules described herein are stable compounds as outlined below. When bonds are shown, both double and single bonds are represented or understood in the context of known rules regarding the compounds shown and the valence interactions.

[0063] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein and target that substrate protein for degradation. For example, ​​In conjunction with, or alone, with an E2 ubiquitin - conjugating enzyme, ubiquitin is added to lysine on a target protein, and then the specific protein substrate is targeted for proteasomal degradation. The IA P E3 ubiquitin ligase protein. Thus, in complex with an E2 ubiquitin - conjugating enzyme, or alone, the E3 ubiquitin ligase is involved in the transfer of ubiquitin to a target protein. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is added to the first ubiquitin, and a third ubiquitin is added to the second ubiquitin. Polyubiquitination marks a protein for proteasomal degradation. However, there are also some ubiquitination events limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins do not become targets for proteasomal degradation, but instead, for example, their intracellular location and function may be altered through binding to other proteins having a domain capable of binding ubiquitin. Further complicating the issue is the fact that another lysine on ubiquitin can be targeted by the E3 and can form a chain. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to generate polyubiquitin recognized by the proteasome. The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient However, there are also some ubiquitination events limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins do not become targets for proteasomal degradation, but instead, for example, their intracellular location and function may be altered through binding to other proteins having a domain capable of binding ubiquitin. The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient However, there are also some ubiquitination events limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins do not become targets for proteasomal degradation, but instead, for example, their intracellular location and function may be altered through binding to other proteins having a domain capable of binding ubiquitin. Further complicating the issue is the fact that another lysine on ubiquitin can be targeted by the E3 and can form a chain. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to generate polyubiquitin recognized by the proteasome. The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient However, there are also some ubiquitination events limited to monoubiquitination, in which case only one

[0064] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or a domestic animal, to whom treatment, including prophylactic treatment using the compositions according to the present disclosure, is provided. For example, for the treatment of specific infections, conditions or pathologies specific to a particular animal such as a human patient Regarding treatment, the term patient refers to certain animals including household animals such as dogs or cats, or agricultural animals such as horses , cows, sheep, etc. Generally, in the present disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by the context in which the term is used.

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

[0066] Compounds and Compositions In one aspect, the present specification provides a compound comprising an E3 ubiquitin ligase binding moiety (ULM) that is an IAP E3 ubiquitin ligase binding moiety (ILM), a cereblon E3 ubiquitin ligase binding moiety (CLM), a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), and / or a mouse double minute 2 homologue (M DM2) E3 ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, the ULM is chemically linked to a target protein binding moiety (PTM) via a linker (L) according to the following structure: (A) PTM-L-ULM wherein L is a binding or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety , and PTM is a target protein binding moiety. The number of moieties, and / or relative positions, in the compounds described herein are provided for purposes of illustration only. Those skilled in the art will recognize that As will be appreciated, the compounds described herein can be synthesized using any desired number of each functional group moiety and / or at the relative positions of each functional group moiety. and / or

[0067] The terms ULM, ILM, VLM, MLM, and CLM are used in their broad sense unless the context indicates otherwise. For example, the term ULM encompasses all ULMs that bind to IAP (i.e., ILM), MDM2 ( i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Further, the term ILM encompasses all possible IAP E3 ubiquitin ligase binding moieties, the term MLM encompasses all possible MDM2 E3 ubiquitin ligase binding moieties, the term VLM encompasses all possible V HL binding moieties, and the term CLM encompasses all cereblon binding moieties including .

[0068] In another aspect, the present disclosure provides bifunctional or multifunctional Functionality compounds (e.g., PROTACs) useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compound is directly or indirectly, e.g., covalently, bound to an Functionality ILM or VLM or CLM or MLM that is bound to a moiety that binds to the target protein (i.e., the protein targeting moiety or "PTM"). In certain embodiments, the ILM / VLM / CLM / MLM and PTM are linked or bound via a chemical linker (L). The ILM binds to an IAP E3 ubiquitin ligase , the VLM binds to VHL, the CLM binds to a cereblon E3 ubiquitin ligase, and the MLM binds to MDM2 and / or the MLM binds to MDM2 Yobi MLM binds to the MDM2 E3 ubiquitin ligase, and PTM recognizes the target protein and promotes the degradation of the target protein by placing the target protein and the ubiquitin ligase protein in proximity to each other. The interaction between each part and its target promotes the degradation of the target protein. Exemplary bivalent compounds can be shown as follows: By recognizing the target protein and arranging the target protein and the ubiquitin ligase protein in proximity to each other, the degradation of the target protein is promoted by the interaction between each part and its target. Exemplary bivalent compounds can be shown as follows: (B) PTM-ILM Off Energy In certain embodiments, the bivalent compound further comprises a chemical linker (L). For example, the bivalent compound can be shown as follows: (B) PTM-ILM (C) PTM-CLM (D) PTM-VLM (E) PTM-MLM In certain embodiments, the bivalent compound further comprises a chemical linker (L). For example, the bivalent compound can be shown as follows: Functionality (F) PTM-L-ILM Functionality (G) PTM-L-CLM (F) PTM-L-ILM (G) PTM-L-CLM (H) PTM-L-VLM (I) PTM-L-MLM Wherein PTM is a protein / polypeptide targeting moiety, L is a chemical linker, ILM is an IAP E3 ubiquitin ligase binding moiety, CLM is a cereblon E3 ubiquitin ligase binding moiety, VLM is a VHL binding moiety, and MLM is an MDM2 E3 ubiquitin ligase binding moiety. In certain embodiments, ULM (e.g., ILM, CLM, VLM, or MLM) has an activity or binds to an E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, MDM2 E3 ubiquitin ligase) with an IC of less than about 200 μM. The IC is determined according to any method known in the art, such as a fluorescence polarization assay.

[0069] In certain embodiments, ULM (e.g., ILM, CLM, VLM, or MLM) shows activity or binds to an E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, MDM2 E3 ubiquitin ligase) with an IC of less than about 200 μM. The IC 50 is determined according to any method known in the art, such as a fluorescence polarization assay. The IC is determined according to any method known in the art, such as a fluorescence polarization assay. 50 is determined according to any method known in the art, such as a fluorescence polarization assay. It can be done.

[0070] In certain additional embodiments, the two Functionality sex compounds described herein are about 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 about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 , 0.001 nM, or about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM of IC 50 shows activity.

[0071] In certain embodiments, the compounds described herein are a plurality of PTMs (targeting the same or different protein targets), a plurality of ULM, one or more ULM (i.e., a plurality / different E3 ubiquitin ligases, such as VHL, IAP, cereblon, and / or MDM2), or combinations thereof. In any of the aspects of the embodiments described herein wherein the PTM and ULM (e.g., ILM, VLM, CLM, and / or MLM) may be bound directly, or via one or more chemical linkers, or combinations thereof. In additional embodiments, when the compound has a plurality of ULM, those ULM may be directed against the same E3 ubiquitin ligase or each ULM may specifically bind to a different E3 ubiquitin ligase. In still further embodiments, when the compound has a plurality of PTMs, those PTMs may bind to the same target protein or each PTM may specifically bind to a different target ta n protein. are directed against the same E3 ubiquitin ligase, or each ULM may specifically bind to a different E3 ubiquitin ligase. In still further embodiments, when the compound has a plurality of PTMs, those PTMs may bind to the same target protein or each PTM may specifically bind to a different target ta n protein.

[0072] In certain embodiments, when the compound comprises a plurality of ULM, the ULM are identical. Additionally in exemplary embodiments, the compound comprises at least one PTM that is directly or chemically linked to the ULM, or both, via a linker (L). In certain additional embodiments, a compound comprising a plurality of ULM further comprises a plurality of PTM. Further in additional embodiments, the PTM are identical or optionally different. In yet further embodiments, when the PTM are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0073] In certain embodiments, the compound may comprise a plurality of ULM and / or a plurality of ULM'. In further embodiments, a compound comprising at least two different ULM, a plurality of ULM, and / or a plurality of ULM' further comprises at least one PTM that is directly or via a chemical linker, or both, linked to the ULM or ULM'. In any of the embodiments described herein, a compound comprising at least two different ULM may further comprise a plurality of PTM. In further additional embodiments, the PTM are identical or optionally different. In yet further embodiments, when the PTM are different, each PTM may bind to the same protein target or may specifically bind to different protein targets. In further embodiments, the PTM themselves are ULM (or ULM'), such as ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM', for example.

[0074] In additional embodiments, the present specification includes its enantiomers, diastereomers, solvates, and polymorphs, including its pharmaceutically acceptable salt forms, such as acid salt forms and base salt forms, and provides the compounds described in the present specification.

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

[0076]

Chemical formula

[0077] Wherein: Each X PTM is independently CH, N; ULM is ILM or VLM or CLM or MLM; L is a binding part or linker part that binds a tetrahydronaphthalene moiety or a tetrahydroisoquinoline moiety to at least one of VLM, C LM, ILM, VLM, or a combination thereof; ; Each R PTM1 is independently OH, halogen, alkoxy (e.g., methoxy or ethoxy), O (CO)R PTM , wherein the substitution may be mono-substituted, di-substituted or tri-substituted, and R PTM is an alkyl or cycloalkyl group or aryl group with 1 to 6 carbons ; Each R PTM2 is independently H, halogen, CN, CF3, linear or branched alkyl, alkoxy (e.g., methoxy or ethoxy), wherein the substitution may be mono-substituted or di-substituted ; Each R PTM3 is independently H, halogen, wherein the substitution may be mono-substituted or di-substituted ; and RPTM4 is H, alkyl, methyl, or ethyl.

[0078] The target protein (e.g., estrogen receptor) can bind to the PTM group according to the present disclosure and includes an oligonucleotide sequence and a polypeptide sequence of sufficient length to do so. The PTM group according to the present disclosure specifically binds to, for example, the estrogen receptor (binds to the target protein) and includes any moiety that binds to the target protein. The compositions described below exemplify some of a series of small molecule target protein binding moieties. Such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the target protein. These binding moieties are preferably linked to the ubiquitin ligase binding moiety via a linker and presented in proximity to the ubiquitin ligase to ubiquitinate and degrade the target protein (to which the protein target moiety is bound) for ubiquitination and degradation. ).

[0079] Using the present disclosure, many pathologies and / or conditions may be treated, and such pathologies and / or conditions include any pathology and / or condition in which the protein is in a deregulated state and the patient would benefit from degradation and / or inhibition of the protein.

[0080] In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound or a salt form thereof described herein, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition modulates the degradation and / or inhibition of a protein in a patient or subject, such as an animal such as a human, and the degraded and / or inhibited ​​​For use in the treatment or amelioration of a disease state or condition modulated via a damaged protein is possible. In certain embodiments, the therapeutic compositions described herein can be used to effect degradation of a target protein for the purpose of treating or ameliorating a disease, e.g., cancer. In certain additional embodiments, the disease is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometritis, or a combination thereof.

[0081] In another aspect, the disclosure relates to a method of treating a disease state of a subject in need thereof or ameliorating symptoms of a disease or condition by degrading a protein or polypeptide, wherein the disease state or condition is modulated via the protein or polypeptide, and the method comprises administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one of the compounds described above, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient, and optionally with an additional bioactive agent, wherein the composition is effective for treating or ameliorating the disease, disorder or symptoms thereof of the subject. The methods of the disclosure may be used to treat a number of disease states or conditions, including cancer and / or endometriosis, by administration of an effective amount of at least one of the compounds described herein. The disease state or condition may be a disease caused by a microorganism or a foreign entity such as, for example, a virus, bacterium, fungus, protozoan or other microorganism, or a disease state caused by overexpression of a protein in which the disease state and / or condition occurs. In another aspect, the present specification describes the use of the compounds according to the disclosure in a biological system by using the compounds according to the disclosure in a biological system In another aspect, the present specification describes the use of the compounds according to the disclosure in a biological system The disease state or condition may be a disease caused by a microorganism or a foreign entity such as, for example, a virus, bacterium, fungus, protozoan or other microorganism, or a disease state caused by overexpression of a protein in which the disease state and / or condition occurs. In another aspect, the present specification describes the use of the compounds according to the disclosure in a biological system

[0082] In another aspect, the present specification describes using the compounds according to the disclosure in a biological system Provided is a method for identifying the degradation effect of a target protein.

[0083] The term "target protein" is used in the following specification to describe a protein or polypeptide that is a target to which the disclosed compounds bind and is degraded by a ubiquitin ligase. Such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs thereof, as well as other small molecules that can target a target protein such as an estrogen receptor. These binding moieties are attached to at least one ULM group (e.g., VLM and / or CLM) via at least one linker group L.

[0084] The term "protein target moiety" or "PTM" is used to describe a small molecule that binds to a target protein or other target protein or polypeptide and places / presents the protein or polypeptide in proximity to a ubiquitin ligase such that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include in particular selective estrogen receptor modulators. The compositions described below exemplify some of a series of small molecule target proteins.

[0085] The compounds and compositions described herein exemplify some of a series of small molecule target protein binding moieties of these types. Such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs thereof, as well as other small molecules that can target the target protein. References cited herein below ​ This reference is incorporated herein by reference in its entirety.

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

[0087] [ka]

[0088] During the ceremony: R in formulas (I), (II), (III), (IV), and (V) 1 is selected from H or alkyl ; R in formulas (I), (II), (III), (IV), and (V) 2 is selected from H or alkyl ; R in formulas (I), (II), (III), (IV), and (V) 3 is H, alkyl, cycloalkyl and heterocycloalkyl; R in formulas (I), (II), (III), (IV), and (V) 5 and R 6 are independently H, alkyl , cycloalkyl, heterocycloalkyl, or more preferably selected from the group consisting of: , (II), (III), (IV), and (V) R 5 and R 6 Both are pyrrolidine or piperidin rings. A benzene ring is formed, and the ring may further optionally be fused to 1 to 2 cycloalkyl, heterocycloalkyl , aryl or heteroaryl rings, each of which may then further be fused to another cyclo alkyl, heterocycloalkyl, aryl or heteroaryl ring to form R in formulas (I), (II), (III), (IV), and (V) 3 and R 5 can together form a 5- to 8-membered ring which may further optionally be fused to 1 to 2 cycloalkyl, heterocycloalkyl alkyl, aryl or heteroaryl rings; R in formulas (I), (II), (III), (IV), and (V) 7 is selected from cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, each of which may further optionally be substituted with 1 to 3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero) cycloalkyl, or (hetero)aryl, or R is -C(O)NH-R 7 4 4 and R is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, hetero 4 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, and they may further optionally be substituted with 1 to 3 substituents as described above substituted.

[0089] As described above, P1, P2, P3, and P4 of formula (II) are each an AVPI tetrapeptide fragment ​correlates with A, V, P, and I of or its non-natural mimics. Similarly, each of formulas (I) and (III ) to (V) has a portion that correlates with A, V, P, and I of an AVPI tetrapeptide fragment or its non-natural mimics.

[0090] In any of the compounds described herein, ILM can have the structure of formula (VI), or its non-natural mimics, which is a derivative of an IAP antagonist described in WO 2008 / 014236, or a pharmaceutically acceptable salt or hydrate thereof:

[0091]

Chemical formula

[0092] Wherein: R1 of formula (VI) is independently selected from H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3- C 1O -cycloalkyl, which are unsubstituted or substituted; R2 of formula (VI) is independently selected from H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3- C 1O -cycloalkyl, which are unsubstituted or substituted; R3 of formula (VI) is independently selected from H, -CF3, -C2H 5、 C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkyn yl, -CH2-Z, or any R2 and R3 together form a heterocyclic ring; Each Z of formula (VI) is independently selected from H, -OH, F, Cl, -CH 3、 -CF 3、 -CH2Cl, -CH2F or -CH2OH; R4 of formula (VI) is C1-C​​​​16 linear or branched alkyl, C1-C 16 -alkenyl, C1-C 16 -a lukinyl, C3-C 10 -cycloalkyl, -(CH2) 0-6 -Z 1、 -(CH2) 0-6 -aryl, and -(CH2)0 -6 is independently selected from -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; R5 of 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 -cycloalkyl lu-(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 independently selected or R5 is selected from amino acid residues, wherein the substituents of alkyl, cycloalkyl, phenyl, and aryl are unsubstituted or substituted; Z1 of formula (VI) is -N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 1O )-C(O)-(CH2)0-6 -C 3-7 -cycloA Lukyl, -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)-O-C 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, -O-C(O)-C 1-10 -alkyl, -O-C(O)-(CH2) 1-6 -C 3- 7-cycloalkyl, -O-C(O)-(CH2) 0-6 -phenyl, -O-C(O)-(CH2) 1-6 -het is independently selected from selected, where alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; het in formula (VI) is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, or an 8- to 12-membered fused ring system containing at least one 5- to 7-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and is independently selected from the heterocyclic ring or fused ring system that is unsubstituted or substituted on a carbon atom or a nitrogen atom; R in formula (VI) is selected from H, -CH -CF3, -CH2OH, or -CH2Cl; 10 is selected from 3、 -CF3, -CH2OH, or -CH2Cl; R and R 11 in formula (VI) 12 are selected from 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 together form het, and U in formula (VI) is independently as shown in formula (VII) below:

[0093] [ka]

[0094] During the ceremony: Each n in formula (VII) is independently selected from 0 to 5; X in formula (VII) is selected from the group of -CH and N; R in formula (VII) a and R b are independently an O atom, a S atom, or a N atom, or C 0-8 -Alkyl wherein one or more of the carbon atoms in the alkyl chain is optionally selected from the group consisting of O, S or is substituted with a heteroatom selected from N, where each alkyl is independently unsubstituted. or replaced; R in formula (VII) d is Re-Q-(R f ) p (R g ) q、 and Ar1-D-Ar2; R in formula (VII) c is selected from the group of H, or any R c and R d Both are cycloalloys. Kill or form het, R c and R d When R5 forms a cycloalkyl or het, is bonded to the formed ring with a C atom or an N atom; p and q in formula (VII) are independently selected from 0 or 1; R in formula (VII) e is selected from the group of C 1-8 -alkyl and alkylidene, and each Re is unsubstituted or substituted; Q is selected from the group of N, O, S, S(O) and S(O)2; Ar1 and Ar2 in formula (VII) are independently selected from the group 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 、-O-C 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phen yl, 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 )、-S-R 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 、-S-C t-10 -alkyl, aryl-C 1-4 -alkyl, or het-C1 -4 -alkyl, where alkyl, cycloalkyl, het and aryl are unsubstituted replaced or substituted -SO2-C -alkyl, -SO2-C 1-2 -alkyl, -SO2-C 1-2 -alkylphenyl, -O-C 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 group, where r is 0 to 2 1,3-dioxolanes, or C 1-7 -alkyl-OH where alkyl, alkylene or arylene is unsubstituted or one or more hal ogens, OH, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, or -CF3 substituted; or each D is independently selected from N(R h ); 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, -C-O-C 0-10 -alkyl-aryl, -SO2-C 1-10 -alkyl, or -SO2 -(C 0-10 -alkylaryl) group; 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, -O-C 1-10-Alkyl, -(CH2) 0-6 -C 3-7 -Cycloalkyl -, -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 )、-S-R 13、 -S(O)-R 13 、-S(O)2-R 13、 -S(O)2-NR1 3R 14、 Or -NR 13 -S(O)2-R 14 Selected from the group of, wherein each alkyl, cycloalkyl, And aryl is unsubstituted or substituted; and any R6, R7, R8 and R9 Together optionally form a ring system; R of formula (VII) 13 And R 14 Are independently H, C 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -Cycloalkyl -, -(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 -[[]]END ​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 group, where each alkyl, cycloalkyl, and aryl is unsubstituted or substituted; or any R 13 and R 14 together with the nitrogen atom form het; wherein the alkyl substituents of R and R 13 in formula (VII) are unsubstituted or substituted, 14 and when substituted, are substituted by one or more substituents selected from C -alkyl, halogen, OH, -O-C 1-10 -alkyl, -S-C 1-6 -alkyl, and -CF3; and R 1-6 -alkyl, and substituted phenyl or aryl of R 13 and R 14 are substituted by one or more substituents selected from halogen, hydroxyl, C 1-4 -alkyl, C 1-4 -a lkoxy, nitro, -CN, -O-C(O)-C 1-4 -alkyl, and -C(O)-O-C 1-4 -aryl. Selected ones are substituted by one or more substituents.

[0095] In certain embodiments, the compound is attached to the ILM of formula (VI) or a non-natural mimetic thereof by at least one additional independently selected linker group, and is independently selected It further includes a second ILM. In certain embodiments, the second ILM is a derivative of formula (VI) or a non-natural mimetic thereof. In certain embodiments, at least one additional independently selected linker group includes two additional independently selected linker groups that chemically bond the ILM and the second ILM. In certain embodiments, at least one additional linker group for the ILM of formula (VI) or a non-natural mimetic thereof chemically bonds a group selected from R4 and R5. For example, the ILM of formula (VI) or a non-natural mimetic thereof and the second ILM of formula (VI) or a non-natural mimetic thereof can be bonded as shown below:

[0096]

Chemical Structure

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

[0098]

Chemical Structure

[0099]

Chemical Structure

[0100] These are derivatives of the IAP antagonists described in WO2008 / 014236. In any of the compounds described herein, the ILM can have the structure of formula (VIII) or a non-natural mimetic thereof, which is 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, as described in ACS Chem. Biol., 557-566, 4 (7) (2009) based on the IA P ligand:

[0101]

Chemical formula

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

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

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

[0105]

Chemical formula

[0106] In any of the compounds described herein, ILM can have the structure of the following formula (IX), or a non-natural mimetic thereof, as described in Mannhold, R., et al. IAP antagon ists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210 Derived from chemical species cross-referenced in -9 (2010):

[0107] [Chemical formula]

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

[0109] In any of the compounds described herein, ILM can have the structure of the following formula (X), which is cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010): Derivable from chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010): Derivable from chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010): Derivable from chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010):

[0110] [Chemical formula]

[0111] Wherein: R in formula (X) 1 is selected from 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] [Chemical formula]

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

[0114] [Chemical formula]

[0115] wherein R in formula (XI) 1 is selected from H or Me, and R in formula (XI) 2 is H or Is

[0116] [Chemical formula]

[0117] Selected from. In any of the compounds described herein, ILM can have the structure of the following formula (XII) and this is cross-referenced to the chemical species in Mannhold, R., et al. IAP antagonists: pro mising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010 ) derived from the chemical species:[[]]

[0118] [Chemical formula]

[0119] Wherein: R of formula (XII) 1 is selected from the following:

[0120] [Chemical formula]

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

[0122] [Chemical formula]

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

[0124] [Chemical formula]

[0125] [Chemical formula]

[0126] In any of the compounds described herein, ILM can have the structure of formula (XIII), or a non-natural mimetic thereof, which is based on the IAP ligands summarized in Flygare, J.A., et al. Small-molecule p an-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 (2 010):

[0127] [Chemistry]

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

[0129] [Chemistry]

[0130] R of 10 is selected from H, alkyl, or aryl; X is selected from CH2 and O; and

[0131] [Chemistry]

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

[0133] [Chemistry]

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

[0135]

Chem.

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

[0137]

Chem.

[0138] X is selected from CH2 and O; and

[0139]

Chem.

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

[0141]

Chem.

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

[0143] In any of the compounds described herein, ILM can have the structure of formula (XV), or a non-natural mimetic thereof, which is a derivative of the IAP ligand described in WO 2008 / 128171:

[0144] ​​​ [Chemical formula]

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

[0146] [Chemical formula]

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

[0148] [Chemical formula]

[0149] X of is selected from CH2 and O; and

[0150] [Chemical formula]

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

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

[0153] [Chemical formula]

[0154] In any of the compounds described herein, ILM is of formula (XVI), or its non-heaven It can have the structure of a natural mimic, which is based on the IAP ligand described in WO 2006 / 069063: wherein:

[0155]

Chem.

[0156] wherein: R of formula (XVI) 2 is selected from alkyl, cycloalkyl and heterocycloalkyl, more preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably selected from cyclohexyl;

[0157]

Chem.

[0158] of formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl, most preferably thiazole; and Ar of formula (XVI) is aryl or heteroaryl. In any of the compounds described herein, ILM can have the structure of formula (XVII), or a non-natural mimic thereof, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010):

[0159] In any of the compounds described herein, ILM can have the structure of formula (XVII), or a non-natural mimic thereof, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010): It can have the structure of a natural mimic, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010): wherein: In any of the compounds described herein, ILM can have the structure of formula (XVII), or a non-natural mimic thereof, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010):

[0160]

Chem.

[0161] In the formula: R in formula (XVII) 1 is selected from the group consisting of halogen (for example, fluorine), cyano,

[0162] [Chemical formula]

[0163] and is selected from the group; X in formula (XVII) is selected from the group consisting of O and CH2.

[0164] In any of the compounds described herein, ILM has the structure of formula (XVIII) and can be, which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis protein s based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2 010):

[0165] [Chemical formula]

[0166] wherein R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, he teroarylalkyl, or halogen (at variable substitution positions).

[0167] In any of the compounds described herein, ILM has the structure of formula (XIX) is made, which is based on the IAP ligands described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (201 0):

[0168] [Chemical formula]

[0169] wherein

[0170] [Chemical formula]

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

[0172] [Chemical formula]

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

[0174] [Chemical formula]

[0175] In any of the compounds described herein, the ILM can have the structure of formula (XX), or a non-natural mimetic thereof, which is based on the IAP ligand described in WO 2007 / 101347 :

[0176] ​ [Chemical formula]

[0177] In formula (XX), X is selected from CH2, O, NH or S. In any of the compounds described herein, ILM can have the structure of formula (XXI) or a non-natural mimetic thereof, which is based on the IAP ligands described in U.S. Patent No. 7,345,081 and U.S. Patent No. 7,419,975:

[0178] [Chemical formula]

[0179] Wherein: R of formula (XXI) 2 is selected from the following:

[0180] [Chemical formula]

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

[0182] [Chemical formula]

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

[0184] [Chemical formula]

[0185] R of 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]

Chemical formula

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

[0188]

Chemical formula

[0189]

Chemical formula

[0190] These are described in WO2009 / 060292, US Patent No. 7,517,906, WO2008 / 134679, WO2007 / 130626 and WO2008 / 128121.

[0191] In any of the compounds described herein, the ILM can have the structure of formula (XXII) or formula (XXI II), or a non-natural mimetic thereof, which are derived from the IAP ligands described in WO 2015 / 006524, and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of ap optosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556 - 62 (2015), and / or its pharmaceutically acceptable salts, tautomers or stereoisomers:

[0192] ​ [Chemical formula]

[0193] In the formula: R in formula (XXII) or formula (XXIII) 1 is optionally substituted alkyl, optionally substituted chloroalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic ryl, optionally substituted arylalkyl, or optionally substituted aryl; R in formula (XXII) or formula (XXIII) 2 is optionally substituted alkyl, optionally substituted chloroalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic ryl, optionally substituted arylalkyl, or optionally substituted aryl; Or R in formula (XXII) or formula (XXIII) 1 and R 2 are independently optionally substituted thio alkyl, where the substituent bonded to the S atom of thioalkyl is optionally substituted alkyl branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 ; In the formula: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2R 23 of R 20 and R 22 are independently OH, NR 24 R 25 or OR 26 selected from ; -CH2CHR 21 COR2 R of 21 is NR 24 R 25 is selected from the group of; -CH2R 23 R of 23 is optionally substituted aryl, or optionally substituted heterocyclyl or selected therefrom, wherein said optional substituents include alkyl and halogen; NR 24 R 25 R of 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R of 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH2O) m C H3, or selected from polyamine chains such as spermine or spermidine; OR 26 R of 26 is selected from optionally substituted alkyl, wherein said optional substituent is OH, 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 aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein said substituent is alkyl, halogen or OH; R of formula (XXII) or formula (XXIII) 5 , R6 , R 7 and R 8 are each independently selected from 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]

Chemical formula

[0196] wherein, “*” is a bonding point of PTM, L or ULM, for example, ILM. In any of the compounds described herein, ILM can have the formula (XXIV) or formula (XXV I), or a non-natural mimetic thereof, and can have a chemical linker to the phosphorus carrier group L, and the structure is derived from the IAP ligands 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 isomer or stereoisomer thereof:

[0197]

Chemical formula

[0198] wherein: R of formula (XXIV), formula (XXV) or formula (XXVI) 1 is optionally substituted alkyl, optionally 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, optionally 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 selected from optionally substituted thio alkyl, where the substituent attached to the S atom of thioalkyl is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -( CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 ; wherein: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2R 23 the R of 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 selected from ; -CH2CHR 21 COR 2 the R of 21 is NR 24 R25 selected from; -CH2R 23 wherein R of 23 is optionally substituted aryl, or optionally substituted heterocyclyl, or selected from, and the optional substituents include alkyl and halogen; NR 24 R 25 wherein R of 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 wherein R of 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH2O) m C H3, or selected from polyamine chains such as spermine or spermidine; OR 26 wherein R of 26 is selected from optionally substituted alkyl, and the optional substituent is OH, halogen or NH2; and m is an integer from 1 to 8; R in formula (XXIV), formula (XXV) or formula (XXVI) 3 and R 4 are independently optionally substituted a lkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted heteroar yl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, and the substituents are alkyl, ha logen or OH; R in formula (XXIV), formula (XXV) or formula (XXVI) 5 , R 6 , R 7 and R8 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0199] In certain embodiments, the ILM according to Formulas (XXII)-(XXVI): R 7 and R 8 are selected from H or Me; R 5 and R 6 are selected from the group comprising:

[0200]

Chem.

[0201] R 3 and R 4 are selected from the group comprising:

[0202]

Chem.

[0203] In any of the compounds described herein, the ILM can have the structure of Formula (XXVII) or Formula (XX VII), or a non-natural mimetic thereof, which structure is derived from the IAP ligands described in WO 2014 / 055 461, and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodim eric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), and / or its pharmaceutically acceptable salts, tautomers or stereoisomers:

[0204]

Chem.

[0205] wherein: R 35 is one or two substituents selected from alkyl, halogen, alkoxy, cyano, and haloalkoxy; and; R in formula (XXVII) and formula (XXVIII) 1 is H, or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; selected from; and; R in formula (XXVII) and formula (XXVIII) 2 is H, or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; selected from; or alternatively, R and R in formula (XXVII) and formula (XXVIII) 1 and R 2 are independently selected from optionally substituted thioalkyl-CR 60 R 6 1 SR 70 wherein R 60 and R 61 are selected from H or methyl, and R 70 is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted hete rocyclyl, -(CH2) v COR 20 -CH2CHR 21 COR 22 or -CH2R 23 selected from; wherein: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2CHR 21 COR 22 wherein R 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 selected from selected; -CH2CHR 21 COR 22 wherein R 21 is selected from NR 24 R 25 selected; -CH2R 23 wherein R 23 is optionally substituted aryl or optionally substituted heterocyclyl selected from, wherein said optional substituents include alkyl and halogen; NR 24 R 25 wherein R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 wherein R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3, or a polyamine chain such as spermine or spermidine of -[CH2CH2(CH2 )δNH]ψCH2CH2(CH2)ωNH2 selected from; wherein δ = 0 to 2, ψ = 1 to 3, ω = 0 to 2; OR 26 wherein R 26 is optionally substituted alkyl, wherein said optional substituents are OH, halogen or NH2; and m is an integer from 1 to 8, R in formula (XXVII) and formula (XXVIII) 3and R 4 is 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 heterocycloalkyl, wherein the substituent is alkyl, halo gen or OH; R in formula (XXVII) and formula (XXVIII) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R in formula (XXVII) and formula (XXVIII) 31 is selected from optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably selected from the group consisting of:

[0206]

Chemical formula

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

[0208]

Chemical formula

[0209] Z in formula (XXVII) is selected from C=O, -O-, -NR, -CONH-, -NHCO-, or does not exist at all; or may well; -(CR 81 R 82 ) m - the R of 81 and R 82 are independently selected from hydrogen, halogen, alkyl or cycloalkyl or R 81 and R 82 can together form a carbocyclic ring;

[0210]

Chemical formula

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

[0212]

Chemical formula

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

[0214]

Chemical formula

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

[0216]

Chem.

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

[0218]

Chem.

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

[0220]

Chem.

[0221] r is 0 or 1. In any of the compounds described herein, ILM can have the structure of formula (XXIX), formula (XXX), formula (XXXI) or formula (XXXII), or a non-natural mimetic thereof, and a chemical linker to linker group L as shown below, which are derived from the IAP ligands described in WO 2014 / 05546 1, and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014): 1, and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014) ic IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014): from:

[0222]

Chem.

[0223] [Chemical formula]

[0224] In the formula: R in Formulas (XXIX) to (XXXII) 2 is selected from H, optionally substituted alkyl, optionally substituted cyclo alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic yl, optionally substituted arylalkyl, or optionally substituted aryl; ; Or alternatively, R in Formulas (XXVII) and (XXVIII) 1 and R 2 are independently selected from H, optionally substituted thioalkyl-CR 6 0 R 61 SR 70 wherein R 60 and R 61 are selected from H or methyl, and R 70 is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted he terocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 ; In the formula: v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2CHR 21 COR 22 R of 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 from selected; -CH2CHR 21 COR 22R of 21 is NR 24 R 25 is selected from; -CH2R 23 R of 23 is optionally substituted aryl, or optionally substituted heterocyclyl or selected from, where said optional substituents include alkyl and halogen; NR 24 R 25 R of 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R of 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3, or a polyamine chain such as spermine or spermidine of -[CH2CH2(CH2 )δNH]ψCH2CH2(CH2)ω r NH2 selected from, where δ = 0 to 2, ψ = 1 to 3, ω = 0 to 2; OR 26 R of 26 is optionally substituted alkyl, where said optional substituent is OH, halogen or NH2; m is an integer from 1 to 8; R of formula (XXIX) to formula (XXXII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and R of formula (XXIX) to formula (XXXII) 31 is further optionally substituted alkyl, aryl, aryl alkyl, heteroaryl or heteroarylalkyl selected from, preferably from selected from the group consisting of:

[0225]

Chem.

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

[0227]

Chem.

[0228] For any of the compounds described herein, the ILM can have the structure of formula (XXXIII) or its non-natural mimics, which are derived from the IAP ligands described in WO2014 / 074658 and WO 2013 / 071035: :

[0229]

Chem.

[0230] Wherein: R of formula (XXXIII) 2 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl , optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXXIII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R of formula (XXXIII) 32 is selected from (C1-C4 alkylene)-R 33 , wherein R 33 is selected from hydrogen, aryl, heteroaryl, or cycloalkyl, optionally further substituted; X in formula (XXXIII) is selected from the following:

[0231]

Chemical formula

[0232] Z and Z' in formula (XXXIII) are independently selected from the following:

[0233]

Chemical formula

[0234] wherein each

[0235]

Chemical formula

[0236] represents a bonding point to the compound, and Z and Z' cannot both be

[0237]

Chemical formula

[0238] in any given compound; Y in formula (XXXIII) is selected from the following:

[0239]

Chemical formula

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

[0241]

Chemical formula

[0242] wherein each

[0243]

Chem.

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

[0245]

Chem.

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

[0247]

Chem.

[0248]

Chem.

[0249] Wherein:

[0250]

Chem.

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

[0252]

Chem.

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

[0254]

Chem.

[0255] represents the first bonding point to Z;

[0256] [Chemical formula]

[0257] represents a 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 where; R 3 is -C(O)R 3 OH, NHCN, NHSO2R 10 NHOR 11 or N(R 12 )(R 13 ) selected from; NHSO2R 10 and NHOR 11 the R of 10 and R 11 are independently hydrogen, optionally substituted -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocycloal selected from kyl; N(R 12 )(R 13 ) the R of 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) from selected, or R 12 and R 13 together with the nitrogen atom to which they are commonly attached, optionally contain one additional heteroatom selected from N, O and S to form a saturated heterocyclyl, wherein the saturated heterocycle is optionally substituted with methyl.

[0258] In any of the compounds described herein, the ILM can have the structure of formula (XXXIV) or formula (XX XV), or a non-natural mimetic thereof, which is derived from the IAP ligand described in WO 2014 / 047024 and / or is a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: wherein: X in formula (XXXIV) or (XXXV) is absent or is a group selected from -(CR

[0259]

Chemical formula

[0260] In the formula: X in formula (XXXIV) or (XXXV) is absent or is -(CR 10 R 11 ) m -, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl,

[0261]

Chemical formula

[0262] Y and Z in formula (XXXIV) or formula (XXXV) are independently selected from C=O, -O-, -NR 9 -, -CONH-, -NHCO- or may not be present; R and R 1 in formula (XXXIV) or formula (XXXV) are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or are selected from, 2 and R and R in formula (XXXIV) or formula (XXXV) are independently optionally substituted thioalkyl and R 1 and R 2 in formula (XXXIV) or formula (XXXV) are independently optionally substituted thioalkyl selected from, where the substituent bonded to the S atom of thioalkyl is optionally substituted alkyl alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 ; wherein v is an integer from 1 to 3; -(CH2) v COR 20 and -CH2CHR 21 COR 22 of R 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 from selected; -CH2CHR 21 COR 22 of R 21 is selected from NR 24 R 25 ; -CH2R 23 of R 23 is optionally substituted aryl, or optionally substituted heterocyclyl selected from, where the optional substituents include alkyl and halogen; NR 24 R 25 of R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 of R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, any optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH 20 ) m C H3, or a polyamine chain; R 26is an optionally substituted alkyl, where the optional substituent is OH, halogen or NH2; -(CR 10 R 11 ) m - where m is an integer from 1 to 8; R in formula (XXXIV) or formula (XXXV) and 3 R 4 are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, where the substituent is alkyl, halogen or OH; R in formula (XXXIV) or formula (XXXV), R, R, R and R are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR R in formula (XXXIV) or formula (XXXV), R, R, 5 R, R, 6 R, 7 R and 8 R are independently selected from hydrogen, halogen, or optionally substituted alkyl; -(CR 10 R 11 ) m - where R and 10 R are independently selected from hydrogen, halogen, or optionally substituted 11 alkyl; ;

[0263]

Chemical formula

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

[0265] [Chemical formula]

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

[0267] In any of the compounds described herein, the ILM can have the structure of formula (XXXVI), or its non- natural mimetic, which are derived from the IAP ligands described in WO 2014 / 025759, and / or its pharmaceutically acceptable salts, tautomers or stereoisomers: ;

[0268] [Chemical formula]​

[0269] In the formula, A in formula (XXXVI) is selected from the following:

[0270]

Chemical formula

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

[0272]

Chemical formula

[0273] Y and Z in formula (XXXVI) are independently selected from -O-, -NR 6 -, or do not exist; 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 cyclo alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted hetero Selected from arylalkyl or optionally substituted heterocycloalkyl; R of formula (XXIV), formula (XXV) or formula (XXVI) 5 R 6 R 7 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or preferably is methyl;

[0274]

Chemical formula

[0275] R of 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]

Chemical formula

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

[0278]

Chemical formula

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

[0280]

Chemical formula

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

[0282]

Chemical formula

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

[0284]

Chemical formula

[0285] r is selected from 0 or 1. In any of the compounds described herein, ILM can have the structure of formula (XXXVII) or formula (X XXVIII), or its non-natural mimetic, which is derived from the IAP ligand described in WO 2014 / 011712 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0286]

Chemical formula

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

[0288] [Chemical formula]

[0289] or does not exist; Y and Z in Formula (XXXVII) and Formula (XXXVIII) are selected independently from -0-, C=0, NR 6 selected from or does not exist; R in Formula (XXXVII) and Formula (XXXVIII) 1 and R 2 are optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylaryl, or optionally substituted selected from aryl; R in Formula (XXXVII) and Formula (XXXVIII) 3 and R 4 are independently optionally substituted alkyl optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl; R in Formula (XXXVII) and Formula (XXXVIII) 5 and R 6 are independently optionally substituted alkyl or optionally substituted cycloalkyl; R in Formula (XXXVII) and Formula (XXXVIII) 7 and R 8 are independently selected from hydrogen, optionally substituted a lkyl, or optionally substituted cycloalkyl, or preferably methyl ;

[0290] [Chemical formula]

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

[0292]

Chemical Structure

[0293] of R 11 ~R 14 is independently selected from hydrogen, halogen, optionally substituted alkyl or OR 15 selected ; OR 15 of R 15 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl ; -(CR 16 R 17 ) m - of R 16 and R 17 is independently selected from hydrogen, halogen, or optionally substituted al kyl; R in formula (XXXVII) and formula (XXXVIII) 50 and R 51 is independently selected from optionally substituted al kyl, or R 50 and R 51 together form a ring; -(CR 16 R 17 ) m - and

[0294]

Chemical Structure

[0295] m and n are independently integers from 0 to 4;

[0296]

Chemical Structure

[0297] o and p are each independently an integer from 0 to 3;

[0298] [Chemical formula]

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

[0300] [Chemical formula]

[0301] r is an integer from 0 to 1. In certain embodiments, R of the ILM of formula (XXXVII) or formula (XXXVIII) 1 and R 2 are t-butyl and R of the ILM of formula (XXXVII) or formula (XXXVIII) 3 and R 4 are tetrahydronaphthalene.

[0302] In any of the compounds described herein, the ILM can have the structure of formula (XXXIX) or formula (XL ), or a non-natural mimetic thereof, which are derived from the IAP ligands described in WO2013 / 071039:

[0303] [Chemical formula]

[0304] Wherein: R of formula (XXXIX) and formula (XL 43 as well as R 44 are each independently further optionally substituted halo ​​Gen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, selected from, and Formula (XXXIX) and R in formula (XL) As well as R 6 And R 8 Are independently selected from hydrogen, optionally substituted alkyl Or optionally substituted cycloalkyl, Each X in formula (XXXIX) and (XL) is independently selected from the following:

[0305]

Chemical formula

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

[0307]

Chemical formula

[0308] Selected from, where each in the formula

[0309]

Chemical formula

[0310] Represents the bonding point of the compound; and Each Y is selected from the following:

[0311]

Chemical formula

[0312]

Chemical formula

[0313] Wherein:

[0314] [Chemistry]

[0315] represents the bonding point to the -C=O part of the said compound;

[0316] [Chemistry]

[0317] represents the bonding point to the amino part of the said compound;

[0318] [Chemistry]

[0319] represents the first bonding point to Z;

[0320] [Chemistry]

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

[0322] [Chemistry]

[0323] or is selected from any of the aforementioned tautomeric forms, wherein: -C(O)R 3 for R 3 is selected from OH, NHCN, NHS02R 10 , NHOR 11 or N(R 12 )(R 13 ); for R in NHS02R 10 and for R in NHOR 11 as well as for R 10 and R 11is independently -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which is optionally substituted, and is selected from hydrogen; N(R 12 )(R 13 ) where each of R 12 and R 13 is independently 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 R 12 )(R 13 ) where R 12 and R 13 together with the nitrogen atom to which they are commonly attached form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O, and S, where the saturated heterocyclic ring is optionally substituted with methyl. In any of the compounds described herein, ILM can have the structure of formula (XLI)

[0324] which are derived from the IAP ligands described in WO2013 / 071039:

[0325]

Chemical formula

[0326] wherein: W in formula (XLI) 1 is selected from O, S, N-R A , or C(R 8a )(R 8b ); W in formula (XLI) 2is O, S, N-R A , or C(R 8c )(R 8d ) selected from; provided that W 1 and W 2 are both not O, or both not S; R in formula (XLI) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(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); When X R is selected from O, N-R 1 , S, S(O), or S(O)2, X A is C( 2 2a R R 2b ); or: X in formula (XLI) 1 is selected from CR 2c R 2d 2 Sa Sa X 2 is CR 2a R 2b and R 2c and R 2a together form a bond; or: X in formula (XLI) and X 1 are independently selected from C and N, and are components of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 2 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; or: X in formula (XLI) 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 ; where each R c is independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, 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 -C1- C6 alkyl-(substituted or unsubstituted heteroaryl); N-R A the R of A is selected from 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 the R of 2a R 2b R 2c R 2d is independently 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 ma or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O )R B is selected from; -C(=O)R B wherein R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cyclo 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 a lkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl ), or -NR D R E is selected from; NR D R E wherein R D and R E are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or un substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or un substituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) is selected from; 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 of formula (XLI) 3 is selected from C1-C3 alkyl or C1-C3 fluoroalkyl; R of formula (XLI) 4 is -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 of 5 is independently H, C1-C3 alkyl, C1-C3 halo alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl) from selected; or: R of formula (XLI) 3 and R 5 together with the atom to which they are attached form a substituted or unsubstituted 5- to 7-membered ring forming; or: R of formula (XLI) 3 is attached to the nitrogen atom of U and forms a substituted or unsubstituted 5- to 7-membered ring; R of 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)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 selected from 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 of 7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- 10 hetero chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or un substituted 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(replaced or unsubstituted heteroaryl)2, -(CH2) P -CH(replaced or unsubstituted aryl -)(replaced or unsubstituted heteroaryl), -(replaced or unsubstituted aryl)-(replaced or un placed aryl), -(replaced or unsubstituted aryl)-(replaced or unsubstituted heteroaryl), -( replaced or unsubstituted heteroaryl)-(replaced or unsubstituted aryl), or -(replaced or un placed heteroaryl)-(replaced or unsubstituted heteroaryl); R 7 p is selected from 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )'s R 8a R 8b R 8c and R 8d are selected from H, C1-C6 alkyl, C1-C6 fluoro alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and replaced or unsubstituted aryl -); or: R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond ; or: R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached contain 1 to 3 heteroatoms selected from S, O, and N, and form a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or un substituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or un A fused 5- to 10-membered aryl ring or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O, and N is formed; Or: And R R 8c And R 8d Are as defined above, and R 8a And R 8b Together with the atoms to which they are attached, form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring containing 1 to 3 heteroatoms selected from S, O, and N; Or: R Or: R 8a And R 8b Are as defined above, and R 8c And R 8d Together with the atoms to which they are attached, form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring containing 1 to 3 heteroatoms selected from S, O, and N; Here, each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1 to 3 R ; And Each R of R Is independently halogen, -OH, -SH, (C=O), CN, 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(=O)NH2, -C(=O)C1-C3 alkyl 9 Is substituted with ; And R 8a 、R 8b 、R 8c And R 8d Of each R 9 Is independently halogen, -OH, -SH, (C=O), CN, 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(=O)NH2, -C(=O)C1-C3 alkyl 、C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=O)NH2, -C(=O)C1-C3 alkyl 、-C(=O)OH, -C(=O)NH2, -C(=O)C1-C3 alkyl Lu, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl), -O(C 1-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 together with the atom to which they are attached is substituted with halogen, -OH, or C1-C3 alkyl, or forms an unsubstituted or substituted methylenedio xy ring or an ethylenedioxy ring.

[0327] In any of the compounds described herein, the ILM can have the structure of formula (XLII) and these are derived from the IAP ligands described in WO2013 / 071039:

[0328]

Chemical formula

[0329] wherein: W in formula (XLII) 1 is O, S, N-R A , or C(R 8a )(R 8b ); W in formula (XLII) 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O and not both 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 selected from unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl-(substituted or unsubstituted heteroaryl); X of formula (XLII) 1 is N-R A In the case where 2 X is C=O or CR 2c R 2d and X 3 is CR 2a R 2b and present; or: X of formula (XLII) 1 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 of formula (XLII) 1 is O, X 2 is CR 2c R 2d and N-R A and X 3 is CR 2a R 2b and; or: X of formula (XLII) 1 is CH3, X 2 is selected from O, N-R A S, S(O), or S(O)2, and X 3 is CR 2a R 2b and; X of formula (XLII) 1 is CR 2e R 2f and X2 is CR 2c R 2d In the case where R 2e and R 2c both form a bond and X of formula (VLII) 3 is CR2a R 2b is; or: X of formula (XLII) 1 and X 3 are both CH2, and X of formula (XLII) 2 is C=0, C=C(R C ),2, or is C=NR C ; where each R C is independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 he terocycloalkyl, 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 of formula (XLI) 1 and X 2 are independently selected from C and N, and are condensed substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, condensed substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl rings, condensed substituted or unsubstituted 5- to 10-membered aryl rings, or are constituents of condensed substituted or unsubstituted 5- to 10-membered heteroaryl rings, and X 3 is , CR 2a R 2b ; or: X of formula (XLI) 2 and X 3 are independently selected from C and N, and are condensed substituted or unsubstituted saturated or is a 3- to 10-membered cycloalkyl ring which may be partially saturated, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and is a constituent of formula (VII LII), and X of formula (VII 1 is CR 2e R 2f ; R of N-R A is selected from H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, A or substituted or unsubstituted heteroaryl; R of CR R 2c R 2d R of CR 2a R 2b R of CR 2e R 2f R of CR 2a R 2b R 2c R of CR 2d R 2e R of CR 2f R of CR R, and R R are independently selected from 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 he B teroaryl), and -C(=O)R R of -C(=O)R B is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl B ; Lukyl, 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 a lkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl ), or -NR D R E selected from; NR D R E wherein R D and R E are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or un substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or un substituted 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 -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) selected from; m in formula (XLII) is selected from 0, 1 or 2; -U- in formula (XLII) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -N 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 is -NHR 5 , -N(R 5 )2, -N+(R 5)3 or -OR 5 is selected from; -NHR 5 , -N(R 5 )2, -N+(R 5 )3, and -OR 5 each R 5 is independently H, C1-C3 alkyl, C1-C3 halo alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl) from selected; or: R of formula (XLII) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atom to which they are attached; form; or: R of formula (XLII) 3 is attached to the nitrogen atom of U and forms a substituted or unsubstituted 5- to 7-membered ring; R of 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)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 selected from 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 of 7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C cycloalkyl, substituted or unsubstituted C2-C 10 cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted 10 C2-C heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C 10 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) 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 yl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or un substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d is H, C1-C6 alkyl, C1-C6 fluorine fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl. selected from the rule; or: R 8a and R 8d is as defined above, and R 8b and R 8c form a bond together death; or: R 8a and R 8d is as defined above, and R 8b and R 8c are combined and substituted or unsubstituted alkyl groups containing 1 to 3 heteroatoms selected from S, O and N. or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted A fused 5- to 10-membered aryl ring or a heteroatom selected from S, O and N. forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring having or: R 8c and R 8d is as defined above, and R 8a and R 8b They are combined together with the atom to which it is attached, forms a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; or: or: R 8a and R 8b are as defined above, and R 8c and R 8d together with the atom to which they are attached, forms a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1 to 3 R ; and each R in R 9 is independently selected from halogen, -OH, -SH, (C=O), CN, 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(=O)NH2, -C(=O)C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 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 ; and R 8a R 8b R 8c and R 8d are independently selected from halogen, -OH, -SH, (C=O), CN, 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(=O)NH2, -C(=O)C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 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 are, together with the atom to which they are attached, substituted with halogen, -OH, or C1-C3 alkyl, or are unsubstituted methylenedioxy ; and each R is independently selected from halogen, -OH, -SH, (C=O), CN, 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(=O)NH2, -C(=O)C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 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 are, together with the atom to which they are attached, substituted with halogen, -OH, or C1-C3 alkyl, or are unsubstituted methylenedioxy ; or two R 9 are, together with the atom to which they are attached, substituted with halogen, -OH, or C1-C3 alkyl, or are unsubstituted methylenedioxy ; Forms a xylylene ring or an ethylenedioxy ring.

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

[0331]

Chemical formula

[0332] Wherein: W of formula (XLIII) 1 is selected from O, S, N-R A , or C(R 8a )(R 8b ); W of formula (XLIII) 2 is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, nor are they both S; R of formula (XLIII) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-( substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl-(substituted or unsubstituted heteroaryl); When X of formula (XLIII) 1 is selected from N-R A , S, S(O), or S(O)2, X of formula (XLIII) 2 is CR 2c R 2d and X of formula (XLIII) 3 is CR 2a R2b and; or: when X in formula (XLIII) 1 is O, X in formula (XLIII) 2 is O, N-R A , S, S(O), or S(O)2, or is selected from the group consisting of, and X in formula (XLIII) 3 is CR 2a R 2b and; or: when X in formula (XLIII) 1 is CR 2e R 2f and X in formula (XLIII) 2 is CR 2c R 2d in which case 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 are components of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring , or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X in formula (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 are components of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially a saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring , or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and the formula (VLII) of X 1 is CR 2e R 2f ; N-R A of 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 , CR 2a R 2b , and CR 2e R 2f of R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f are independently 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 he teroaryl), and -C(=O)R B selected from; -C(=O)R B of R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cyclo 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 a lkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl l), or -NR D R E ; NR D R E 's R D and R E are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or un substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or un substituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocyclo alkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); m of formula (XLIII) is 0, 1 or 2; -U- of 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 of formula (XLIII) 3 is C1-C3 alkyl, or C1-C3 fluoroalkyl; R of formula (XLIII) 4 is -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ; -NHR 5 , -N(R5 ) 2, -N+(R 5 ) 3, and -OR 5 Each R 5 is independently selected from H, C1-C3 alkyl, C1-C3 halo alkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); selected; or: R of formula (XLIII) 3 and R 5 together with the atom to which they are attached form a substituted or unsubstituted 5- to 7-membered ring to form; or: R of formula (XLIII) 3 is attached to the nitrogen atom of U and forms a substituted or unsubstituted 5- to 7-membered ring; R of 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 selected from 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 of 7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- 10 hetero chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl- (substituted or un substituted 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 yl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or un substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or un selected from (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 )'s R 8a 、R 8b 、R 8c 、and R 8d are selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl; -yl; or: R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond ; or: R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached contain 1 to 3 heteroatoms selected from S, O and N, and are substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted fused 5- to 10-membered aryl rings, or substituted or unsubstituted fused 5- to 10-membered heteroaryl rings containing 1 to 3 heteroatoms selected from S, O and N; form; or: R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached contain 1 to 3 heteroatoms selected from S, O and N, and are substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic rings, substituted or unsubstituted fused 5- to 10-membered aryl rings, or substituted or unsubstituted fused 5- to 10-membered heteroaryl rings containing 1 to 3 heteroatoms selected from S, O and N; ​​​forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: R 8a and R 8b are as defined above, and R 8c and R 8d together with the atom to which they are attached contain 1 to 3 heteroatoms selected from S, O and N, or form an unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; forms an unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1 to 3 R ; and 9 is substituted; and ; and R 8a R 8b R 8c and R 8d each R 9 is independently halogen, -OH, -SH, (C=O), CN, C1-C4 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 1-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 together with the atom to which they are attached are substituted with halogen, -OH, or C1-C3 alkyl, or form an unsubstituted or substituted methylenedioxy xy ring or ethylenedioxy ring.

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

[0334]

Chemical formula

[0335] wherein: W in formula (XLIV) 1 is selected from O, S, N-R A , or C(R 8a )(R 8b ); W in formula (XLIV) 2 is selected from O, S, N-R A , or C(R 8c )(R 8d ), provided that W 1 and W 2 are not both O, nor are they both S; W in formula (XLIV) 3 is selected from O, S, N-R A , or C(R 8e )(R 8f ), provided that W 1 , W 2 and W 3 do not contain two adjacent oxygen or sulfur atoms; R in formula (XLIV) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-( substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl-(substituted or unsubstituted heteroaryl); When X in formula (XLIV) 1 is O, X in formula (XLIV)2 is selected from CR 2c R 2d and N-R A and, for the W of formula (XLIV), 3 is CR 2a R 2b ; or: For X of formula (XLIV), 1 when X of formula (XLIV) is CH2, X of formula (XLIV) 2 is O, N-R A , S, S(O), or S(O)2 and for X of formula (XLIV), 3 is CR 2a R 2b ; or: For X of formula (XLIV), 1 when X is CR 2e R 2f and X of formula (XLIV) is CR 2 R 2c R 2d then R 2e and R 2c together form a bond and X of formula (XLIV) is CR 3 R 2a R 2b ; or: For X of formula (XLIV), 1 and X 3 are both CH2, and X of formula (XLII) 2 is C=0, C=C(R C )2, or C=NR C ; where each R C is independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycl oalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted selected from -C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C 1-C6 alkyl- (substituted or unsubstituted heteroaryl); or: X of formula (XLIV) 1 and X 2 are independently selected from C and N, and are 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 constituent of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (X LIV) 3 is CR 2a R 2b ; or: X of formula (XLIV) 2 and X 3 are independently selected from C and N, and are 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 constituent of a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (V LIV) 1 is CR 2e R 2f ; R of N-R A is selected from H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, A or substituted or unsubstituted heteroaryl; ; R of CR 2c R 2d CR 2a R 2b CR 2e R 2f and R of CR2a , R 2b , R 2c , R 2d , R 2e , and R 2f are independently 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 he teroaryl), and -C(=O)R B selected from; -C(=O)R B of R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cyclo 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 a lkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl ), or -NR D R E selected from; NR D R E of R D and R E are independently H, substituted or unsubstituted C1-C6 alkyl, substituted or non substituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or is selected from 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 -C1-C6 alkyl- (substituted or unsubstituted heteroaryl); m in formula (XLIV) is selected from 0, 1 or 2; -U- in formula (XLIV) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -N H(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLIV) is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; 3 R in formula (XLIV) is selected from -NHR 4 , -N(R 5 )2, -N+(R 5 )3, or -OR 5 ; 5 Each R of -NHR , -N(R 5 )2, -N+(R 5 )3, and -OR 5 is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl); 5 5 or: R in formula (XLIV) and R together with the atom to which they are attached form a substituted or unsubstituted 5- to 7-membered ring; or: 3 R in formula (XLIII) 5 is attached to the nitrogen atom of U and forms a substituted or unsubstituted 5- to 7-membered ring; or: R in formula (XLIII) 3 is attached to the nitrogen atom of U and forms a substituted or unsubstituted 5- to 7-membered ring;​​ R of 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 selected from 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 of 7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroal Kill, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Hetero Chloroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1- C6 alkyl-(substituted or unsubstituted C3-C 10 Cycloalkyl), -C1-C6 alkyl- (substituted or non Substituted 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 ari -l)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or non Substituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -( Substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or non Substituted heteroaryl)-(substituted or unsubstituted heteroaryl); selected from 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 ) of 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 hete Selected from lower alkyl, and substituted or unsubstituted aryl; or: C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R 8f )'s R 8a , R 8d , R 8e , and R 8f are as defined above, and R 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 )'s R 8a , R 8b , R 8d , and R 8f are as defined above, and R 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 )'s R 8a , R 8d , R 8e , and R 8f are as defined above, and R and R 8b and R 8c together with the atom to which they are attached contain 1 to 3 heteroatoms selected from S, O and N, and are a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or unsubstituted fused 5- to 10-membered aryl - a phenyl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O, and N; or: or: C(R 8a )(R 8b ), C(R 8c )(R 8d ), and the R 8e ), R 8f ), R 8a ), and R 8b ), and R 8d ), and R 8f are as defined above, and R and R 8c and R 8e together with the atom to which they are attached form a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O, and N; or: or: or: C(R )(R ), and the R 8c ), R 8d ), R 8e ), and R 8f are as defined above, and R 8c and R 8d and R 8e and R 8f are as defined above, and R and R 8a and R 8b together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring containing 1 to 3 heteroatoms selected from S, O, and N; or: or: or: C(R 8a )(R 8b ), and the R 8e ), R 8f ) of C(R8a , R 8b , R 8e , and R 8f are as defined above and R 8c and R 8d together with the atom to which they are attached, contain 1 to 3 heteroatoms selected from S, O and N and form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: C(R 8a )(R 8b ) and C(R 8c )(R 8d )'s R 8a , R 8b , R 8c , and R 8d are as defined above and R 8e and R 8f together with the atom to which they are attached, contain 1 to 3 heteroatoms selected from S, O and N and form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro ring or heterospiro ring; or: where each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl , heterocycloalkyl, aryl or heteroaryl is substituted with 1 to 3 R 9 ; and ; and R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f each R 9 is independently halogen, -OH, -SH, (C=O), C N, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy Si, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=O)NH2, -C(=O) C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 al kyl), -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 Rs 9 are, together with the atoms to which they are attached substituted or unsubstituted with halogen, -OH, or C1-C3 alkyl to form a methylenedioxy ring or an ethylenedioxy ring.

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

[0337]

Chemical formula

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

[0339]

Chem.

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

[0341]

Chem.

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

[0343]

Chem.

[0344] is a 5-membered heterocyclic ring selected from the following:

[0345]

Chem.

[0346] In certain embodiments, for formula (XLVIII)

[0347]

Chem.

[0348] is

[0349]

Chem.

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

[0351] [Chemical Formula]

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

[0353] [Chemical Formula]

[0354] Wherein: R in formula (XLIX), formula (L), or formula (LI) 3 is independently selected from H or ME;

[0355] [Chemical Formula]

[0356] is a 5-membered heterocyclic ring selected from the following:

[0357] [Chemical Formula]

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

[0359] [Chemical Formula]

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

[0361] [Chemical formula]

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

[0363] [Chemical formula]

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

[0365] [Chemical formula]

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

[0367] [Chemical formula]

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

[0369] [Chemical formula]

[0370] In the formula: R in formula (LIII) and formula (LIV) 1 is selected from the following:

[0371]

Chemical formula

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

[0373]

Chemical formula

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

[0375] In any of the compounds described herein, ILM can have the structure of formula (LV) or formula (LVI) as shown in formula (LV) or formula (LVI) or a non-natural mimetic thereof, and can be chemically bonded to a linker:

[0376]

Chemical formula

[0377] In any of the compounds described herein, ILM can have the structure of formula (LVII), or a non-natural mimetic thereof, which is described in Cohen, F, et al., Orally bioavailabl ​Azabicyclooctane scaffold-based antagonists of inhibitor of apoptosis proteins Based on the IAP ligands described in J. Med. Chem., 52(6), 1723-30 (2009):

[0378]

Chemical formula

[0379] Wherein: R1 of formula (LVII) is selected from the following:

[0380]

Chemical formula

[0381]

Chemical formula

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

[0383]

Chemical formula

[0384] In certain embodiments, ILM is selected from the group consisting of, and the chemical bond between ILM and linker group L is shown: :

[0385]

Chemical formula

[0386] ; and

[0387] [Chemical formula]

[0388] In any of the compounds described in this specification, ILM is selected from the group consisting of the following structures, which are derived from the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013): (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013):

[0389] [Chemical formula]

[0390] Or

[0391] [Chemical formula]

[0392] In certain embodiments, ILM is selected from the group consisting of the following, and the chemical bond between ILM and the linker group L is shown:

[0393] [Chemical formula]

[0394] ; And

[0395] [Chemical formula] ​​​​

[0396] In any of the compounds described herein, the ILM can have the structure of formula (LVIII), or a non-natural mimetic thereof, which is derived from the IAP ligand described in Asano, M, et al., Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitors of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-5737 (2013):

[0397]

Chem.

[0398]

[0399] Wherein X in formula (LVIII) is one or two substituents independently selected from H, halogen, or cyano.

[0400] In any of the compounds described herein, the ILM can have the structure of formula (LIX) or formula (LX), or a non-natural mimetic thereof, as shown, and can be chemically bonded to the linker group L:

[0401]

Chem.

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

[0403] In any of the compounds described herein, ILM can have the structure of formula (LXI), or a non-natural mimetic thereof, which is derived from the IAP ligands described in Ardecky, RJ, et al., Design, sysnthesi 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):

[0404] [Chemical formula]

[0405] wherein: of formula (LXI)

[0406] [Chemical formula]

[0407] is a natural amino acid or a non-natural amino acid; and R of formula (LXI) 2 is selected from the following:

[0408] [Chemical formula]

[0409] ​In any of the compounds described herein, the ILM can have a structure as shown in formula (LXII) or formula (LXI II), or a non-natural mimetic thereof, and can be chemically bonded to the linker group L:

[0410]

Chemical Structure

[0411]

Chemical Structure

[0412] In formula (LXI),

[0413]

Chemical Structure

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

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

[0416] ​ [ka]

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

[0418] [ka]

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

[0420] [ka]

[0421] ;

[0422] [ka]

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

[0424] [ka]

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

[0426]

Chemical formula

[0427] X of is one or two substituents independently selected from halogen, hydroxy, methoxy, nitro, and trifluoromethyl; and is;

[0428]

Chemical formula

[0429] Z of is O or NH;

[0430]

Chemical formula

[0431] HET of is monocyclic heteroaryl or fused bicyclic heteroaryl; and the --- in formula (LIX) is an optional double bond.

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

[0433]

Chemical formula

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

[0435]

Chemical formula

[0436]

Chemical formula

[0437] In this specification, the term "independently" is used to indicate that the independently applied variables vary independently for each application.

[0438] The term "alkyl" should mean, within its context, a straight-chain, branched-chain, or cyclic fully saturated hydrocarbon radical or group of alkyl, preferably a C1-C (more preferably C1-C6, or alternatively C1-C3) alkyl group, which may optionally be substituted. Examples of alkyl groups are, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-he 10 ptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclo propyl, cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentyl e thyl, cyclohexyl ethyl, and cyclohexyl. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the present disclosure may be used to covalently bind to a dehalogenase enzyme. These compounds generally contain a side chain (often bound via a polyethylene glycol group), and the side chain terminates at its distal end with an alkyl group having a halogen substituent (often chlorine or bromine), thereby causing a covalent bond between the compound containing the moiety and the target protein.

[0439] The term "alkenyl" refers to a straight-chain, branched-chain, or cyclic C2-C (preferably C2-C6) hydrocarbon radical containing at least one C=C bond. 10 ​

[0440] The term "alkynyl" refers to a linear, branched or cyclic C2-C 10 (preferably C2-C6) hydrocarbon radical containing at least one C≡C bond.

[0441] When the term "alkylene" is used, it refers to an optionally substituted -(CH2) n - group ( n is generally an integer from 0 to 6). When substituted, the alkylene group is preferably substituted with one or more of the methylene groups by a C1-C6 alkyl group (including cyclopropyl group or t-butyl group), but may be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain disclosed elsewhere in this specification. In certain embodiments, the alkylene group may be substituted with urethane or an alkoxy group (or other groups), which may further be substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, and in many cases 1 to 4 ethylene glycol units in the chain), and an alkyl group is substituted (but not limited to, preferably on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with one halogen group, preferably a chlorine group. In yet other embodiments, the alkylene (in many cases, methylene ) group may be substituted with, for example, natural or unnatural amino acids, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine side chains and may be further substituted with an alkyl group (but not limited to, preferably on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with one halogen group, preferably a chlorine group. In yet other embodiments, the alkylene (in many cases, methylene ) group may be substituted with, for example, natural or unnatural amino acids, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine side chains and may be further substituted with an alkyl group (but not limited to, preferably on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with one halogen group, preferably a chlorine group. In yet other embodiments, the alkylene (in many cases, methylene ) group may be substituted with, for example, natural or unnatural amino acids, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine side chains and may be further substituted with an alkyl group (but not limited to, preferably on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with one halogen group, preferably a chlorine group. In yet other embodiments, the alkylene (in many cases, methylene ) group may be substituted with, for example, natural or unnatural amino acids, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine side chains It may be substituted with an amino acid side chain group such as a group.

[0442] The term "unsubstituted" shall mean substituted only with a hydrogen atom. C0 The range of carbon atoms containing means that there is no carbon and it is replaced with H. Therefore, C0- The range of carbon atoms of C6 contains 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, there is H instead of carbon.

[0443] The term "substituted" or "optionally substituted" means any position of carbon (or nitrogen) on the molecule within the context with one or more substituents (independently up to a maximum of 5 substituents, preferably up to three substituents, often 1 or 2 substituents which may themselves further contain substituents that may be substituted), and that is, if there are multiple substituents, each substituent is independent of another substituent, and as substituents, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2) , halogen (especially on an alkyl group, especially preferably 1, 2, or 3 halogens on a methyl group such as trifluoromethyl), an alkyl group (preferably C1-C , more preferably C1-6) 10 , aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), a alkoxy group (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), a thioether (C1-C6 alkyl or aryl), an acyl (preferably C1-C6 acyl yl), an ester or thioester (preferably C1-C6 alkyl or aryl), and an alkylene ester (the bond is not an ester functional group but on an alkylene group, preferably or substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or ar those containing a reel, halogen (preferably F or Cl), amine (5- or 6-membered cyclic al kyleneamine and further containing a C1-C6 alkylamine or C1-C6 dialkylamine, wherein 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 a polyethylene glycol chain, and further bonded thereto is an alkyl group containing one halogen, preferably a chlorine substituent), hydrazine, amide, which preferably contains one or two C1-C6 alkyl groups (1 or carboxamide optionally substituted with two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or those substituted with an alkanoic acid (preferably C1-C6 a lkyl or aryl). Substituents according to the present disclosure may include, for example, a -SiR1R2R3 group, wherein each of R1 and R2 is described separately herein, and R3 is H or a C1-C6 alkyl group, and preferably R1, R2, R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above-mentioned groups may be directly bonded to the substituted moiety, or the substituent may be optionally substituted (C H2) m - via, or optionally substituted -(OCH2) m -, -(OCH2CH2) m -, or -(CH2CH2O) m - group, to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety may be attached to (**ite**), and they may be substituted with any one or more of the above substituents The -(CH2) of the alkylene group m - or -(CH2) n - group or other chains such as the ethylene glycol chain specified above may be substituted at any position on the chain. On the alkylene group Preferred substituents include halogen or a C1-C6 (preferably C1-C3) alkyl group, which may optionally be one or two hydroxyl groups, one or two ether groups (O- C1-C6 group), up to three halo groups (preferably F), or an amino acid side chain described elsewhere in this specification, and may optionally be a substituted amide (preferably a carboxamide substituted as described above) or a urethane group (often having one or two C0-C6 alkyl substituents, which group may also be further substituted). In certain embodiments the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl group, or an amino acid side chain described elsewhere in this specification. In the present disclosure parts of the molecule may optionally be substituted with up to five substituents, preferably up to three substituents In most cases, the parts substituted in the present disclosure are substituted with one or two substituents The term "substituted" (each substituent is independent of any other substituent) in the context of its use refers to C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carbox amide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxy In the context of its use, the term "substituted" (each substituent is independent of any other substituent) refers to C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxy In most cases, the parts substituted in the present disclosure are substituted with one or two substituents.

[0444] The term "substituted" (each substituent is independent of any other substituent) within the context of its use refers to C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carbox amide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxy C1-C6), sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxy ​ester or carbonyl ester), C1-C6 keto, urethane -O-C(O)-NR1R2 or -N(R 1)-C(O)-O-R1, nitro, cyano, and amine (especially, C1-C6 alkylene-NR1R2, mono or di-C1-C6 alkyl-substituted amines, which may optionally be substituted with one or two hydroxyl groups and are also meant to include). Each of these groups contains 1 to 6 carbon atoms within the context, unless otherwise indicated. In certain embodiments, depending on the context in which the substituent is used, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2 ), - (wherein, m and n are 1, 2, 3, 4, 5 or 6 in the context herein), -S- , -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) ) m OH, -(CH2) SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) OC(O)-(C1-C6 n alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) C(O)-NR1R2, -( OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) O-(C1-C6 alkyl), -(CH2O) n C(O)-( C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R ), -S(O)2-R n ), -S(O)2-R n ), -S(O)2-R S, -S(O)-R S (R S is , C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogen (F, Cl, Br, I , preferably F or Cl). R1 and R2 are each H in the context or is a C1-C6 alkyl group (optionally substituted with one or two hydroxyl groups, or up to three halogen groups , preferably fluorine). The term "substituted" also means, within the chemical context of the compounds defined and the substituents used, an optionally substituted aryl group or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. The alkylene group may also be substituted as otherwise disclosed herein , preferably an optionally substituted C1-C6 alkyl group (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, with the attendant provision of chiral centers), the side chain of an amino acid group as otherwise described herein, the above amide group, or a urethane group, an O-C(O)-NR1R2 group, wherein R1 and R2 may be substituted with groups as otherwise described herein but many other groups may also be used as substituents . Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer substituents, and preferably one or two substituents. In a compound, substitution is required at a particular position of the molecule (mainly for reasons of valence), but when substitution is not shown, the substituent is considered to be H, or it should be noted that it is understood as such, in the context of substitution, unless otherwise indicated in the context of substitution. . It should be noted that in a compound, substitution is required at a particular position of the molecule (mainly for reasons of valence), but when substitution is not shown, the substituent is considered to be H, or it is understood as such, in the context of substitution, unless otherwise indicated in the context of substitution. Please note that in the context of substitution, unless otherwise indicated in the context of substitution, the substituent is considered to be H, or it is understood to be so.

[0445] The term "aryl" or "aromatic", in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or a fused ring (e.g., naphthyl, anthracenylphenyl, phenanthrenyl, etc.), and can be attached to a compound at any available stable position on the ring or as otherwise specified in the presented chemical structure, in accordance with the present disclosure. Other examples of aryl groups, in context, include heterocyclic aromatic ring systems, such as "heteroaryl" groups having one or more nitrogen atoms, oxygen atoms or sulfur atoms in the ring, for example imidazole, furyl, pyrrole, furanyl, thiophene, thiazole, pyridine, py rimidine, pyrazine, triazole, oxazole, etc., or fused ring systems such as indole, qui noline, indolizine, azaindolizine, benzofurazan, etc., which can be optionally substituted as described above. Among the heteroaryl groups that may be mentioned, in particular, nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, py rimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, inda zole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydro isoquinoline, tetrahydroisoquinoline, quinolidine, phthalazine, naphthyridine, qui noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria dine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolyl, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, inda zole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydro isoquinoline, tetrahydroisoquinoline, quinolidine, phthalazine, naphthyridine, qui noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria dine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolyl, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, furans, pyrrolopyridines, pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from among nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted. The term "substituted aryl" refers to an aromatic carbocyclic ring composed of at least one aromatic ring or a plurality of fused rings at least one of which is aromatic, where the ring is substituted with one or more substituents. For example, an aryl group can include substituents selected from the following: -(CH2) OH, -(CH2)

[0446] -O-(C1-C6)alkyl, -(CH2) -O- (CH2) -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, where the alkyl group on the amine is optionally one or two hydroxyl groups or up to (CH2) n -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, wherein the alkyl group on the amine is optionally one or two hydroxyl groups or up to n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, and the alkyl group on the amine is optionally one or two hydroxyl groups or up to two methyl groups, and the alkyl groups may be optionally substituted with one or more substituents selected from the following: halogen, -(CH2) with three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3 , OMe, OCF3, NO2, or CN groups (each of which can be substituted at the ortho, meta, and / or para positions, preferably the para position) of the phenyl ring, an optionally substituted phenyl group (it is preferred that the phenyl group itself is linked via a linker to a PTM group containing a ULM group) and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (ortho, meta, and / or para positions of the phenyl ring, preferably the para position) of at least one of the substituted ones, an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole containing a methyl-substituted isoxazole, an optionally substituted oxazole containing a methyl-substituted oxazole, an optionally substituted thiazole containing a methyl-substituted thiazole , an optionally substituted isothiazole containing a methyl-substituted isothiazole , an optionally substituted pyrrole containing a methyl-substituted pyrrole, an optionally substituted imidazole containing a methylimidazole, an optionally substituted benzimidazole or methoxybenzimidazole , an optionally substituted oxyimidazole or methyloxyimidazole , an optionally substituted diazolyl group containing a methyldiazolyl group, an optionally substituted triazolyl group containing a methyl-substituted triazolyl group, a halo- (preferably F) or methyl-substituted pyridine group or an optionally substituted pyridine group containing an oxapyridine group (wherein the pyridine group is bonded to the phenyl group by oxygen), an optionally substituted furan, an optionally substituted benzofuran , an optionally substituted dihydrobenzofuran, an optionally substituted indole, i Indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

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

[0448] The term "heteroaryl" or "heteraryl" includes, but is not limited to, optionally substituted quinoline (which can be 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 substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl-substituted and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted (CH2) -O-C 1-C6 alkyl group, or optionally substituted (CH2) -C(O)-O-C1-C6 alkyl group substituted with m -O-C 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 may mean a group having the following chemical structure:

[0449] [Chemical Formula]

[0450] wherein: S c is CHR SS , NR URE , or O; R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (e.g., CF3 ), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to 3 halo groups), or optionally substituted acetylenic group -C≡C-R wherein R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl a ) and is an acetylenic group; is an acetylenic group; R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to 3 halo groups); is; R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl) where each group is optionally substituted with one or two hydroxyl groups or up to 3 halo groups, preferably fluorine groups, or an optionally substituted heterocyclic ring, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperazine, etc., each of which is optionally substituted, and Y is N or C-R wherein R is H, OH, CN, NO2, halo (preferably Cl or C F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to 3 halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) YC (preferably substituted with one or two hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylene group -C≡C-R YC wherein R is H or a C1-C 6 alkyl group (preferably C1-C3 alkyl) and is an acetylene group. The terms "aralkyl" and "heteroarylalkyl" refer to groups containing aryl or heteroaryl respectively, as defined above, and alkyl, and / or heteroalkyl, and / or carbocyclic and / or heterocycloalkyl ring systems, in accordance with the above definitions. As used herein, the term "arylalkyl" refers to an aryl group as defined above attached to an alkyl group as defined above. An arylalkyl group is an alkyl a group a substituted with an aryl group.

[0451]

[0452] ​​​​​​Attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above.

[0453] The term "heterocyclic ring" refers to a cyclic group containing at least one heteroatom, such as N, O or S, and may be aromatic (heteroaryl) or non-aromatic. Therefore, the heteroaryl moiety is included under the definition of heterocyclic ring depending on the context of its use. Exemplary heteroaryl groups are described above in this specification. Exemplary heterocyclic rings include, in particular, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio and is attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above.

[0454] Exemplary heterocyclic rings include, in particular, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio and is attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above. Exemplary heterocyclic rings include, in particular, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio and is attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above. Exemplary heterocyclic rings include, in particular, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio and is attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above. Exemplary heterocyclic rings include, in particular, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio and is attached to the parent moiety via a kill group, in which case the alkyl group has 1 to 6 carbons atoms. The aryl group in the arylalkyl group may be substituted as described above. Examples include ranil and thian.

[0455] The heterocyclic group may be optionally substituted with one selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thio aryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thio alkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, hetero aryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2- alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo(=O), and -SO2-heteroaryl Optionally substituted with one selected from the group consisting of. Such a heterocyclic group may have a single ring or a plurality of condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, pheno xazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, pheno xazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, Indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., and N-alko xy-nitrogen-containing heterocycles are included. The term "heterocyclic" also refers to any of the heterocycles being condensed with a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolyl , isoquinolyl, tetrahydroquinolyl, etc.) to form a bicyclic group.

[0456] The term "cycloalkyl" means a monocyclic or polycyclic alkyl group or a monovalent group derived from cycloalkane as defined herein, including but not limited to saturated monocyclic hydrocarbon groups having 3 to 20 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" means a monocyclic or polycyclic alkyl group substituted with one or more substituents such as amino, halogen, alkyl, substituted alkyl, carbonyloxy, carbony lmercapto, aryl, nitro, mercapto or sulfo, etc., but not limited thereto, and these general substituents have the same meaning as the corresponding group definitions defined in this description. The term "heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S or P. The term "substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S or P, and the group is selected from the group consisting of halogen, alkyl, substituted alkyl, carbony loxy, carbony lmercapto, aryl, nitro, mercapto or sulfo. ​​​​​​​​​ contains one or more substituents selected from, but the general term of these substituents has the same meaning as the definition of the corresponding group defined in this description and has the same meaning as the definition of the corresponding group defined in this description

[0457] The term "hydrocarbyl" is meant to mean a compound containing carbon and hydrogen, and may be fully saturated, partially unsaturated, or aromatic, and includes aryl groups, alkyl groups, alkenyl groups, and alkynyl groups

[0458] In this specification, the term "independently" is used to indicate that the independently applied variables vary independently for each application and vary independently

[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 can be covalently bonded independently to a linker and / or a linker bonded to one or more PTM, ULM, ILM, or ILM' groups

[0461] Exemplary MLM In certain additional embodiments, the MLM of the bivalent compound includes chemical moieties such as substituted imidazoline, substituted Functionality spiro-indolinone, substituted pyrrolidine, substituted piperidinone, substituted morpholinone, substituted substituted pyrrolopyrimidine, substituted imidazolopyridine, substituted thiazoloimidazoline, substituted pyrrolo pyrrolidinone, and substituted isoquinolinone and chemical moieties such as substituted imidazoloimidazoline, substituted pyrrolopyrrolidinone, and substituted isoquinolinone

[0462] In additional embodiments, the MLM is adjacent positioned as a cis configuration or a trans configuration and includes the above-described core structure with a bis-aryl substitution.

[0463] In further additional embodiments, the MLM is in RG7112, RG7388, SAR405838, AMG-232, AM-720 9, DS-5272, MK-8242, and NVP-CGM-097, as well as analogs or derivatives thereof and includes structural characteristic portions such as these.

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

[0465] [Chemical formula]

[0466] In the above formulas (A-1) to (A-8), X in formulas (A-1) to (A-8) is selected from the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone, and N-R a or selected from the group; R a is 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 formulas (A-1) to (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 group, and may be one or two atoms; R1 and R2 in formulas (A-1) to (A-8) are independently selected from the group consisting of an aryl group or a heteroaryl group, the heteroaryl group has one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or may be substituted with 1 to 3 substituents independently selected from the following group, or may be unsubstituted: halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons, and dialkylamine containing 2 to 6 carbons; R3 and R4 in formulas (A-1) to (A-8) are independently selected from the group consisting of H, methyl, and C1-C6 alkyl; R5 in formulas (A-1) to (A-8) is selected from the group consisting of an aryl group or a heteroaryl group, the heteroaryl group has one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or may be substituted with 1 to 3 substituents independently selected from the following group, or may be unsubstituted: halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons, and dialkylamine containing 2 to 6 carbons; R5 in formulas (A-1) to (A-8) is selected from the group consisting of an aryl group or a heteroaryl group, the heteroaryl group has one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, Lucoxy, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons , sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons , dialkylamine containing 2 to 6 carbons, alkyl ether (C2 - C6), alkyl ketone (C3 - C6), morpholinyl, alkyl ester (C3 - C6), alkyl cyanide (C3 - C6) ; In formula (A-1) to formula (A-8), R6 is H or -C(=O)R b wherein, R in formula (A-1) to formula (A-8) b is alkyl, cycloalkyl, mono-substituted, di-substituted or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piper idinyl, 4-N-R c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl or selected from the group consisting of, wherein, R in formula (A-1) to formula (A-8) c is alkyl, fluorine-substituted alkyl, cyanoalkyl, hydro xyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidoalkyl, alkyl sulfone, alkyl sulfoxide, alkyl amide, aryl, heteroaryl, mono-substituted , di-substituted and tri-substituted aryl or heteroaryl, CH2CH2R d , as well as CH2CH2CH2R d selected from the group consisting of, wherein, R in formula (A-1) to formula (A-8) d is alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl , selected from the group consisting of heteroaryl and substituted heteroaryl; In formulas (A-1) to (A-8), R7 is H, C1-C6 alkyl, cyclic alkyl, fluorine-substituted alkyl , cyano-substituted alkyl, a 5- or 6-membered heteroaryl or aryl, a 5- or 6 -membered substituted heteroaryl or aryl, and is selected from the group consisting of; In formulas (A-1) to (A-8), R8 is -R e -C(O)-R f , -R e -alkoxy, -R e -aryl, -R e -hetero aryl, and -R e -C(O)-R f -C(O)-R g and is selected from the group consisting of, wherein: In formulas (A-1) to (A-8), R e is alkylene containing 1 to 6 carbons, or a bond; In formulas (A-1) to (A-8), R f is a 4- to 7-membered substituted heterocyclic ring; In formulas (A-1) to (A-8), R g is selected from the group consisting of aryl, heteroaryl, substituted aryl or substituted he teroaryl, and a 4- to 7-membered heterocyclic ring; In formulas (A-1) to (A-8), R9 is a mono-substituent, di -substituent or tri-substituent on the fused bicyclic aromatic ring in formula (A-3), where the substituents are independently selected from the group consisting of Cl or F-substituted or unsubstituted halogen, alkene, alkyne, alkyl and is selected from the group consisting of; In formulas (A-1) to (A-8), R 10 is selected from the group consisting of an aryl group or a heteroaryl group wherein the heteroaryl group has one or two heteroatoms such as sulfur or nitrogen It may contain a child, and the aryl group or heteroaryl group may be monocyclic or bicyclic Well, the aryl group or heteroaryl group may be substituted with 1 to 3 substituents including halogen, F, Cl, -CN, alkene, a lkynyl, C1-C6 alkyl group, C1-C6 cycloalkyl, -OH, alkoxy containing 1 to 6 carbons , fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, 1 to 6 sulfones containing carbon atoms, ketones containing 2 to 6 carbon atoms, or may be unsubstituted; ; R in formulas (A-1) to (A-8) 11 is -C(O)-N(R h )(R i ), wherein R h and R i are selected from the following group: H, C1-C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, hete roaryl, mono-substituted, di-substituted or tri-substituted aryl or heteroaryl, alk ylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted alkylcar boxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl; wherein R in formulas (A-1) to (A-8) h and R i are independently selected from the group consisting of H, 4-hydroxy cyclohexane, monohydroxy and dihydroxy-substituted alkyl (C3-C6), 3-hydroxy cyclobutane, phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acid ; R in formulas (A-1) to (A-8) 12 and R 13 are independently selected from the group consisting of H, lower alkyl (C1-C6), lower a Rukenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4-membered, 5-membered and 6-membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5-membered and 6-membered aryl and heteroaryl, selected from; R 12 and R 13 may combine to form a 5-membered or 6-membered ring with or without substitution on the ring; R in formulas (A-1) to (A-8) is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl 14 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic , cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl ; R in formulas (A-1) to (A-8) is CN; 15 R in formulas (A-1) to (A-8) is C1-C6 alkyl, C1-C6 cycloalkyl, C2-C6 alkenyl 16 , C1-C6 alkyl or C cycloalkyl in which one or more hydrogens are substituted by fluorine, C 1~6 alkyl or C 3~6 cyclo alkyl in which one CH2 is substituted by S(=O), -S or -S(=O)2, or cycloalkyl, terminal CH3 substituted by S(=O)2N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O)2(alkyl), -C(=O)2(alkyl), -O(alkyl) alkyl or cycloalkyl, C1-C6 alkyl or alkyl-cycloalkyl in which hydrogen is substituted by a hydroxyl group, optionally 3- to 7-membered cycloalkyl or heterocycloalkyl containing a -(C=0)- group, or a group consisting of a 5- to 6-membered aryl group or heteroaryl group from the group; or selected, and the heterocycloalkyl or heteroaryl group may contain 1 to 3 heteroatoms independently selected from O, N or S, and the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl group, hydroxylated C1-C6 alkyl, thioether-containing C1-C6 alkyl, ether, sul fone, sulfoxide, fluorine-substituted ether or cyano group, or may be unsubstituted; R in formula (A-1) to formula (A-8) is selected from the group consisting of (CH2) C(O)NR R 17 wherein, R n and R k R l are independently selected from H, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxy k alkyl, C1-C6 alkyl in which one or more hydrogens are substituted with fluorine, C1-C6 alkyl in which one carbon is substituted with S( O), S(O)(O), C1-C6 alkoxyalkyl in which one or more hydrogens are substituted with fluorine, C l alkyl in which hydrogen is substituted with a cyano group, 5-membered and 6-membered aryl or heteroaryl, alkylaryl having an alkyl group containing 1 to 6 carbons, and alkylheteroaryl having an alkyl group containing 1 to 6 carbons, and the aryl group or heteroaryl group may be further substituted; R in formula (A-1) to formula (A-8) is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl wherein the substitution is preferably -N(C 1~6 alkyl)(cycloalkyl ), -N(C alkyl)(cycloalkyl ), and the aryl group or heteroaryl group may be further substituted; R in formula (A-1) to formula (A-8) is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl 18 wherein the substitution is preferably -N(C alkyl)(cycloalkyl), -N(C 1-4 alkyl)(cycloalkyl ), -N(C 1-4(alkyl)alkyl-cycloalkyl, and -N(C 1-4 (alkyl)[(alkyl )-(heterocyclic-substituted)-cycloalkyl]; R of formula (A-1) to formula (A-8) 19 is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and these aryl groups and heteroaryl groups are halogen, C1-C6 alkyl, C1-C6 cycloalkyl, CF3, F, CN, alkyne, alkyl sulfone and may be substituted, and the halogen substitution may be mono-substituted, di-substituted or tri-substituted; R of formula (A-1) to formula (A-8) and R 20 are independently selected from C1-C6 alkyl, C1-C6 cycloalkyl 21 , C1-C6 alkoxy, hydroxylated C1-C6 alkoxy, and fluorine-substituted C1-C6 alk oxy, and in the formula, R and R 20 are further bonded and may form a 5-, 6-, and 7-membered ring or 21 a heterocyclic ring, and this may be further substituted; R of formula (A-1) to formula (A-8) is selected from the group consisting of H, C1-C6 alkyl, C1-C6 cycloalkyl, carboxylic acid 22 , carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea, nitrogen-containing 5-membered heterocyclic ring and the 5-membered heterocyclic ring may be further substituted with C1-C6 alkyl, alkoxy, fluorine substituted alkyl, CN, and alkyl sulfone; R of formula (A-1) to formula (A-8) is aryl, heteroaryl, -O-aryl, -O-heteroaryl 23 ​Reel, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cyclo loalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(al kyl)-heteroaryl, and the aryl group or heteroaryl group may be substituted with halogen , C1-C6 alkyl, hydroxylated C1-C6 alkyl, cycloalkyl, fluorine-substituted C1- C6 alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide; ; R in formula (A-1) to formula (A-8) 24 is selected from the group consisting of -CH2-(C 1-6 alkyl), -CH2-cycloalkyl, -CH2-ari yl, CH2-heteroaryl, and the alkyl, cycloalkyl, a ryl and heteroaryl may be substituted with halogen, alkoxy, hydroxylated alkyl, cyan o-substituted alkyl, cycloalkyl, and substituted cycloalkyl; R in formula (A-1) to formula (A-8) 25 is C 1-6 alkyl, C 1-6 alkyl-cycloalkyl, alkoxy substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5, 6 and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen containing saturated heterocycles, and these saturated heterocycles may be substituted with C1-C6 alkyl, fluorine-substituted C1-C6 alkyl, alkoxy, aryl and heteroaryl groups; ; R in formula (A-1) to formula (A-8) 26 is C 1-6 alkyl, C 3-6 cycloalkyl selected from the group consisting of and the alkyl or cycloalkyl may be substituted with -OH, alkoxy, fluorine-substituted alkoxy , fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl, and -S(O)2-alkyl; R in formulas (A-1) to (A-8) 27 is selected from the group consisting of aryl, heteroaryl, and bicyclic heteroaryl, and the aryl group or heteroaryl group may be substituted with C1-C6 alkyl, alk oxy, NH2, NH-alkyl, halogen, or -CN, and the substitution may be independent and may be mono-substituted, di-substituted, or tri-substituted; R in formulas (A-1) to (A-8) is selected from the group consisting of aryl, 5-membered and 6-membered heteroaryl, bicyclic hete 28 roaryl, cycloalkyl, saturated heterocycles such as piperidine, piperidinone, tet rahydropyran, N-acyl-piperidine, and the cycloalkyl, saturated heterocycle, aryl, or heteroaryl may be further substituted with -OH, alkoxy, halogen-containing mono-sub stitution, di-substitution, or tri-substitution, -CN, alkyl sulfone, and fluorine-substituted alkyl group; and R in formulas (A-1) to (A-8) is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted al kyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl 1” . In certain embodiments, the heterocycles in R and R in formulas (A-1) to (A-8)

[0467] are substituted pyrro f lysine, substituted piperidine, and substituted piperizine. g

[0468] ​​ More specifically, non-limiting examples of MLMs include those shown below, as well as “hybrid” molecules resulting from one or more combinations of different properties shown in the following molecules. are exemplified.

[0469] Using the MLMs of Formulas A-1 to A-8, the following PROTACs can be prepared to target the degradation of a specific protein, where “L” is a linker (i.e., a linker group) and “PTM” is a ligand that binds to the target protein.

[0470] In certain embodiments, the present specification provides a di Functionality functional molecule comprising a structure selected from the group consisting of:

[0471]

Chemical formula

[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’’ are as defined in Formulas (A-1) to (A- 8) in this specification.

[0473] In certain embodiments, this specification provides a bifunctional or chimeric molecule having the following structure: PTM-L-MLM, wherein PTM is a protein target binding moiety bound to MLM by L, wherein L is a linker that is a bond (i.e., absent) or a chemical linker. In certain embodiments, MLM has a structure selected from the group consisting of A-1-1, A-1-2, A-1-3, and A-1-4:

[0474]

Chemical formula

[0475] Wherein: R1’ and R2’ of Formulas A-1-1 to A-1-4 are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF3, and NO2 ; R3’ is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, and -OCH(CH3)2 ; R4’ of Formulas 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; For R5’ of Formulae A-1-1 to A-1-4, it is selected from the group consisting of halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1- pyrrolidinyl, -NH2, -N(CH3)2, and -NHC(CH3)3; and For R6’ of Formulae A-1-1 to A-1-4, it is selected from the structures represented below, wherein the linker attachment point is shown as “*”. Apart from R6’ as the linker attachment point, R4’ can also serve as a linker attachment point When R4’ is the linker attachment point, the linker will be attached to the terminal atom of the R4’ group as shown above .

[0476] In certain embodiments, the linker attachment point of Formulae A-1-1 to A-1-4 is at least one of, or both of, R4’ or R6’.

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

[0478]

Chemical formula

[0479]

Chemical formula

[0480] selected from the group consisting of, wherein “*” indicates the attachment point of the linker. ​In certain embodiments, the linkers of Formulas A-4-1 to A-4-6 are attached to at least one of R1’, R2’, R3’, R4’, R5’ , or a combination thereof.

[0481] In certain embodiments, the present specification provides a bifunctional molecule or chimeric molecule having the following structure: PTM-L-MLM, wherein PTM is a protein target binding moiety attached to MLM by L , and wherein L is a linker that is a bond (i.e., absent) or chemical . In certain embodiments, MLM has a structure selected from the group consisting of the following A-4-1, A-4-2, A-4-3, A-4-4, A-4 -5, and A-4-6:

[0482]

Chemical formula

[0483] Wherein: 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 and di-substituted or tri-substituted halogen . R8’ of Formulas A-4-1 to A-4-6 is H, -F, -Cl, -Br, -I, -CN, -NO2, ethynyl, cyclopropyl , methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -O H, other C 1-6 alkyl, other C 1-6 alkenyl and C 1-6 alkynyl, selected from the group consisting of mono-substituted, di- substituted or tri-substituted; R9’ of Formulas A-4-1 to A-4-6 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, al Kinyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl and substituted cycloalkenyl selected from the group consisting of ; Z in Formulas A-4-1 to A-4-6 is selected from the group consisting of H, -OCH3, -OCH2CH3, and halogen; R10’ and R11’ in Formulas 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 selected from the group consisting of wherein alkyl may be substituted with OR’ and heteroaryl-(CH2) n -heterocyclic ring; wherein the heterocyclic ring may optionally be substituted with alkyl, hydroxyl, COOR' and COR'; wherein R’ and R" are selected from H, alkyl, halogen-substituted alkyl, hydroxyl, NH2 , NH(alkyl), N(alkyl)2, oxo, carboxy, cycloalkyl and heteroaryl selected; m, n, and p are independently 0 to 6; R12’ of Formula A-4-1 to Formula A-4-6 is selected from the group consisting of -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl) , -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl)2, -S( O)-(alkyl), S(O)2-(alkyl), -C(O)-(cyclic amine), and -O-aryl-(alkyl ), -O-aryl-(alkoxy); R1” of Formula A-4-1 to Formula A-4-6 is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl , cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl .

[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 at least one of Z, R8’, R9’, R10’, R11”, R12”, or R1”.

[0486] The methods used for designing the chimeric molecules presented in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLM using Formulas A -2, Formula A-3, Formula A-5, Formula A-6, Formula A-7 and Formula A-8, and in this case the solvent-exposed region of MDM can be optionally attached to the linker “L”, which linker will be attached to the target protein ligand “PTM” to construct a PROTAC.

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

[0488]

Chemical formula

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

[0490]

Chemical formula

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

[0492]

Chemical formula

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

[0494]

Chemical formula

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

[0496] Exemplary CLM Neo-Imide Compound In one aspect, the present specification provides compounds useful for the binding and / or inhibition of celebron. In certain embodiments, the compound is selected from the group consisting of the following chemical structures: :

[0497]

Chemical Formula

[0498] Wherein: W in formulas (a) to (f) is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH, and N-alkyl; X in formulas (a) to (f) is independently selected from the group consisting of O, S, and H2; Y in formulas (a) to (f) is independently selected from the group consisting of CH2, -C=CR’, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a) to (f) is independently selected from the group consisting of O, and S or H2, provided that both X and Z cannot be H2; G and G’ in formulas (a) to (f) are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R’OCOOR, R’OCONRR”, CH2-heterocyclyl optionally substituted with R’, and benzyl optionally substituted with R’; Q1 to Q4 in formulas (a) to (f) represent a carbon C substituted with a group independently selected from R, R’, N, or N-oxide; A in formulas (a) to (f) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, H, and F; R in formulas (a) to (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 (straight or branched, optionally substituted), -cycloalkyl, -hetero Cyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, - Br, -I, -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, a are selected from aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl; each is optionally substituted; In formulas (a) to (f), n is an integer of 1 to 10 (e.g., 1 to 4);

[0499] [ka]

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

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

[0502] [Chemical formula]

[0503] wherein: independently, W in formula (a) - formula (f) is selected from the group consisting of CH2, CHR, C=O, SO2, NH, and N-alkyl; selected; independently, X in formula (a) - formula (f) is selected from the group consisting of O, S, and H2; independently, Y in formula (a) - formula (f) is selected from the group consisting of CH2, -C=CR’, NH, N-alkyl, N-aryl, N-hetero aryl, N-cycloalkyl, N-heterocyclyl, O, and S; independently, Z in formula (a) - formula (f) is selected from the group consisting of O, and S or H2, provided that both X and Z cannot be H2; independently, G and G’ in formula (a) - formula (f) are selected from the group consisting of H, alkyl (linear, branched), OH, R’OCOO R, R’OCONRR”, CH2-heterocyclyl optionally substituted with R’, and benzyl optionally substituted with R’; selected; Q1 - Q4 in formula (a) - formula (f) represent a carbon C substituted with a group independently selected from R, R’, N, or N-oxide; represented; independently, A in formula (a) - formula (f) is selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cyclo alkyl, Cl, H, and F; R in formula (a) - 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,-heteroaryl,- 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 In formulas (a) to (f), R’ and R” are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, heterocyclyl, and they are each optionally substituted; In formulas (a) to (f), n is an integer from 1 to 10 (e.g., 1 to 4); In formulas (a) to (f), represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and In formulas (a) to (f), Rn contains 1 to 4 independent functional groups or atoms, and optionally one of them is modified and covalently bonded to a PTM, chemical linker group (L), ULM, CLM (or CLM’) or a combination thereof.

[0504]

Chemical formula

[0505] In specific embodiments described herein, CLM or ULM contains a chemical structure selected from the following group: In specific embodiments described herein, CLM or ULM contains a chemical structure selected from the following group: In specific embodiments described herein, CLM or ULM contains a chemical structure selected from the following group: In specific embodiments described herein, CLM or ULM contains a chemical structure selected from the following group:

[0506] In specific embodiments described herein, CLM or ULM contains a chemical structure selected from the following group: including:

[0507]

Chemical formula

[0508] In the formula: W in formula (g) is independently selected from the group consisting of CH2, C=O, NH, and N-alkyl; R in formula (g) is independently selected from H, methyl, alkyl (e.g., C1-C6 alkyl (linear, branched, optionally substituted)); ;

[0509]

Chemical formula

[0510] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and ; and Rn in formula (g) contains 1 to 4 independently selected functional groups or atoms, and optionally one of them is modified and covalently bonded to a PTM, chemical linker group (L), ULM, CLM (or CLM’), or a combination thereof. ;

[0511] In any of the embodiments described herein, W, X, Y, Z, G, G’, R, R’, R’’, Q1-Q4, A, and Rn in formulas (a)-(g) are independently covalently bonded to a linker, and / or a linker bonded to one or more PTM, ULM, CLM, or CLM’ groups. ; ; ;

[0512] More specifically, non-limiting examples of CLM include those shown below, as well as “hybrid” molecules resulting from one or more combinations of different properties shown in the following molecules. ; ;

[0513]

Chemical formula

[0514] [Chemistry]

[0515] [Chemistry]

[0516] [Chemistry]

[0517] [Chemistry]

[0518] [Chemistry]

[0519] [Chemistry]

[0520] In any of the compounds described in this specification, CLM comprises a chemical structure selected from the following group: :

[0521] [Chemistry]

[0522] [Chemistry]

[0523] [Chemistry]

[0524] Wherein: In formula (h) to formula (ad), W is independently selected from CH2, CHR, C=O, SO2, NH, and N-alkyl; ; In formula (h) to formula (ac), Q1, Q2, Q3, Q4, and Q5 represent a carbon C independently substituted with a group selected from R’, N, or N-oxide; ; In formula (h) to formula (ad), R 1 is selected from H, CN, C1-C3 alkyl; In formula (h) to formula (ad), R 2 is selected from the group of H, CN, C1-C3 alkyl, CHF2, CF3, and CHO; In formula (h) to formula (ad), R 3 is selected from H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; ; In formula (h) to formula (ad), R 4 is selected from H, alkyl, or substituted alkyl; In formula (h) to formula (ad), R 5 is H or lower alkyl; In formula (h) to (ad), X is C, CH, or N; In formula (h) to formula (ad), R’ is selected from H, halogen, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; ; In formula (h) to (ad), R is H, OH, lower alkyl, lower alkoxy, cyano, lower alkoxy halide, or lower alkyl halide. ;

[0525]

Chemical formula

[0526] In formula (h) to (ad), is a single bond or a double bond; and the CLM is covalently bonded to PTM, a chemical linker group (L), ULM, CLM (or CLM’), or a combination thereof. ;

[0527] In any aspect or embodiment described herein, CLM or CLM’ is connected to PTM, chemical linker group (L), ULM, CLM, CLM’, )~R groups 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) via a covalent bond. or a combination thereof.

[0528] In any of the embodiments described herein, CLM or CLM’ is connected to PTM, chemical linker group (L), ULM, CLM, CLM’, )~W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R’, Q1, Q2, Q3, Q4, and Q5 via , a covalent bond to PTM, chemical linker group (L), ULM, CLM, CLM’, or a combination thereof .

[0529] In any of the embodiments described herein, W, X, R 1 , R 2 , R 3 , R 4 , R’, Q1, Q2, Q3, Q4, and Q5 of formula (h)~formula (ad) are independently, may be covalently bonded to the linker well, and / or may be covalently bonded to a linker that binds to one or more PTM, ULM, ULM’, CLM or CLM’ groups.

[0530] More specifically, non-limiting examples of CLM include those shown below, as well as “hybrid” molecules or compounds resulting from a combination of one or more properties of the following compounds :

[0531] [Chemical formula]

[0532] [Chemical formula]

[0533] In the formula: In formulas (ae) to (ap), W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH, and N-alkyl; selected; R in formulas (ae) to (ap) 1 is selected from the group consisting of H, CN, and C1-C3 alkyl; R in formulas (ae) to (ap) 3 is selected from the group consisting of H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; selected; R in formulas (ae) to (ap) is H;

[0534] [Chemical formula]

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

[0536] In any of the embodiments described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, and Rn may be independently covalently bonded to a linker and / or covalently bonded to a linker that is bonded to one or more PTM, ULM, ULM', CLM, or CLM' groups. bonded.

[0537] In any of the embodiments described herein, R 1 , R 2 , Q1 Q2, Q3, Q4, and Rn may be independently covalently attached to a linker and / or covalently attached to a linker that is attached to one or more PTM, ULM, ULM’, CLM or CLM’ groups.

[0538] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn of formulas (ae) to (ap) may be independently covalently attached to a linker and / or to a linker that is attached to one or more PTM, ULM, ULM’, CLM or CLM’ groups.

[0539] In any aspect or embodiment described herein, R of formulas (ae) to (ap) is n modified and covalently attached to a linker group (L), a second CLM having the same chemical structure as PTM, ULM, CLM, CLM’, a second linker, or any plurality or combination thereof.

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

[0541]

Chemical formula

[0542]

Chemical formula

[0543] Wherein R’ is halogen and R 1 is as described above with respect to formulas (h) to (ab) or formulas (ac) to (an).

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

[0545]

Chemical formula

[0546] wherein R’ is halogen. Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM and includes a chemical structure selected from the group of the following ULM-a :

[0547]

Chemical formula

[0548] , wherein the dashed line indicates the attachment of 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 -portion, and at least one PTM, ULM’ or VLM’ or CLM’ or ILM’ or MLM’ is attached to the other end of the linker; X in formula ULM-a 1 , X 2 is each independently selected from the group consisting of a bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO, and S O2; R in formula ULM-a Y3 , R Y4 are each independently selected from the group consisting of H, linear or branched C 1~6 alkyl, and they are optionally one or more halo, optionally substituted C alkyl,1~6 is substituted by an alkoxyl (e.g., optionally substituted by 0 to 3 R P groups); R in formula ULM-a P is 0, 1, 2 or 3 groups, each independently selected from H, halo, -OH, C 1-3 alkyl groups; W in formula ULM-a 3 is optionally substituted -T-N(R 1a R 1b )X 3 , -T-N(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-hetero cycle group; X in formula ULM-a 3 is C=O, R 1 , R 1a , R 1b ; R 1 , R 1a , R 1b each is independently a straight-chain or branched C1-C6 alkyl group optionally substituted by H, one or more halo or -OH groups, R C=O, R Y3 C=S, R Y3 SO, R Y3 SO2, N(R Y3 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 ); T in formula ULM-a is X 1is covalently bonded; W of formula ULM-a 4 is optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroar yl group, or optionally substituted -NR 1 -T-heterocyclic ring, wherein -NR 1 is X 2 is covalently bonded and R 1 is H or CH3, preferably H.

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

[0550] In a particular embodiment, W of formula ULM-a 4 is

[0551]

Chemical formula

[0552] wherein R 14a、 R 14b、 are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl.

[0553] In any of the embodiments, W of formula ULM-a 5 is phenyl or a 5- to 10-membered heteroaryl selected from the group of R of formula ULM-a 15 is H, halogen, CN, OH, NO2, NR 14a R 14b 、OR 14a 、CONR 14a R 14b 、NR 14a C OR 14b 、SO2NR 14a R 14b 、NR 14a SO2R 14b 、optionally substituted alkyl, optionally substituted halo alkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalk yl, or cycloheteroalkyl; In additional embodiments, the W 4 substituent for use in the present disclosure further specifically includes the W 4 substituents present in the specific compounds disclosed herein (not limited to the specific disclosed compounds). Each of these W 4 substituents may be used in combination with any number of W 3 substituents, and those are also disclosed herein.

[0554] In certain additional embodiments, ULM-a is optionally substituted with 0 to 3 R P groups in the pyrrolidine moiety. Each R is independently H, halo, -OH, C P alkyl, C=O. 1-3

[0555] In any of the embodiments described herein, the W of formula ULM-a 3 、W 4 may be covalently bonded to a linker that is attached to one or more PTM groups. And in the formula, the dashed line represents at least one PTM, another ULM (ULM’), or at least one ​ Shows the binding site of the chemical linker moiety that binds either the PTM or ULM’ or both to the ULM .

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

[0557]

Chemical formula

[0558] Wherein: W of formula ULM-b 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0559]

Chemical formula

[0560] selected from the group of; R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl yl, or haloalkyl, or R 9, R 10 , and the carbon atom to which they are attached is , optionally substituted cycloalkyl to form; R of formula ULM-b 11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted substituted heteroaryl, optionally substituted aryl,

[0561]

Chemical formula

[0562] selected from the group of; R of formula ULM-b12 is selected from the group consisting of H or optionally substituted alkyl; R of formula ULM-b 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl , optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl carbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclic yl)carbonyl, or optionally substituted aralkyl; R of formula ULM-b 14a、 R 14b is each independently selected from the group consisting of H, haloalkyl, or optionally substituted alkyl; W of formula ULM-b 5 is selected from the group consisting of phenyl or 5- to 10-membered heteroaryl, R of formula ULM-b 15 is H, halogen, CN, OH, NO2, N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a C OR 14b , SO2NR 14a R 14b , NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted halo alkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each optionally substituted); R of formula ULM-b 16 is independently selected from the group consisting of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o of formula ULM-b is 0, 1, 2, 3, or 4; R of formula ULM-b 18is independently selected from the group consisting of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or linker; and and p of formula ULM-b is 0, 1, 2, 3, or 4, and in the formula, the dashed line represents at least one PTM , another ULM (ULM’), or the binding site of a chemical linker moiety that binds at least one PTM or ULM’ or both to ULM .

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

[0564]

Chemical formula

[0565] wherein 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. In certain embodiments, R of formula ULM-b

[0566] is selected from methyl, ethyl, isopropyl and cyclop 17 ropyl. In certain additional embodiments, R of formula ULM-b

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

[0568]

Chemical formula

[0569] In certain embodiments, R of formula ULM-b11 is selected from the group consisting of:

[0570]

Chemical formula

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

[0572]

Chemical formula

[0573] Wherein: For R1 in formula ULM-c, formula ULM-d, and formula ULM-e, it is H, ethyl, isopropyl, tert-butyl, sec -butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted hetero aryl, or haloalkyl; For R in formula ULM-c, formula ULM-d, and formula ULM-e is H, haloalkyl, optionally substituted alkyl 14a methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclo propyl; For R in formula ULM-c, formula ULM-d, and formula ULM-e is H, halogen, CN, OH, NO 15 optionally substituted 2、 heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cyclo heteroalkyl; selected from the group consisting of: For X in formula ULM-c, formula ULM-d, and formula ULM-e, it is C or C=O. ​R3 of formula ULM-c, formula ULM-d, and formula ULM-e is absent or is an optionally substituted 5-membered or 6-membered heteroaryl; and In the formula, the dashed line indicates the binding site of a chemical linker moiety that binds at least one PTM, another ULM (ULM’), or at least one PTM and / or ULM’ or both to the ULM.

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

[0575]

Chemical formula

[0576] Wherein: R of formula ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl l, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f is H; R of formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl cyclobutyl, cyclopentyl, or cyclohexyl; R of formula ULM-f 11 is

[0577]

Chemical formula

[0578] or optionally substituted heteroaryl; p of formula ULM-f is 0, 1, 2, 3, or 4; Each R of formula ULM-f 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted which is an alkyl, haloalkyl, haloalkoxy or linker; R of formula ULM-f 12 is H, C=O; R of formula ULM-f 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl , optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkyl ylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocycly l)carbonyl, or optionally substituted aralkyl, R of formula ULM-f 15 is H, halogen, Cl, CN, OH, NO 2、 optionally substituted heteroaryl, any optionally substituted aryl,

[0579]

Chemical formula

[0580] and is selected from the group consisting of, wherein the dashed line in formula ULM-f is a binding site of at least one PTM, another ULM (ULM’), or a chemical linker moiety that binds at least one PTM or ULM’ or both to ULM is shown.

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

[0582]

Chemical formula

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

[0584]

Chemical formula

[0585]

Chem.

[0586]

Chem.

[0587]

Chem.

[0588] Here, the phenyl rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, where the dashed line indicates the binding site of a chemical linker moiety that binds at least one PTM, another ULM (ULM’), or at least one PTM or ULM’ or both to ULM-a. Yes.

[0589] In one embodiment, the phenyl rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are functionalized as esters and can be made part of a prodrug.

[0590] In certain embodiments, the hydroxyl groups on the pyrrolidine rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are each ester-bonded to a prodrug moiety.

[0591] In any of the aspects or embodiments described herein, ULM, and, if present, ULM’, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, is, independently of one another, a group according to the following chemical structure:

[0592]

Chemical formula

[0593] Wherein: R of ULM-g 1’ is an optionally substituted C1-C6 alkyl group, an optionally substituted -(CH2) n OH, an optionally substituted -(CH2) n SH, an optionally substituted (CH2) n -O-(C1-C6) alkyl group, an optionally substituted (CH2) containing the epoxy moiety WCOCW, an optionally substituted (CH2) n -WCOCW-(C0-C6) alkyl group, wherein each W is independently H or a C1-C3 alkyl group, an optionally substituted -(CH2) n COOH, an optionally substituted -(CH2) n C(O)-(C1-C6 alkyl), an optionally substituted -(CH2) n NHC(O)-R1, an optionally substituted -(CH2) n C(O)-NR1R2, an optionally substituted -(CH2) n OC(O)-NR1R2, -(CH2O) n H, an optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), an optionally substituted -(CH2) n C(O)-O-(C1-C6 alkyl), an optionally substituted -(CH2O) n COOH, an optionally substituted -(OCH2) n O-(C1-C6 alkyl ), optionally substituted -(CH2O) n C(O)-(C1-C6 alkyl), optionally substituted -(OCH2) n NHC(O )-R1, optionally substituted -(CH2O) 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 a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine); R of ULM-g S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl group or heterocyclic group, or -(CH2) m NR1R2 group; X and X' of ULM-g are each independently C=O, C=S, -S(O), S(O)2 (preferably X and X' are both C=O); R of ULM-g 2’ is 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, optionally substituted -(CH2) n -(C=O) v NR1(SO2) w -heterocyclic, 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 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-he Teroaryl, or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) w -Heterocyclic ring, optionally substituted -X -X R2’ -Alkyl group; optionally substituted -X R2’ -Aryl group; optionally substituted -X R2’ -Heteroaryl group; optionally substituted -X R2’ -Is a heterocyclic group; R of ULM-g 3’ Is 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 Is optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N Is 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 -(CH2) n -C(O) u (NR1) v (SO2) w - Heteroaryl, optionally substituted -(CH2) n -C(O)u (NR1) v ( SO2) w - A complex ring, optionally substituted - NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w - Alkyl, optionally substituted - NR substituted - 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 - A complex ring, 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 substituted -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 -heterocyclic ring; -(CH2) n -(V) n’ -(CH2 ) n -(V) n’ -alkyl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted - (CH2) n -(V) n’ -(CH2) n -(V) n’ -heterocyclic ring ’ 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; optional substituted-X R3’ - aryl group; optionally substituted-X R3’ - heteroaryl group; optionally substituted-X R3’ - is a heterocyclic group; optionally substituted; R of ULM-g 1N and R 2N are each independently H, a C1-C6 alkyl optionally substituted with one or two hydroxyl groups or up to three halogen groups, or an optionally substituted -(CH2) n -a ryl, -(CH2) n -heteroaryl, or -(CH2) n -heterocyclic group; V of ULM-g is O, S or NR1; R1 of ULM-g is the same as above; R of ULM-g 1 and R 1’ are each independently H or a C1-C3 alkyl group; X of ULM-g R2’ and X R3’ are each independently an optionally substituted -CH2) n -, -CH2) n -CH(X v )=CH (X v )-(cis or trans), -CH2) n -CH≡CH-, -(CH2CH2O) n -, or a C3-C6 cycloal kyl group, wherein X v is H, halo, or an optionally substituted C1-C3 alkyl group; Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' of ULM-g is independently 0 or 1; Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' of ULM-g is independently 0 or 1; Each u of ULM-g is independently 0 or 1; Each v of ULM-g is independently 0 or 1; Each w of ULM-g is independently 0 or 1; and R of ULM-g 1’ R 2’ R 3’ One or more of R, R, R, X, and X' is optionally modified such that P When PTM is not ULM', it is covalently attached to the PTM group via a linker group, and when PTM is ULM' case, one of R, R, R, X, and X' of each of ULM and ULM' 1’ R 2’ R 3’ One or more of R, X, and X' is optionally modified and covalently attached to each other directly or via a linker group. When PTM is not ULM', it is covalently attached to the PTM group via a linker group, and when PTM is ULM'

[0594] In any of the aspects or embodiments described herein, ULM, and when present ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof is each independently a group according to the following chemical structure:

[0595]

Chemical formula

[0596] Wherein: R of ULM-h 1’ R 2’ and R 3’ are each the same as described above, and X is C=O, C=S, -S(O) is a group, or an S(O)2 group, more preferably a C=O group, and the R of ULM-h 1’ , R 2’ , and R 3’ if any one or more of are optionally modified such that the PTM is not UL M', a linker group that is further covalently bonded to the PTM group is attached, or if the PTM is ULM ', for each of ULM and ULM', the R 1’ , R 2’ , R 3’ if any one or more of are optionally modified to be covalently bonded to each other directly or via a linker group.

[0597] In any of the embodiments or implementations described herein, ULM, and where present ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof, each independently follows the following chemical structure:

[0598]

Chemical formula

[0599] wherein: the R of ULM-I 1’ , R 2’ , and R 3’ if any one or more of are optionally modified such that the PTM is not UL M', a linker group that is further covalently bonded to the PTM group is attached, or if the PTM is ULM ', for each of ULM and ULM', the R 1’ , R 2’ , R 3’ if any one or more of are optionally modified to be covalently bonded to each other directly or via a linker group.

[0600] In a more preferred embodiment of the present disclosure, the R of ULM-g to ULM-i​​​1’ is preferably a hydroxyl group, or a group that can be metabolized into a hydroxyl group or a carboxylic acid group, whereby the compound becomes a prodrug form of the active compound. Examples of preferred R groups include, for example, -(CH 1’ 2) OH, (CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CH2O) n H, optionally substituted -(CH2 ) n OC(O)-(C1-C6 alkyl), or optionally substituted -(CH2) n C(O)-O-(C1-C6 alkyl), where n is 0 or 1. In the formula, R is a carboxylic acid group, a hydroxyl group, or an amine group, or contains them, and the hydroxyl group, carboxylic acid group, or 1’ amine (each of which can be optionally substituted) can be further chemically modified to provide a covalent bond to a linker group that binds to a PTM group (including the ULM’ group); X and X' of ULM-g and ULM-h, if present, are preferably a C=O, C=S, -S(O) group or a S(O)2 group, more preferably a C=O group; R of ULM-g to ULM-i is preferably an optionally substituted -NR -T-aryl, an optionally substituted -NR -T-heteroaryl group, or an optionally substituted -NR -T-heterocycle, where R 2’ is H or CH3, preferably H, and T is an optionally substituted -(CH2) 1 - group, where each of the methylene groups is preferably a halogen, an a as described elsewhere in this specification 1 -NR 1 -T-heterocycle, where R 1 is H or CH3, preferably H, and T is an optionally substituted -(CH2) n - group, where each of the methylene groups is preferably a halogen, an a as described elsewhere in this specification One or two substituents selected from amino acid side chains, or C1-C3 alkyl groups, preferably may be optionally substituted with one or two methyl groups which may be optionally substituted, and n is 0 ~6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T is a -(CH2O) n - group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - group, and all of those groups may be optionally substituted.

[0601] Preferred aryl groups for R of ULM-g to ULM-i 2’ include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, and the phenyl or naphthyl groups are optionally bonded to PTM (including ULM' groups) via a linker group, and / or halo gens (preferably F or Cl), amines, monoalkylamines or dialkylamines (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3 , OMe, OCF3, NO2 or CN groups (each of which may be substituted at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position), optionally substituted phenyl groups (the phenyl group itself of which is optionally bonded to a PTM group containing a ULM' group via a linker group), optionally substituted with and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN groups (at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position) of at least one of which is optionally substituted, optionally substituted naphthyl groups, optionally substituted Optionally substituted heteroaryl, preferably methyl-substituted isoxazole Optionally substituted isoxazole, optionally substituted oxazole containing methyl-substituted oxazole Optionally substituted thiazole containing methyl-substituted thiazole, methyl-substituted i Optionally substituted isothiazole containing methyl-substituted isothiazole, optionally substituted pyrrole containing methyl-substituted pyrrole Optionally substituted pyrrole, optionally substituted imidazole containing methylimidazole, Optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted Oxime imidazole or methyloxime imidazole, optionally substituted diazolyl group containing a methyldiazolyl group Optionally substituted diazolyl group, optionally substituted triazolyl group containing a methyl-substituted triazolyl group Halogen-(preferably F) or a methyl-substituted pyridine group or o Optionally substituted pyridine group containing a xapyridine group (the pyridine group is bonded to the phenyl group by oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted Dihydrobenzofuran, optionally substituted indole, indolizine or aza i Indolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, any of the following chemical Is a group optionally substituted according to the structure. In the formula:

[0602]

Chemical formula

[0603] Wherein: S of ULM-g~ULM-i c Is CHR SS NR URE Or O; R of ULM-g~ULM-i HETis H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group -C≡C-R a wherein, in the formula, R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl) and is an acetylene group; For ULM-g to ULM-i, R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1 -C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); For ULM-g to ULM-i, R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), and each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted phenyl group , an optionally substituted heteroaryl group, or an optionally substituted heterocycle, such as piperidine , morpholine, pyrrolidine, tetrahydrofuran; For ULM-g to ULM-i, R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted An aryl (phenyl or naphthyl), heteroaryl or heterocyclic group, and these groups are selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, te trahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperi ne, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably substituted with F or Cl), benzofuran, ind ole, indolizine, azaindolizine; R of ULM-g to ULM-i PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and each n of 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 ne, piperidine, piperazine or morpholine (each of these groups, when substituted, is preferably substituted with methyl or halo (F, Br, Cl), and each of these groups can be optionally attached to a PTM group (including the ULM' group) via a linker group. In a specific preferred embodiment, ULM-g to ULM-i

[0604] is

[0605]

Chemical formula

[0606] is

[0607] [Chemistry]

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

[0609] ULM-g to ULM-i Of R 2’ Preferred heteroaryl groups for include optionally substituted quinoline (bonded to the pharmacophore or replaceable on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3- or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or groups according to the following chemical structures:

[0610]

[0611] [Chemistry]

[0611] wherein: the S of ULM-g to ULM-i c is CHR SS , NR URE or O; the R of ULM-g to ULM-i HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with 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 substituted with up to three halo groups), or optionally substituted acetylene group -C≡C-R a wherein, in the formula, R of ULM-g~ULM-i a is H or C1-C6 alkyl group (preferably C1-C3 alkyl) is an acetylene group; R of ULM-g~ULM-i SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1 -C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably one or two hydroxyl groups or substituted with up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R of ULM-g~ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or an optionally substituted heterocyclic ring, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene ring, piperidine, piperazine, etc., each of which is optionally substituted, and Y of ULM-g~ULM-i C is N or C-R YC wherein, in the formula, R YCis H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-R a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl), and each of the groups may optionally be attached via a linker group to a PTM group (including the ULM' group). .

[0612] Preferred heterocyclic groups for R of ULM-g to ULM-i include tetrahydrofuran, tet 2’ rahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morph oline, oxane or thiane, and each of the groups may optionally be substituted or may be a group according to the following chemical structure: wherein:

[0613] [Chemical formula]

[0614] wherein: R of ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl or heterocyclic group; R of ULM-g to ULM-i and R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group, and Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (in many cases, 0 or 1). Each of the groups can optionally be linked via a linker group to a PTM group (including the ULM' group). .

[0615] Preferred R substituents of ULM-g to ULM-i 2' include those found in the specific compounds disclosed herein (including the specific compounds disclosed in the present specification and the drawings attached hereto). R substituents (but not limited to the disclosed specific compounds) are also specifically mentioned. Each of these R substituents R 2' can be used in combination with any number of R substituents, which are also disclosed herein. 2' R of ULM-g to ULM-i is preferably optionally substituted -T-aryl, optionally substituted - 3’ T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR -T-aryl, optionally substituted -NR

[0616] R of ULM-g to ULM-i 3’ is preferably optionally substituted -T-aryl, optionally substituted - T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle, where 1 R is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted -(CH2) - group, in which each of the methylene groups is preferably selected from halogen, a C1-C 1 3 alkyl group, or the side chain of an amino acid otherwise described herein, and is preferably optionally substituted with one or two substituents, preferably optionally substituted methyl. - n - group, and each of the methylene groups is preferably selected from halogen, a C1-C 3 alkyl group, or the side chain of an amino acid otherwise described herein, and is preferably optionally substituted with one or two substituents, preferably optionally substituted methyl. One or two substituents, preferably optionally substituted methyl, and may be optionally substituted. ; and n is from 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Some Alternatively, T is -(CH2O) n - group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - group may be such that each of these groups is optionally substituted.

[0617] ULM-g to ULM-i Of R 3’ Preferred aryl groups for are optionally substituted phenyl group or naphthyl group, preferably a phenyl group, and in this case the phenyl group or naphthyl group is a linker group and / or optionally substituted halogen (preferably F or Cl), amine, monoalkylamine or dialkylamine (preferably dimethylamine), amide group (preferably Is -(CH2) m -NR1C(O)R2, wherein m, R1 and also 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, optionally substituted aryl, hetero aryl or heterocyclic group, or (CH2) m NR1R2 group), and each of them may be substituted at the ortho, meta, and / or para positions (preferably para position) of the phenyl ring, or may be optionally bonded to the PTM group (including the ULM' group) via aryl (preferably phenyl), heteroaryl, or heterocycle. The preferred phenyl group of the above substituents is optionally substituted phenyl group (i.e., the phenyl group of the substituent itself is preferably F, Cl, O substituted phenyl group (that is, the phenyl group of the substituent itself is preferably F, Cl, O substituted phenyl group (i.e., the phenyl group of the substituent itself is preferably F, Cl, O at least one of H, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or a linker group substituted, and these groups are attached to a PTM group (including the ULM’ group), in which case the substitution occurs at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), above optionally substituted naphthyl group, optionally substituted heteroaryl (preferably optionally substituted isoxazole including methyl-substituted isoxazole, methyl-substituted optionally substituted oxazole including methyl-substituted oxazole, methyl-substituted thiazole optionally substituted thiazole including methyl-substituted thiazole, optionally substituted pyrrole including methyl-substituted pyrrole, methylimidazole, benzylimidazole or methoxybenzylimidazole optionally substituted imidazole including oxoimidazole or methyloxoimidazole, methyl-substituted diazole group including methyl-diazole group, optionally substituted triazole group including methyl-substituted triazole group, halo (preferably F) or a pyridine group including a methyl-substituted pyridine group or an oxapyridine group (the pyridine group is bonded to a phenyl group by oxygen ), or an optionally substituted heterocycle (tetrahydrof ran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, te trahydroquinoline, oxane, or thiane). Each group of aryl, heteroaryl or heterocycle can be optionally attached to a PTM group (including the ULM’ group) by a linker group.

[0618] For the R of ULM-g~ULM-i 3’ Preferred heteroaryl groups are optionally substituted qui noline (bonded to the pharmacophore or substituted on any carbon atom within the quinoline ring obtained), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine) , optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxa zole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thio phene, optionally substituted thiazole (preferably methyl-substituted and / or thiol-sub stituted), optionally substituted isothiazole, optionally substituted triazole (preferably with a methyl group, a triisopropylsilyl group, optionally substituted (CH2) m -O-C1-C6 alkyl group , or optionally substituted (CH2) m -C(O)-O-C1-C6 alkyl group-substituted 1,2,3-triazole -ol), optionally substituted pyridine (2, 3, or 4-pyridine), or a group represented by the following chemical structure :

[0619]

Chemical formula

[0620] wherein: S of ULM-g to ULM-i c is CHR SS , NR URE or O; R of ULM-g to ULM-i HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably with one or two hydroxyl groups or up to three halogens a group substituted with a RO group (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-R a wherein, in the formula, R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl) and is an acetylene group; For R of ULM-g to ULM-i SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1 -C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); For R of ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), and each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably a fluorine group, or an optionally substituted heterocyclic ring, e.g., piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene piperidine, piperazine, etc., each of which is optionally substituted, and For Y of ULM-g to ULM-i C is N or C-R YC wherein, in the formula, R YC is H, OH, CN, NO2, halo (preferably or Cl or F), optionally substituted C1-C6 alkyl (preferably one or two hydroxy groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably one or two hydroxy groups or up to three halo groups), or optionally substituted acetylene group -C≡C-R wherein, R is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl). Each of the heteroaryl groups may optionally be attached via a linker group to a PTM group (including the ULM' group). Preferred heterocyclic groups for R a include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane or thiane, each group may optionally be substituted or may be a group according to the following chemical structure: wherein: a R for ULM-g to ULM-i is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole .

[0621] ULM-g to ULM-i Of R 3’ For R The preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane or thiane, each group may optionally be substituted or may be a group according to the following chemical structure: wherein each group may optionally be substituted or may be a group according to the following chemical structure: wherein:

[0622]

Chemical formula

[0623] wherein: R PRO for ULM-g to ULM-i is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group, and these groups are oxazole, isoxazole, thiazole, isothiazole, imidazole or these Of groups are oxazole, isoxazole, thiazole, isothiazole, imidazole , Diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, te Tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperi ne, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably substituted with F or Cl), benzofuran, ind ole, indolizine, azaindolizine, selected from the group consisting of; R of ULM-g to ULM-i PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group, and each n of 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 can be optionally bonded to a PTM group (including the ULM' group) via a linker group.

[0624] Preferred R substituents of ULM-g to ULM-i 3' include those found in the specific compounds disclosed herein (including the specific compounds disclosed in the present specification and the accompanying drawings of the present specification). R substituents (but not limited to the specific compounds disclosed) are also specifically mentioned. Each of these R substituents may be used in combination with any number of R 3' substituents, and those are also disclosed in the present specification. 3’ In another specific preferred embodiment, R of ULM-g to ULM-i 2’ is an optionally substituted -NR1-X -alkyl group, -NR1-X

[0625] -aryl group; an optionally substituted -NR1-X 2’ is, an optionally substituted -NR1-X R2 ’ -alkyl group, -NR1-X R2’ -aryl group; an optionally substituted -NR1-X​R2’ -HET, optionally substituted -NR1-X R2’ -aryl-HET, or optionally substituted -NR1-X R2’ -HET-aryl and wherein: R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H); X of ULM-g to ULM-i R2’ is optionally substituted - ( CH2) n -, - ( CH2) n -CH(X v )=CH(X v )(cis or trans), -(CH2) n -CH≡CH-, -(CH2CH2O) n -, or a C3-C6 cycloalkyl group; and X of ULM-g to ULM-i v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; The alkyl of ULM-g to ULM-i is an optionally substituted C1-C 10 alkyl (preferably C1-C6 alkyl yl) group (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); The aryl of ULM-g to ULM-i is an optionally substituted phenyl group or naphthyl group (preferably a phenyl group); and The HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxymiidazole, pyrrole, pyrrolidine ene, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothio Drotiem, pyridine, piperidine, piperazine, morpholine, benzofuran, indole le, indolizine, azaindolizine, quinoline (when substituted, each is preferably a C1-C 3 alkyl group, preferably methyl, or a halo group, preferably F or Cl substituted) , or a group having the following structure:

[0626]

Chemical formula

[0627] S of ULM-g to ULM-i c is CHR SS , NR URE or O; R of ULM-g to ULM-i HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with 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 substituted), or optionally substituted acetylene group -C≡C-R a wherein R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R of ULM-g to ULM-i SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1 -C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three halo groups substituted), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three substituted with halo groups); For R of ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C1-C6 alkyl), and each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or is optionally substituted with a heterocyclic ring, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene piperidine, piperazine, etc., each of which is optionally substituted; For Y of ULM-g to ULM-i C is N or C-R YC wherein R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-R wherein a R is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl) a ; ; For R of ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group, and these Of groups are oxazole, isoxazole, thiazole, isothiazole, imidazole , diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperi dine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably is a methyl group, or a halo group, preferably substituted with F or Cl), benzofuran, ind ole, indolizine, azaindolizine, and is selected from the group consisting of; R of ULM-g to ULM-i PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group, and each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1) .

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

[0629] In another specific preferred embodiment of the present disclosure, R of ULM-g to ULM-i 3’ is an optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -R S3’ group, an optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V ) n’ -R S3’ group, an optionally substituted -X R3’ -alkyl group, an optionally substituted -X R3’ -aryl group; an optionally substituted -X R3’ -HET group, an optionally substituted -X R3’ -aryl-HET group, or -X, optionally substituted R3’ -a -HET-aryl group, wherein: R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), an optionally sub stituted 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’ ; 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 a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; alkyl is an optionally substituted C1-C 10 alkyl (preferably C1-C6 alkyl) group ( in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br ); aryl is an optionally substituted phenyl group or naphthyl group (preferably a phenyl group); and HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oxymiidazole, pyrrole, pyrrolidine, furan, di hydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pi Lysine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group having the following structure: , quinoline (when substituted, each preferably a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group having the following structure: , quinoline (when substituted, each preferably a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group having the following structure: is a group according to the following structure:

[0630]

Chemical formula

[0631] S of ULM-g to ULM-i c is CHR SS , NR URE or O; R of ULM-g to ULM-i HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted acetylene group -C≡C-R wherein R a is an acetylene group which is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl); R of ULM-g to ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1 SS -C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C groups), or optionally substituted -C (O)(C1-C6 alkyl) (preferably one or two hydroxyl groups or up to three halo groups substituted); For R in ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or - C(O)(C0-C6 alkyl), and each group is optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocyclic ring, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene piperidine, piperazine, etc., each of which is optionally substituted; For Y in ULM-g to ULM-i C is N or C-R YC wherein R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-R wherein a R is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl) a ; ; For R in ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group, and these Of groups are oxazole, isoxazole, thiazole, isothiazole, imidazole , diazole, oxyimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperi dine, piperazine, morpholine, quinoline (each preferably a C1-C3 alkyl group, preferably is a methyl group, or a halo group, preferably substituted with F or Cl), benzofuran, ind ole, indolizine, azaindolizine, selected from the group consisting of; R of ULM-g to ULM-i PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1) ; Each m' of ULM-g to ULM-i is 0 or 1; and Each n' of ULM-g to ULM-i is 0 or 1; wherein, preferably, each of said compounds of an alkyl group, an aryl group or a Het group is optionally , bonded to a PTM group (including the ULM' group) via a linker group.

[0632] In another embodiment, R 3 ' of ULM-g to ULM-i is -(CH2) n -aryl, -(CH2CH2O) n -aryl , -(CH2) n -HET or -(CH2CH2O) n -HET, wherein: Said aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents , and in this case the substituents are preferably -(CH2) n OH, itself being CN, halo (most Large and three halo groups), OH, -(CH2) n O(C1-C6) alkyl, amine, mono- or di-(C1-C6 al kyl)amine and is further optionally substituted with a C1-C6 alkyl selected therefrom, in which case the alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (pre ferably F, Cl) groups, or the aryl group of ULM-g~ULM-i is -(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) alky l, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) substituted therewith, in which case the alkyl group of the amine is 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 group and is optionally substituted, wherein V is O, S or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), and thus R PEG is H or an optionally substituted C1-C6 alkyl group (including those optionally substituted with a carboxyl group) or or The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothia azole, imidazole, diazole, oxyimidazole, pyrrole, pyrrolidine, f uran, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothi ene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, ind ole, indolizine, azaindolizine (when substituted, each is preferably a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or an optionally substituted heterocycle containing a heteroaryl selected from the group consisting of groups having the following structures:

[0633]

Chemical formula

[0634] S of ULM-g to ULM-i c is CHR SS , NR URE or O; R of ULM-g to ULM-i HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., C...

Claims

1. Structure: 【Chemical 1】 A pharmaceutical composition comprising an effective amount of a compound having the following structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated as a tablet, Pharmaceutical composition.

2. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, [Chemical Formula 2] 、 The pharmaceutical composition according to claim 1.

3. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 1. [Chemical Formula 3] 、

4. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 1.

5. The compound having the structure: [[STRUCTURE]] 【Chemical Formula 4】 、 The pharmaceutical composition according to claim 1.

6. The compound having the structure: [[STRUCTURE]] The pharmaceutical composition according to claim 1. [Chemical Formula 5]

7. The compound having the structure: [[STRUCTURE]] The pharmaceutical composition according to claim 1.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is administered to a patient at a dose of about 25 to about 250 mg. 【Chemical Formula 6】

9. The pharmaceutical composition according to any one of claims 1 to 8, for treating a disease or disorder (excluding breast cancer) associated with the accumulation and aggregation of estrogen receptors in a subject.

10. For treating a disease or disorder (excluding breast cancer) associated with the accumulation and aggregation of estrogen receptors in a subject, A pharmaceutical composition comprising an effective amount of a compound having the following structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof. 【Chemical Formula 7】

11. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 10.

12. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 10.

13. The compound having the structure: [[STRUCTURE]] or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 10. 【Chemical 8】

14. The compound having the structure: [[STRUCTURE]] The pharmaceutical composition according to claim 10. 【Chemical Formula 9】 、

15. The compound having the structure: [[STRUCTURE]] The pharmaceutical composition according to claim 10.

16. The compound having the structure: [[STRUCTURE]] 【Chemical Formula 10】 、 The pharmaceutical composition according to claim 10.

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

18. The pharmaceutical composition according to claim 17, wherein the disease or disorder is uterine cancer. 【Chemical 11】 、 ​ ​ ​ 【Chemical Formula 12】 ​ ​ ​ 【Chemical Formula 13】 ​ ​ ​ 【Chemical 14】 ​ ​ ​ ​ The pharmaceutical composition according to claim 17, wherein the disease or disorder is endometriosis. The pharmaceutical composition according to any one of claims 9 to 19, wherein the subject is further administered an additional anti-cancer agent in an effective amount.

21. The pharmaceutical composition according to claim 20, wherein the additional anticancer agent is estramustine, docetaxel, ketoconazole, goserelin acetate, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zolendronate, everolimus, pazopanib, carboplatin, cisplatin, oxaliplatin, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, raloxifene, paclitaxel, abraxane, or trastuzumab. **Claim 22**: The pharmaceutical composition according to claim 20, wherein the additional anti-cancer agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 inhibitor, a Bcl-2 inhibitor, an HDAC inhibitor, a c-Met inhibitor, a PARP inhibitor, a Cdk inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1 / 2 inhibitor, a JAK / STAT inhibitor, a checkpoint 1 inhibitor, a checkpoint 2 inhibitor, a focal adhesion kinase inhibitor, a map kinase inhibitor, or a VEGF trap antibody. **Claim 23**: The pharmaceutical composition according to any one of claims 20 to 22, wherein the compound and the additional anti-cancer agent are administered to the subject at different times. **Claim 24**: The pharmaceutical composition according to any one of claims 20 to 22, wherein the additional anti-cancer agent is formulated as a tablet. **Claim 25**: The pharmaceutical composition according to any one of claims 20 to 22, wherein the compound and the additional anti-cancer agent are formulated as separate tablets and administered to the subject simultaneously or at different times.

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