RU2797808C2 - Estrogen receptor proteolysis modulators and related uses thereof - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to bifunctional compounds of the general formula CLM-L-PTM having the properties of estrogen receptor inhibitors and their use in the treatment of estrogen receptor-associated breast cancer. In the general formula CLM-L-PTM, PTM is PTM-I or PTM-II, CLM is the chemical structure of (a) or (e), L is a chemical linker moiety comprising a chemical structural unit represented by the formula -(A^L)_q- where (A^L)_q is a group that is connected to CLM and PTM; X_PTM is O; each of X_PTM1 and X_PTM2 is independently N or CH; R_PTM1 is OH or OC_1-3 alkyl; R_PTM2 and R_PTM4 are independently selected from H, OH, halogen, CF₃ and OC_1-3 alkyl; R_PTM3 and R_PTM5 are H; W is CH₂ or C=O; each X is O; Z is O; G is H; Q₁, Q₂, Q₃ and Q₄ are N or CH; A is H or linear and branched C_1-6 alkyl; where n is 1, R is -OR', -NR'R" or -CR'R"-, wherein R is covalently bonded to the chemical linker moiety; R' and R” are independently selected from bond, H, C_1-6 alkyl; is a bond that may or may not provide a stereospecific configuration; q is an integer from 3 to 15; each A^L is independently selected from a bond, CR^L1 R^L2, O, NR^L3, CONR^L3, CO and C_3-8 heterocyclyl; and R^L1, R^L2 and R^L3 are each independently H, halogen and C_1-8 alkyl, each heterocyclyl having one or two heteroatoms, each heteroatom independently selected from nitrogen.

EFFECT: obtaining estrogen receptor proteolysis modulators.

8 cl, 2 dwg, 5 tbl, 245 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/450,740, filed January 26, 2017, and U.S. Provisional Patent Application No. 62/587,378, filed November 16, 2017, both of which are incorporated herein. document in its entirety.

INCLUSION BY REFERENCE

[0002] US Patent Application Serial No. 15/230354, filed August 5, 2016; and US Patent Application 15/206497, filed July 11, 2016; and US Patent Application 15/209648, filed July 13, 2016; and US Patent Application Serial No. 15/730728, filed October 11, 2017; and US Patent Application Serial No. 14/686640, filed April 14, 2015, published as US Patent Application Publication No. 2015/0291562; and US Patent Application Serial No. 14/792414, filed July 6, 2015, published as US Patent Application Publication No. 2016/0058872; and US Patent Application Serial No. 14/371956, filed July 11, 2014, published as US Patent Application Publication No. 2014/0356322; and US Patent Application Serial No. 15/074820, filed March 18, 2016, published as US Patent Application Publication No. 2016/0272639; and US Patent Application Serial No. 62/452972, filed January 31, 2017; and US Patent Application Serial No. 15/706064, filed September 15, 2017, entitled “INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADES,” filed January 31, 2017; and International Patent Application No. PCT/US2016/023258, filed March 18, 2016, published as International Patent Application Publication No. WO 2016/149668, all of which are incorporated herein by reference in their entirety. In addition, all sources referenced herein are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0003] Disclosed are bifunctional compounds containing a target protein binding moiety and an E3 ubiquitin ligase binding moiety, as well as associated uses. Bifunctional compounds are useful as targeted ubiquitination modulators, particularly at the estrogen receptor (ER), which the bifunctional compounds of the present invention disrupt and/or otherwise inhibit, and in the treatment of ER-mediated diseases and conditions, for example in the treatment of breast cancer .

BACKGROUND OF THE ART

[0004] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved in the upregulation and downregulation of gene expression. The natural hormone for the estrogen receptor is 17-beta-estradiol (E2) and related metabolites. Binding of estradiol to the estrogen receptor causes dimerization of the receptor, and the dimer in turn binds to estrogen response elements (EREs) on DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing DNA downstream of the ERE into mRNA, which is eventually translated into protein. Alternatively, the interaction of the ER with DNA may be mediated through the mediation of other transcription factors, in particular fos and jun. Because the expression of a large number of genes is regulated by the estrogen receptor, and because the estrogen receptor is expressed in multiple cell types, modulation of the estrogen receptor through binding to either natural hormones or synthetic ER ligands can have significant effects on the physiology and pathophysiology of the organism.

[0005] For a number of diseases, their etiology and/or pathology is mediated by ER. Collectively, these diseases are called estrogen-dependent diseases. Estrogens are critical for female sexual development. In addition, estrogens have important functions in maintaining bone density, regulating blood lipid levels, and appear to have neuroprotective effects. Consequently, decreased estrogen production in postmenopausal women is associated with a number of diseases such as osteoporosis, atherosclerosis, depression and cognitive impairment. In turn, certain types of proliferative diseases, such as breast and uterine cancer and endometriosis, are induced by estrogens and, therefore, antiestrogens (ie estrogen antagonists) have utility in the prevention and treatment of these types of disorders.

[0006] There are two different forms of the estrogen receptor, commonly called calamus, each of which is encoded by a separate gene (ESR1 and ESR2, respectively). Both ERs are widely expressed in different tissue types, but there are some significant differences in their expression patterns. ERα is found in the endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In men, the ERα protein is found in the epithelium of the efferent ducts. ERβ protein expression has been confirmed in kidney, brain, bone, heart, lung, intestinal mucosa, prostate and endothelial cells. Therefore, the development of selective ligands may thus ensure that the beneficial aspects of estrogen are retained.

[0007] Breast cancer is the most common malignancy affecting women, and the incidence of the disease is increasing worldwide. In particular, estrogens act as endocrine growth factors for at least one third of breast cancers, and tumor deprivation of this stimulus is an established therapy for advanced disease in premenopausal women, achieved by stopping ovarian function through surgery, radiation therapy or by medical means, and in women after menopause - by using aromatase inhibitors.

[0008] An alternative approach to estrogen withdrawal is to antagonize estrogen using antiestrogens. They are drugs that bind to and compete for estrogen receptors (ERs) present in estrogen-sensitive tissue. Traditional nonsteroidal antiestrogens, such as tamoxifen, effectively compete for ER binding, but their effectiveness is often limited by the partial agonism they exhibit, resulting in incomplete blocking of estrogen-mediated activity. A specific or “pure” antiestrogen with high affinity for the ER and without any agonistic effect may offer advantages in the treatment of estrogen-dependent disease compared with traditional non-steroidal antiestrogens. Fulvestrant is the first of a new class of effective pure antiestrogens and is characterized by complete absence of the partial agonist, estrogen-like activity associated with currently available antiestrogens such as tamoxifen.

[0009] Therefore, there is a need for other approaches to antagonize the ER receptor. One approach would be to develop selective ER suppressors or disruptors that reduce the level of ER expression at either the transcriptional or protein level.

[0010] Several methods are available to manipulate protein levels, including proteolytic targeting chimeric molecules (PROTACs) containing a ligand that recognizes a target protein bound to a ligand that binds to a specific E3 ubiquitin ligase. It would be desirable to provide a small molecule that can simultaneously bind to the ER and E3 ubiquitin ligase and that promotes ER ubiquitination and leads to ER degradation by the proteasome.

[0011] Most small molecule drugs bind enzymes or receptors in dense and well-defined pockets. On the other hand, targeting protein-protein interactions using small molecules is notoriously difficult due to their large contact surface and the involvement of fine grooves or flat contact surfaces. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination and are therefore more attractive therapeutic targets than conventional proteasome inhibitors due to their specificity for certain protein substrates. Designing ligands for E3 ligases has proven difficult, partly due to the fact that they must disrupt protein-protein interactions. However, recent developments have made it possible to obtain specific ligands that bind to such ligases. For example, since the discovery of nutlins, the first small molecule E3 ligase inhibitors, additional compounds that target E3 ligases have been reported, but the field remains underdeveloped. For example, since the discovery of nutlins, the first small molecule inhibitors of the mouse double minute (MDM2) E3 ligase homologue 2 (MDM2), additional compounds have been reported that target MDM2 (i.e., human double minute 2 or HDM2) E3 ligases (J Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0012] The p53 tumor suppressor gene has an important function in cell growth arrest and apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982) , and inactivation of p53 has been proposed as one of the major pathways for tumor cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310). Approximately 50% of patients who have cancer have a p53 mutation (M. Hollstein, et al. Science (1991), 233, 49-53), while patients with wild-type p53 often have p53 suppression by MDM2 through protein-protein interaction of p53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). Under normal cellular conditions without an oncogenic stress signal, MDM2 maintains p53 at low concentrations. In response to DNA damage or cellular stress, p53 levels increase, and this also causes an increase in MDM2 levels due to negative feedback from the p53/MDM2 autoregulatory system. In other words, p53 regulates MDM2 at the level of transcription, and MDM2 regulates p53 at the level of its activity (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

[0013] Several mechanisms may explain the suppression of p53 by MDM2. MDM2 first binds to the N-terminal domain of p53 and blocks the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). MDM2 then translocates p53 from the nucleus to the cytoplasm to promote proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 carries out its own E3 ligase activity, which involves conjugating ubiquitin to p53 for its destruction via the ubiquitin proteasome system 26s (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). In this regard, since MDM2 functions as an E3 ligase, recruiting MDM2 to a disease-causing protein and causing its ubiquitination and degradation is a very interesting approach for drug development.

[0014] One E3 ligase with promising therapeutic potential is the VHL tumor suppressor, the substrate recognition subunit of the VCB E3 ligase complex, which also consists of elongins B and C, Cul2 and Rbx1. The major substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that increases gene expression such as the proangiogenic growth factor VEGF, and the cytokine erythropoietin, which induces red blood cell production in response to low oxygen levels. The first small molecule Hippel-Lindau (VHL) protein ligands binding to the substrate recognition subunit of E3 ligase were prepared and crystal structures were obtained indicating that the compound mimics the binding mechanism of the transcription factor HIF-1α, the major substrate of VHL.

[0015] Cereblon is a protein that is encoded by the CRBN gene in humans. CRBN orthologues are highly conserved among organisms ranging from plants to humans, highlighting its physiological importance. Cereblon is part of an E3 ubiquitin ligase complex with DNA damage binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex carries out the ubiquitination of a number of other proteins. Through a mechanism that is not yet fully understood, ubiquitination of target proteins by cereblon leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as the formation of limbs and the otic vesicle. The net result is that this ubiquitin ligase complex is essential for limb growth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA-binding protein.

[0016] Thalidomide, which has been approved for the treatment of a number of immunological indications, has also been approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogues are also currently being investigated for use in the treatment of various other types of cancer. Although the specific mechanism of thalidomide's antitumor activity has not yet been elucidated, it is known to inhibit angiogenesis. New literature that addresses the biology of imides includes Lu et al. Science 343, 305 (2014) and et al. Science 343, 301 (2014).

[0017] It should be noted that thalidomide and its analogues, such as pomolynamide and lenalinomide, are known to bind cereblon. Such agents bind to cereblon, altering the specificity of the complex, which induces the ubiquitination and destruction of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors required for the growth of multiple myeloma. Indeed, higher cereblon expression has been associated with increased efficacy of imide-based drugs in the treatment of multiple myeloma.

[0018] Inhibitors of apoptosis proteins (IAPs) are a family of proteins involved in the suppression of apoptosis, i.e. cell death. The human IAP family includes 8 members, and numerous other organisms contain IAP homologues. IAPs contain an E3 ligase-specific domain and baculovirus IAP repeat (BIR) domains that recognize substrates and promote their ubiquitination. IAPs promote ubiquitination and can directly bind and inhibit caspases. Caspases are proteases (eg, caspase-3, caspase-7 and caspase-9) that mediate apoptosis. In this regard, through the binding of caspases, IAPs prevent cell death. However, a proapoptotic stimulus can lead to the release of the mitochondrial proteins DIABLO (also known as second mitochondrial activator of caspases or SMAC) and HTRA2 (also known as Omi). Binding of DIABLO and HTRA2 appears to block IAP activity.

[0019] SMAC interacts with essentially all known IAPs, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Brace, and survivin. The first four amino acids (AVPI) of mature SMAC bind to the IAP moiety, which is believed to be key for blocking the antiapoptotic effects of IAP.

[0020] Bifunctional compounds, such as those described in US Patent Application Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference), act to recruit endogenous proteins to E3 ubiquitin ligase for degradation. In particular, publications describe bifunctional or chimeric proteolytic targeting compounds (PROTACs) that find use as modulators of targeted ubiquitination of a variety of polypeptides and other proteins (such as the estrogen receptor), which are then degraded and/or otherwise inhibited by using bifunctional compounds.

[0021] There is still a need in the art for effective treatments for disease associated with ER overexpression or aggregation. However, nonspecific effects and the inability to both target and modulate the ER remain obstacles to the development of effective treatments. In this regard, small molecule therapeutics that target the ER and that improve or enhance the substrate specificity of cereblon, MDM2, and IAP will be extremely useful.

SHORT DESCRIPTION

[0022] The present invention describes bifunctional compounds whose function is to recruit endogenous proteins to E3 ubiquitin ligase for destruction, and methods for their use. In particular, the present invention provides bifunctional or chimeric proteolytic targeting compounds (PROTACs) that find use as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, such as the estrogen receptor, which are then degraded and/or otherwise inhibited by using the bifunctional compounds described herein. The advantage of the compounds presented herein is that a wide range of pharmacological activities are possible, consistent with the destruction/inhibition of target polypeptides from virtually any class or family of proteins. Also provided herein are methods of using an effective amount of the compounds described herein to treat or alleviate a disease condition such as cancer, such as breast cancer.

[0023] In this regard, in one aspect of the present invention there are provided bifunctional compounds or PROTAC compounds that contain an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase ligand or "ULM" group) and a moiety that binds a target protein (ie, a protein/polypeptide targeting ligand, or "PTM" group) such that the target protein/polypeptide is placed in close proximity to a ubiquitin ligase to effect degradation (and inhibition) of the protein. In a preferred embodiment, the ULM (ubiquitin ligase modulator) may be a Hippel-Lindau (VHL) binding fragment of the E3 ubiquitin ligase complex (VLM), or a cereblon binding fragment of the E3 ubiquitin ligase complex (CLM), or an E3 binding fragment -ubiquitin ligase, which is the mouse double minute homolog 2 (MDM2) (MLM), or the IAP-binding fragment of the E3 ubiquitin ligase complex (i.e., “ILM”). For example, the structure of a bifunctional compound can be depicted as:

[0024] The corresponding positions of the PTM and ULM fragments (eg, VLM, CLM, MLM or ILM), as well as their number, as illustrated herein, are presented by way of example only and are not intended to limit the connections in any way. One skilled in the art will appreciate that the bifunctional compounds described herein can be synthesized such that the number and position of the corresponding functional moieties can be varied as needed.

[0025] In certain embodiments, the bifunctional compound further comprises a chemical linker (“L”). In this example, the structure of a bifunctional compound can be depicted as:

wherein PTM is a protein/polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group linking PTM to ULM, and ULM is an IAP E3 ubiquitin ligase complex binding moiety or Hippel protein-binding moiety. Lindau (VHL) of the E3 ubiquitin ligase complex (VLM), or the cereblon binding fragment of the E3 ubiquitin ligase complex (CLM), or the E3 ubiquitin ligase homolog mouse double minute homologue 2 (MDM2) binding fragment (MLM).

[0026] For example, the structure of a bifunctional compound can be depicted as:

where PTM is a fragment targeting a protein/polypeptide; "L" represents a linker (eg, a bond or chemical linker group) linking PTM and at least one of VLM, CLM, MLM, ILM, or a combination thereof; VLM is a Hippel-Lindau protein-binding fragment of the E3 ubiquitin ligase complex that binds to the VHL E3 ligase complex; CLM is the cereblon-binding fragment of the E3 ubiquitin ligase complex that binds to cereblon; MLM is a fragment that binds the E3 ubiquitin ligase MDM2; and ILM is an IAP binding fragment that binds to the IAP.

[0027] In some preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. Accordingly, in certain additional embodiments, the ILM of the bifunctional compound comprises the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or non-natural mimetics thereof, respectively. In additional embodiments, the amino acids in the AVPI tetrapeptide fragment are linked to each other via amide bonds (ie, -C(O)NH- or -NHC(O)-).

[0028] In certain embodiments, the compounds described herein contain multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0029] In certain embodiments, the ILM contains chemical moieties, such as the moieties described herein.

[0030] In additional embodiments, the VLM may be hydroxyproline or a derivative thereof. In addition, other subject VLMs are included in US Patent Application Publication No. 2014/03022523, which, as noted above, is incorporated herein in its entirety.

[0031] In one embodiment, the CLM contains a chemical group derived from an imide, thioimide, amide, or thioamide. In a specific embodiment, the chemical group is a phthalimide group or an analogue or derivative thereof. In a certain embodiment, CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof. Other contemplated CLMs are described in US Patent Application Publication No. 2015/0291562, which is incorporated herein in its entirety.

[0032] In certain embodiments, the MLM may be nutlin or a derivative thereof. In addition, other subject MLMs are included in US Patent Application No. 15/206497, filed July 11, 2016, which, as noted above, is incorporated herein in its entirety. In certain additional embodiments, the MLM of the bifunctional compound contains chemical moieties such as substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, and substituted Pure isoquinolinones.

[0033] In additional embodiments, MLM provides the basic structures noted above with adjacent bis-aryl substitutions arranged in cis or trans configurations.

[0034] In certain embodiments, "L" represents a link. In further embodiments, the linker "L" is a linker molecule with a linear structure with a number of non-hydrogen atoms ranging from 1 to 20. The linker molecule "L" may contain, but is not limited to, functional groups such as ester, amide, alkane, alkene, alkyne group, keto group, hydroxyl group, carboxylic acid group, thioester, sulfoxide and sulfonic groups. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclic moieties. Halogen substitution such as Cl, F, Br and I may be included in the linker. In the case of fluorine substitution, one or more fluorine atoms may be included.

[0035] In certain embodiments, VLM is a trans-3-hydroxyproline derivative wherein both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides.

[0036] In certain embodiments, CLM is a piperidine-2,6-dione derivative, wherein the piperidine-2,6-dione may be substituted at the 3-position, and wherein the 3-substitution may involve substitution with bicyclic heteroaromatic compounds with a compound at form of a C-N bond or a C-C bond. Examples of CLMs include, but are not limited to, pomalidomide, lenalidomide and thalidomide and derivatives thereof.

[0037] In a further aspect, the disclosure provides therapeutic compositions containing an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation and/or inhibition in a patient or subject, for example, an animal such as a human, and can be used to treat or alleviate disease states or conditions that are modulated by protein degradation/inhibition. In certain embodiments, the therapeutic compositions described herein can be used to promote the destruction of proteins of interest to treat or alleviate a disease, such as cancer. In yet another aspect, the present invention provides a method for causing ubiquitination/degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising ILM and PTM, PTM and VLM, or PTM and CLM, or PTM and MLM, preferably linked by a linker moiety described later herein, wherein VLM/ILM /CLM/MLM are linked to the PTM through a linker to target a protein that binds to the PTM for destruction. Likewise, a PTM can be linked to a VLM, or a CLM, or an MLM, or an ILM via a linker to target a protein or polypeptide for destruction. Target protein degradation will occur by placing the target protein in close proximity to the E3 ubiquitin ligase, thereby resulting in target protein destruction/inhibition of its effects and control of protein levels. The control of protein levels provided by the present invention provides treatment for a disease state or condition modulated by a target protein by reducing the level of that protein in the patient's cells.

[0038] In yet another aspect, the disclosure provides methods of treating or alleviating a disease, disorder, or symptom thereof in a subject or patient, such as an animal such as a human, comprising administering to the subject in need thereof a composition containing an effective amount, such as a therapeutic amount an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or alleviating a disease or disorder or a symptom thereof in a subject.

[0039] In another aspect, the specification provides methods for identifying the effects of disruption of proteins of interest in a biological system using compounds of the present invention.

[0040] The foregoing general applications are given by way of example only and are not intended to limit the scope of the present invention and the appended claims. Additional objects and advantages associated with the compositions, methods and processes of the present invention will be apparent to one skilled in the art in light of the claims, descriptions and examples. For example, various aspects and embodiments of the present invention can be used in numerous combinations, all of which are expressly contemplated herein. Such additional aspects and embodiments are expressly included within the scope of the present invention. Publications and other materials used herein to highlight the prior art of the present invention and, in specific cases, to provide additional details regarding its implementation, are incorporated by reference.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0041] The accompanying drawings, which are included in and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the teachings of the present invention. The graphics are intended to illustrate an embodiment of the present invention only and should not be construed as limiting the present invention. Additional objects, features and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing illustrative embodiments of the present invention in which:

[0042] Figures 1A and 1B. Illustration of the basic operating principle of PROTAC. (Figure 1A) Exemplary PROTACs contain a protein targeting moiety (PTM; dark shaded box), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that binds or attaches the PTM to ULM. (Fig. 1B) Illustrates the functional application of the PROTACs described herein. Briefly, ULM recognizes and binds to a specific E3 ubiquitin ligase, and PTM binds and recruits the target protein, bringing it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase forms a complex with an E2 ubiquitin-conjugating protein and, either alone or with the help of the E2 protein, catalyzes the addition of ubiquitin (dark circles) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for destruction by the cell's proteasomal machinery.

[0043] Figure 2A. ERα disruption by compound 11 in MCF7 cells after 24 h incubation: column 1, DMSO control; column 2, 3 µM pomalidomide; column 3, 30 nM compound 11 plus 3 µM pomalidomide; column 4, 30 nM compound 11; column 5, 300 nM compound 11; column 6, 30 nM compound 11; and column 7, 3 nM compound 11.

[0044] Figure 2B. Disruption of ERα by fulvestrant, compound 140, compound 152, AZD9496, RAD1901 and GDC810 in T47D cells after incubation for 24 hours. The concentration values for all compounds are 6, 25 and 100 nM.

DETAILED DESCRIPTION

[0045] The following detailed description is presented to assist one skilled in the art with respect to the practice of the present invention. Modifications and changes to the embodiments described herein may be made by those skilled in the art without departing from the spirit or scope of the present invention. All publications, patent applications, patents, figures and other sources mentioned herein are expressly incorporated by reference in their entirety.

[0046] The present invention describes compositions and methods that relate to the surprising and unexpected discovery that E3 ubiquitin ligase complex protein (e.g., inhibitors of apoptosis proteins (IAPs), Hippel-Lindau protein (VHL) E3 ubiquitin ligase complex, Cereblon E3 -ubiquitin ligase complex or E3 ubiquitin ligase, which is a mouse double minute homolog 2 (MDM2) ubiquitinates the target protein as soon as it and the target protein are placed in close proximity to each other by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase complex protein and the target protein Accordingly, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") linked to a target protein binding moiety ("PTM"), thereby allowing ubiquitination of the selected target protein (such as the estrogen receptor [ER]) to ensure the destruction of the target protein by the proteasome (see Figures 1A and 1B). The present invention also provides a composition library and its use.

[0047] In certain aspects, the present invention provides compounds that contain a ligand, for example, a low molecular weight ligand (i.e., having a molecular weight of less than 2000, 1000, 500, or 200 daltons) that is capable of binding to a ubiquitin ligase such as IAP , VHL, MDM2 or Cereblon. The compounds also contain a moiety that is capable of binding to a target protein such that the target protein is placed in close proximity to the ubiquitin ligase to cause degradation (and/or inhibition) of the protein. Low molecular weight may mean, in addition to the above, that the molecule is not a peptidyl, i.e. not usually considered a peptide, e.g. contains less than 4, 3 or 2 amino acids. In accordance with the present description, the PTM, ULM or PROTAC molecule may be low molecular weight.

[0048] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention relates. The terminology used in the description is intended to describe specific embodiments only and is not intended to limit the present invention.

[0049] Where a range of values is presented, each intermediate value is intended to be to the nearest tenth of a lower limit unit, unless the context clearly requires otherwise (as, for example, in the case of a group containing a specified number of carbon atoms, in which case the number of each carbon atom that falls within the range), between the upper and lower limits of this range, and any other specified or intermediate value within this specified range are covered by the present invention. The upper and lower limits of such smaller ranges, which may be independently included within the smaller ranges, are also covered by the present invention, subject to any specifically excluded limit within said range. If the specified range includes one or both limits, ranges excluding both of these included limits are also included in the present invention.

[0050] The following terms are used to describe the present invention. Where a term is not specifically defined herein, such term has the meaning generally recognized by those of ordinary skill in the art when used in the context of its use in describing the present invention.

[0051] The singular forms used herein and in the accompanying claims are used herein to refer to one or more than one (i.e., at least one) grammatical entities of that singular form unless the context clearly indicates other. By way of example, "element" means one element or more than one element.

[0052] The phrase “and/or” as used herein in the description and claims should be understood to mean “one or both” of the elements so combined, i.e. elements that in some cases are present together, and in other cases present separately. Multiple elements listed using “and/or” must be interpreted in the same way, i.e. "one or more" of the elements so combined. Other elements other than those specifically identified by the expression “and/or” may optionally be present, whether related or unrelated to the elements specifically identified. Thus, by way of non-limiting example, reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising,” may refer in one embodiment to A only (not necessarily including elements other than B); in another embodiment, only to B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0053] As used herein in the description and claims, the term “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating objects in a list, “or” or “and/or” should be understood as inclusive, i.e. including at least one, but also including more than one, of a number or list of items and optionally additional non-listed items. Only terms clearly indicating the contrary, such as “only one of” or “exactly one of,” or, if used in the claims, “consisting of,” will refer to the inclusion of exactly one element from a number or list of elements. In general, the term “or” as used herein should be understood only to indicate exclusive alternatives (i.e., “one or the other, but not both”) when preceded by exclusivity terms such as “either,” “ one of", "only one of" or "exactly one of".

[0054] In the claims, as well as in the above description, all transitional phrases such as “comprising”, “comprising”, “carrying”, “having”, “accommodating”, “providing”, “holding”, “consisting of” etc. should be understood as open, i.e. meaning inclusive without limitation. Only the transitional phrases “consisting of” and “substantially consisting of” must be closed or semi-closed transitional phrases, respectively, as set forth in section 2111.03 of the United States Patent Office Manual of Patent Examination Procedures.

[0055] As used herein in the specification and claims, the phrase “at least one” with respect to a list of one or more elements is to be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of absolutely all of the elements specifically listed in the list of elements, and not excluding any combinations of elements from the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase “at least one” refers may optionally be present, whether or not they are related to those specifically identified elements. Thus, by way of non-limiting example, “at least one of A and B” (or equivalently “at least one of A or B”, or equivalently “at least one of A and/or B”) may refer in one in an embodiment, to at least one, optionally including more than one, A, without the presence of B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, without the presence of A (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A and at least one, optionally including more than one, B (and optionally including other elements), etc.

[0056] It should also be understood that in certain methods described herein that involve more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are set forth, unless the context indicates otherwise.

[0057] The terms “co-administration” and “co-administration” or “combination therapy” refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and time-separated administration (administration of one or more more therapeutic agents at a time different from the time of administration of the additional therapeutic agent or agents), provided that the therapeutic agents are present in the patient to some extent, preferably in effective amounts, at the same time. In certain preferred aspects, one or more compounds of the present invention described herein are co-administered in combination with at least one additional biologically active agent, including, in particular, an anticancer agent. In particularly preferred aspects, coadministration of the compounds results in synergistic activity and/or therapy, including anticancer activity.

[0058] The term “compound” as used herein, unless otherwise noted, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as its pharmaceutically acceptable salts and derivatives, including prodrugs and/or deuterated forms thereof, as applicable in the appropriate context. Deuterated small molecules in question are molecules in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0059] When used in the appropriate context, the term "compound" generally refers to a single compound, but it may also include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. In the appropriate context, the term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compounds to the site of activity. It should be noted that in describing the compounds of the present invention, among other things, numerous substituents and variables associated therewith are described. Those of ordinary skill in the art will understand that the molecules that are described herein are stable compounds as generally described herein. If a bond is shown, both the double bond and the single bond are presented or understood in the context of the compound shown and the well-known rules of valency interaction.

[0060] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for destruction. For example, IAP is an E3 ubiquitin ligase complex protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the addition of ubiquitin to a lysine on a target protein and then targets specific protein substrates for destruction by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. In general, ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is added to the first, a third is added to the second, and so on. Through polyubiquitination, proteins are marked for destruction by the proteasome. However, there are some ubiquitination phenomena that are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted by the proteasome for destruction, but instead their cellular location or function can be altered, for example by binding to other proteins that contain domains that can bind ubiquitin. Further complicating the matter is that E3 can target different lysines on ubiquitin to form chains. The most abundant lysine is Lys48 in the ubiquitin chain. This lysine is used to form polyubiquitin, which is recognized by the proteasome.

[0061] The term “patient” or “subject” is used throughout this specification to describe an animal, preferably a human or pet, that is receiving treatment, including prophylactic treatment, with the compositions of the present invention. For the treatment of those infections, conditions or disease states that are specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including a domestic animal such as a dog or cat, or a farm animal, such as horse, cow, sheep, etc. In general, as used herein, the term patient refers to a human patient unless otherwise stated or implied by the context of use of the term.

[0062] The term “effective” is used to describe the amount of a compound, composition or component that, when used in the context of its intended use, produces the intended result. The term “effective” includes all other terms of effective amount or effective concentration that are otherwise described or used in this application.

[0063] Compounds and compositions

[0064] In one aspect, the disclosure provides compounds comprising an E3 ubiquitin ligase binding moiety ("ULM"), that is, an IAP binding moiety of the E3 ubiquitin ligase complex ("ILM"), a moiety binding to the cereblon of the E3 ubiquitin ligase complex (“CLM”), the Hippel-Lindau protein (VHL) binding fragment of the E3 ubiquitin ligase complex (VLM), and/or the E3 ubiquitin ligase mouse double minute homolog 2 (MDM2) binding fragment (MLM). In an illustrative embodiment, the ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the structure:

(A) PTM-L-ULM,

where L represents a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and/or relative positions of moieties in the compounds illustrated herein are provided as an example only. One skilled in the art will appreciate that the compounds described herein can be synthesized with any desired number and/or relative position of the corresponding functional moieties.

[0065] The terms ULM, ILM, VLM, MLM and CLM are used in their inclusive sense unless the context otherwise indicates. For example, the term ULM includes all ULMs, including those that bind IAP (i.e. ILM), MDM2 (i.e. MLM), Cereblon (i.e. CLM) and VHL (i.e. VLM) . In addition, the term ILM includes all possible fragments that bind to the IAP of the E3 ubiquitin ligase complex, the term MLM includes all possible fragments that bind the E3 ubiquitin ligase MDM2, the term VLM includes all possible fragments that bind to VHL, and the term CLM includes all fragments that bind with cereblon.

[0066] In another aspect, the present invention provides bifunctional or multifunctional compounds (eg, PROTAC) useful for regulating protein activity by inducing destruction of a target protein. In certain embodiments, the compound comprises an ILM, or VLM, or CLM, or MLM, linked, for example linked covalently, directly or indirectly, to a moiety that binds the target protein (i.e., a protein targeting moiety, or "PTM") . In certain embodiments, the ILM/VLM/CLM/MLM and the PTM are connected or linked via a chemical linker (L). ILM binds IAP E3 ubiquitin ligase complex, VLM binds VHL, CLM binds cereblon E3 ubiquitin ligase complex, and MLM binds E3 ubiquitin ligase MDM2, and PTM recognizes the target protein, and the interaction of the corresponding fragments with their targets promotes the destruction of the target protein by placing the target protein in close proximity to the protein of the ubiquitin ligase complex. An exemplary bifunctional compound can be depicted as:

(B) RTM-ILM,

(C) RTM-CLM,

(D) RTM-VLM,

(E) RTM-MLM.

[0067] In certain embodiments, the bifunctional compound further comprises a chemical linker (“L”). For example, a bifunctional compound can be depicted as:

(F) RTM-L-ILM,

(G) RTM-L-CLM,

(H) RTM-L-VLM,

(I) RTM-L-MLM,

where PTM is a protein/polypeptide targeting moiety, L is a chemical linker, ILM is an IAP binding moiety of the E3 ubiquitin ligase complex, CLM is a cereblon binding moiety of the E3 ubiquitin ligase complex, VLM is a moiety binding to the E3 ubiquitin ligase complex. with VHL, and MLM is a fragment that binds the E3 ubiquitin ligase MDM2.

[0068] In certain embodiments, the ULM (e.g., ILM, CLM, VLM, or MLM) exhibits activity on or binds to an E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase complex, cereblon E3 ubiquitin ligase complex, VHL, or E3 ubiquitin ligase MDM2) with IC ₅₀ of less than about 200 μM. IC ₅₀ can be determined in accordance with any method known in the art, for example, using fluorescence polarization analysis.

[0069] In certain additional embodiments, the bifunctional compounds described herein exhibit activity with an IC ₅₀ of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 , 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 µM, or less than about 100, 50, 10, 1,0.5 ,0.1,0.05,0.01,0.005,0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0070] In certain embodiments, the compounds described herein contain multiple PTMs (targeting the same or different target proteins), multiple ULMs, one or more ULMs (i.e., fragments that specifically bind to multiple/different E3 -ubiquitin ligases, for example, VHL, IAP, cereblon and/or MDM2) or a combination thereof. In any of the aspects or embodiments described herein, PTM and ULM (eg, ILM, VLM, CLM and/or MLM) can be directly linked or linked by one or more chemical linkers or combinations thereof. In additional embodiments, if a compound contains multiple ULMs, the ULMs may be related to the same E3 ubiquitin ligase, or each respective ULM may specifically bind to a different E3 ubiquitin ligase. In yet further embodiments, if a compound contains multiple PTMs, the PTMs may bind to the same target protein or each respective PTM may specifically bind to a different target protein.

[0071] In certain embodiments, if a connection contains multiple ULMs, the ULMs are identical. In additional embodiments, in a compound containing a number of ULMs (eg, ULM, ULM', etc.), at least one PTM is directly linked to the ULM or linked via a chemical linker (L) or both. In certain additional embodiments, a compound comprising a number of ULMs further comprises a plurality of PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, if the PTMs are different, the respective PTMs may bind the same target protein or specifically bind to different target proteins.

[0072] In certain embodiments, the connection may comprise a ULM series and/or a ULM' series. In further embodiments, a compound comprising at least two different ULMs, a series of ULMs and/or a series of ULM's, further comprises at least one PTM directly linked to the ULM or ULM' or linked via a chemical linker or both another. In any of the embodiments described herein, a connection comprising at least two different ULMs may further comprise multiple PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, if the PTMs are different, the respective PTMs may bind the same target protein or specifically bind to different target proteins. In still further embodiments, the PTM itself is a ULM (or ULM'), such as ILM, VLM, CLM, MLM, ILM', VLM', CLM' and/or MLM'.

[0073] In additional embodiments, the disclosure provides the compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salt forms, such as acid and base addition salt forms.

[0074] Illustrative ILM

[0075] Tetrapeptide fragments of AVPI

[0076] In any of the compounds described herein, the ILM may contain a tetrapeptide fragment alanine-valine-proline-isoleucine (AVPI) or a non-natural mimetic thereof. In certain embodiments, the ILM is selected from the group consisting of chemical structures represented by formulas (I), (II), (III), (IV) and (V),

Where

R ¹ for formulas (I), (II), (III), (IV) and (V) is selected from H or alkyl;

R ² for formulas (I), (II), (III), (IV) and (V) is selected from H or alkyl;

R ³ for formulas (I), (II), (III), (IV) and (V) is selected from H, alkyl, cycloalkyl and heterocycloalkyl;

R ⁵ and R ⁶ for formulas (I), (II), (III), (IV) and (V) are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably R ⁵ and R ⁶ taken together for formulas (I), (II), (III), (IV) and (V), form a pyrrolidine or piperidine ring, optionally further fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which can then be further fused with another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring,

R ³ and R ⁵ for formulas (I), (II), (III), (IV) and (V), taken together can form a 5-8 membered ring, optionally additionally fused with 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;

R ⁷ for formulas (I), (II), (III), (IV) and (V) is selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is further optionally substituted 1-3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or R ⁷ is -C(O)NH-R ⁴ , and

R ⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, further optionally substituted with 1-3 substituents described above.

[0077] As shown above, P1, P2, P3 and P4 in formula (II) correspond to A, V, P and I, respectively, of the tetrapeptide fragment of AVPI or a non-natural mimetic thereof. Similarly, each of formulas (I) and (III) - (V) contains parts corresponding to A, V, P and I of the tetrapeptide fragment of AVPI or a non-natural mimetic thereof.

[0078] With any of the compounds described herein, ILM may be characterized by the structure of formula (VI), which is a derivative of the IAP antagonists described in publ. WO No. 2008/014236, or its corresponding non-natural mimetic,

Where

R ₁ in formula (VI) is independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl or C ₃ -C ₁₀ cycloalkyl, which are unsubstituted or substituted;

R ₂ in formula (VI) is independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl or C ₃ -C ₁₀ cycloalkyl, which are unsubstituted or substituted;

R ₃ in formula (VI) is independently selected from H, -CF ₃ , -C ₂ H ₅ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, -CH ₂ - Z, or any R ₂ and R ₃ together form a heterocyclic ring;

each Z in formula (VI) is independently selected from H, -OH, F, Cl, -CH ₃ , -CF ₃ , -CH ₂ Cl, -CH ₂ F or -CH ₂ OH;

R ⁴ in formula (VI) is independently selected from C ₁ -C ₁₆ -straight or branched chain alkyl, C ₁ -C ₁₆ -alkenyl, C ₁ -C ₁₆ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, -(CH ₂ ) _0-6 -Z ₁ , -(CH ₂ ) _0-6 -aryl and -(CH ₂ ) _0-6 -het, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

R ₅ in formula (VI) is independently selected from H, C _1-10 -alkyl, aryl, phenyl, C _3-7 -cycloalkyl, -(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C _{1- 10-} alkylaryl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl-(CH ₂ ) _0-6 -phenyl, -(CH ₂ ) _0-4 -CH [(CH ₂ ) _1-4 -phenyl ] ₂ , indanyl, -C(O)-C _1-10 -alkyl, -C(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O)-(CH ₂ ) _{0 -6} -phenyl, -(CH ₂ ) _0-6 -C(O)-phenyl, -(CH ₂ ) _0-6 -het, -C(O)-(CH ₂ ) _1-6 -het, or R ₅ is selected from an amino acid residue, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted;

Z ₁ in formula (VI) is independently selected from -N(R ₁₀ )-C(O)-C _1-10 -alkyl, -N(R ₁₀ )-C(O)-(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -N(R ₁₀ )-C(O)-(CH ₂ ) _0-6 -phenyl, -N(R ₁₀ )-C(O)(CH ₂ ) _1-6 -het, - C(O)-N(R ₁₁ )(R ₁₂ ), -C(O)-O-C _1-10 -alkyl, -C(O)-O-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(O)-O-(CH ₂ ) _0-6 -phenyl, -C(O)-O-(CH ₂ ) _1-6 -het, -O-C(O)-C _{1- 10} -alkyl, -OC(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -O-C(O)-(CH ₂ ) _0-6 -phenyl, -OC(O)-( CH ₂ ) _1-6 -het, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

het in formula (VI) is independently selected from a 5-7 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system containing at least one 5-7 -membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heterocyclic ring or fused ring system is unsubstituted or substituted at a carbon or nitrogen atom;

R ₁₀ in formula (VI) is selected from H, -CH ₃ , -CF ₃ , -CH ₂ OH or -CH ₂ Cl;

R ₁₁ and R ₁₂ in formula (VI) are independently selected from H, C _1-4 -alkyl, C _3-7 -cycloalkyl, -(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, (CH ₂ ) _{0 -6-} phenyl, where alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R ₁₁ and R ₁₂ together with a nitrogen atom form het, and

U in formula (VI) is independently as shown in formula (VII),

Where

each n in formula (VII) is independently selected from 0-5;

X in formula (VII) is selected from the group consisting of -CH and N;

R _a and R _b in formula (VII) are independently selected from the group consisting of O, S or N or C _0-8 -alkyl atoms, wherein one or more carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, and each alkyl is independently either unsubstituted or substituted;

R _d in formula (VII) is selected from the group consisting of Re-Q-(R _f ) _p (R _g ) _q and Ar ₁ -D-Ar ₂ ;

R _c in formula (VII) is selected from the group consisting of H, or any R _c and R _d together form cycloalkyl or het; Moreover, if R _c and R _d form a cycloalkyl or het, R ₅ is attached to the formed ring at the C or N atom;

p and q in formula (VII) are independently selected from 0 or 1;

R _e in formula (VII) is selected from the group consisting of C _1-8 -alkyl and alkylidene, and each Re is either unsubstituted or substituted;

Q is selected from the group consisting of N, O, S, S(O) and S(O) ₂ ;

Ar ₁ and Ar ₂ in formula (VII) are independently selected from the group consisting of substituted or unsubstituted aryl and het;

R _f and R _g in formula (VII) are independently selected from H, -C1-10-alkyl, C _1-10 -alkylaryl, -OH, -O-C _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH ₂ ) _1-6 -het, -O-(CH ₂ ) _1-6 -het, -OR ₁₃ , -C(O)-R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N(R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S( O)-R ₁₃ , -S(O) ₂ -R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ , -NR ₁₃ -S(O) ₂ -R ₁₄ , -SC _t-10 -alkyl, aryl -C _1-4 -alkyl or het-C _1-4 -alkyl, where alkyl, cycloalkyl, het and aryl are unsubstituted or substituted, -SO ₂ -C _1-2 -alkyl, -SO ₂ -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 selected from the group consisting of -CO-, -C(O)-C _1-7 -alkylene or arylene, -CF ₂ -, -O-, -S(O) _r , where r is 0-2,1,3-dioxalane or C _1-7 -alkyl-OH; where alkyl, alkylene or arylene are unsubstituted or substituted with one or more halogen atoms, OH, -O-C _1-6 -alkyl, -S-C _1-6 -alkyl or -CF ₃ ; or each D is independently selected from N(R _h );

Rh is selected from the group consisting of 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 -alkylaryl, -COC _01-10 -alkyl, -C-O-C _0-10 -alkylaryl, -SO ₂ -C _1-10 -alkyl or -SO ₂ -(C _{0 -10} -alkylaryl);

R ₆ , R ₇ , R ₈ and R ₉ in formula (VII) are independently selected from the group consisting of H, -C _1-10 -alkyl, -C _1-10 -alkoxy, aryl-C _1-10 -alkoxy, -OH, -OC _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -O-(CH ₂ ) _0-6 -aryl, phenyl, -(CH ₂ ) _1-6 -het, -O-(CH ₂ ) _1-6 -het, -OR ₁₃ , -C(O)-R ₁₃ , -C(O)-N(R ₁₃ )(R ₁₄ ), -N(R ₁₃ )(R ₁₄ ), -SR ₁₃ , -S(O)-R ₁₃ , -S(O) ₂ -R ₁₃ , -S(O) ₂ -NR ₁₃ R ₁₄ or -NR ₁₃ -S(O) ₂ -R ₁₄ ; wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted; and any R ₆ , R ₇ , R ₈ and R ₉ together optionally form a ring system;

R ₁₃ and R ₁₄ in formula (VII) are independently selected from the group consisting of H, C _1-10 -alkyl, -(CH ₂ ) _0-6 -C _3-7 -cycloalkyl, -(CH ₂ ) _0-6 -(CH) _0-1 -(aryl) _1-2 , -C(O)-C _1-10 -alkyl, -C(O)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, - C(O)-O-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -O-fluorenyl, -C(O)-NH-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -aryl, -C(O)-(CH ₂ ) _0-6 -het, -C(S)-C _1-10 -alkyl, -C (S)-(CH ₂ ) _1-6 -C _3-7 -cycloalkyl, -C(S)-O-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -O-fluorenyl, -C(S)-NH-(CH ₂ ) _0-6 -aryl, -C(S)-(CH ₂ ) _0-6 -aryl or -C(S)-(CH ₂ ) _{1 -6} -het, where each alkyl, cycloalkyl and aryl is unsubstituted or substituted, or any R ₁₃ and R ₁₄ together with a nitrogen atom form het;

wherein the alkyl substituents on R ₁₃ and R ₁₄ in formula (VII) are unsubstituted or substituted, and if they are substituted, they are substituted by one or more substituents selected from C _1-10 -alkyl, halogen, OH, -OC _{1- 6} -alkyl, -SC _1-6 -alkyl and -CF ₃ ; and the substituted phenyl or aryl in R ₁₃ and R ₁₄ is substituted with one or more substituents selected from halogen, hydroxyl, C _1-4 -alkyl, C _1-4 -alkoxy, nitro, -CN, -O-C(O)- C _1-4 -alkyl and -C(O)-O-C _1-4 -aryl; or a pharmaceutically acceptable salt or hydrate thereof.

[0079] In certain embodiments, the compound further comprises an independently selected second ILM attached to the ILM of formula (VI) or a non-natural mimetic thereof by at least one additional independently selected linker group. In one embodiment, the second ILM is a derivative of formula (VI) or a non-natural mimetic thereof. In a certain embodiment, the at least one additional independently selected linker group provides two additional independently selected linker groups chemically connecting the ILM and the second ILM. In one embodiment, at least one additional linker group for the ILM of formula (VI) or a non-natural mimetic thereof chemically connects groups selected from R ₄ and R ₅ . For example, an ILM of formula (VI) and a second ILM of formula (VI) or a non-natural mimetic thereof may be combined as shown below.

[0080] In certain embodiments of the ILM, at least one additional independently selected linker group L and the second ILM are characterized by a structure selected from the group consisting of:

which are derivatives of IAP antagonists described in publ. WO No. 2008/014236.

[0081] In any of the compounds described herein, the ILM may be characterized by the structure of formula (VIII), which is based on the structure of the IAP ligands described in Ndubaku, S., et al. Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566.4 (7) (2009), or its corresponding non-natural mimetic,

wherein each of A1 and A2 in formula (VIII) is independently selected from optionally substituted monocyclic fused rings, aryls and heteroaryls; And

R in formula (VIII) is selected from H or Me.

[0082] In a specific embodiment, the linker group L is attached to A1 in formula (VIII). In another embodiment, the linker group L is attached to A2 in formula (VIII).

[0083] In a specific embodiment, the ILM is selected from the group consisting of

[0084] In any of the compounds described herein, the ILM may be characterized by the structure of formula (IX), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its corresponding non-natural mimetic,

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

[0085] In any of the compounds described herein, the ILM may be characterized by a structure of formula (X), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its corresponding non-natural mimetic,

Where

R ¹ in formula (X) is selected from H, -CH ₂ OH, --CH ₂ CH ₂ OH, --CH ₂ NH ₂ , --CH ₂ CH ₂ NH ₂ ;

X in formula (X) is selected from S or CH ₂ ,

R ² in formula (X) is selected from

R ³ and R ⁴ in formula (X) are independently selected from H or Me.

[0086] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XI), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its corresponding non-natural mimetic,

where R ¹ in formula (XI) is selected from H or Me, and R ² in formula (XI) is selected from H or

[0087] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XII), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or its corresponding non-natural mimetic,

Where

R ¹ in formula (XII) is selected from

R ² in formula (XII) is selected from

[0088] In any of the compounds described herein, the IAP binding moiety of the E3 ubiquitin ligase complex is selected from the group consisting of:

[0089] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XIII), which is based on the structure of 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), or its corresponding non-natural mimetic,

Where

Z in formula (XIII) is absent or represents O;

R ¹ in formula (XIII) is selected from

R ¹⁰ V selected from H, alkyl or aryl,

X is selected from CH2 and O, and

is a nitrogen-containing heteroaryl.

[0090] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XIV), which is based on the structure of 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), or its corresponding non-natural mimetic,

Where

Z in formula (XIV) is absent or represents O,

R ³ and R ⁴ in formula (XIV) are independently selected from H or Me,

R ¹ in formula (XIV) is selected from

R ¹⁰ V selected from H, alkyl or aryl,

X in selected from CH2 and O; And

V or is a nitrogen-containing heteroaryl.

[0091] In any of the connections described herein, the ILM is selected from the group consisting of

which are derivatives of the ligand o in, disclosed in publ. US Patent No. 2008/0269140 and US Patent No. 7244851.

[0092] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XV), which is a derivative of the IAP ligand described in publ. WO No. 2008/128171, or its corresponding non-natural mimetic,

Where

Z in formula (XV) is absent or represents O;

R ¹ in formula (XV) is selected from

R ¹⁰ V selected from H, alkyl or aryl;

X in selected from CH2 and O; And

V or is a nitrogen-containing heteroaryl, and

R ² in formula (XV) is selected from H, alkyl or acyl.

[0093] In a specific embodiment, the ILM is characterized by the following structure:

[0094] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XVI), which is based on the structure of the IAP ligand described in publ. WO No. 2006/069063, or its corresponding non-natural mimetic,

Where

R ² in formula (XVI) is selected from alkyl, cycloalkyl and heterocycloalkyl, more preferably from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably from cyclohexyl,

in formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl, and most preferably a thiazole, and

Ar in formula (XVI) represents aryl or heteroaryl.

[0095] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XVII), which is based on the structure of the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres , Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or its corresponding non-natural mimetic,

Where

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

X in formula (XVII) is selected from the group consisting of O or CH2.

[0096] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XVIII), which is based on the structure of the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres , Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or its corresponding non-natural mimetic,

wherein R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halogen (at various substitution positions).

[0097] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XIX), which is based on the structure of the IAP ligands described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres , Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or its corresponding non-natural mimetic,

Where is a 6-membered nitrogen-containing heteroaryl.

[0098] In a certain embodiment, the ILM according to the composition is selected from the group consisting of

[0099] In certain embodiments, the ILM according to the composition is selected from the group consisting of:

[00100] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XX), which is based on the structure of the IAP ligands described in publ. WO No. 2007/101347, or its corresponding non-natural mimetic,

where X in formula (XX) is selected from CH ₂ , O, NH or S.

[00101] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XXI), which is based on the structure of the IAP ligands described in US Pat. No. 7,345,081 and US Pat. No. 7,419,975, or a corresponding non-natural mimetic,

Where

R ² in formula (XXI) is selected from

R ⁵ in formula (XXI) is selected from And And

W in formula (XXI) is selected from CH or N, and

R ⁶ in And independently represents a mono- or bicyclic fused aryl or heteroaryl.

[00102] In certain embodiments, the ILM in the connection is selected from the group consisting of

[00103] In certain embodiments, the ILM in the connection is selected from the group consisting of

which are described in publ. WO No. 2009/060292, US Patent No. 7517906, publ. WO No. 2008/134679, publ. WO No. 2007/130626 and publ. WO No. 2008/128121.

[00104] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXII) or (XXIII), which is derived from the structure of the IAP ligands described in publ. WO No. 2015/006524 and Perez 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 corresponding non-natural mimetic,

Where

R ¹ in formula (XXII) or (XXIII) is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted aryl alkyl or optionally substituted aryl,

R ² in formula (XXII) or (XXIII) represents optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted aryl alkyl or optionally substituted aryl,

or alternatively, R ¹ and R ² in formula (XXII) or (XXIII) are independently optionally substituted thioalkyl, wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ,

Where

v is an integer 1-3;

R ²⁰ and R ²² in -(CH ₂ ) _v COR ²⁰ and -CH ₂ R ²³ are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ in -CH ₂ CHR ²¹ COR ² is selected from the group consisting of NR ²⁴ R ²⁵ ;

R ²³ in -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ in NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ in NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ₂ O) _m CH ₃ or a polyamine chain such as spermine or spermidine ;

R ²⁶ in OR ²⁶ is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m represents an integer 1-8;

R ³ and R ⁴ in formula (XXII) or (XXIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ in formula (XXII) or (XXIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; And

X is selected from a bond or chemical linker group, and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00105] In certain embodiments, X represents a link or is selected from the group consisting of

where "*" represents the attachment point of a PTM, L, or ULM, such as an ILM.

[00106] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXIV) or (XXVI), which is derived from the structure of the IAP ligands described in publ. WO No. 2015/006524 and Perez 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 corresponding non-natural mimetic, and a chemical linker to the clinker group L, as shown

Where

R ¹ in formula (XXIV), (XXV) or (XXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

R ² in formula (XXIV), (XXV) or (XXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

or alternatively

R ¹ and R ² in formula (XXIV), (XXV) or (XXVI) are independently selected from optionally substituted thioalkyl, wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, - (CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ,

Where

v is an integer 1-3;

R ²⁰ and R ²² in -(CH ₂ ) _v COR ²⁰ and -CH ₂ R ²³ are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ in -CH ₂ CHR ²¹ COR ² selected from NR ²⁴ R ²⁵ ;

R ²³ in -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ in NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ in NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ₂ O) _m CH ₃ or a polyamine chain such as spermine or spermidine ;

R ²⁶ in OR ²⁶ is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m represents an integer 1-8;

R ³ and R ⁴ in formula (XXIV), (XXV) or (XXVI) independently represent optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optional substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ in formula (XXIV), (XXV) or (XXVI) independently represent hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00107] In a specific embodiment, in the ILM in accordance with formulas (XXII) - (XXVI),

R ⁷ and R ⁸ are selected from H or Me;

R ⁵ and R ⁶ are selected from the group consisting of

R ³ and R ⁴ are selected from the group consisting of

[00108] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXVII) or (XXVII), which is derived from the structure of the IAP ligands described in publ. WO No. 2014/055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or its corresponding non-natural mimetic,

Where

R ³⁵ represents 1-2 substituents selected from alkyl, halogen, alkoxy, cyano and halogen-alkoxy;

R ¹ in formula (XXVII) and (XXVIII) is selected from H or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl,

R ² in formula (XXVII) and (XXVIII) is selected from H or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl,

or alternatively

R ¹ and R ² in formula (XXVII) and (XXVIII) are independently selected from optionally substituted thioalkyl -CR ⁶⁰ R ⁶¹ SR ⁷⁰ , where R ⁶⁰ and R ⁶¹ are selected from H or methyl, and R ⁷⁰ is selected from optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl a, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ,

Where

v is an integer 1-3;

R ²⁰ and R ²² in -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ in -CH ₂ CHR ²¹ COR ²² selected from NR ²⁴ R ²⁵ ;

R ²³ in -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ in NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ in NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _m CH ₃ or polyamine chain -[CH ₂ CH ₂ (CH ₂ )δNH]ψCH ₂ CH ₂ (CH ₂ )ϖNH ₂ such as spermine or spermidine;

where δ=0-2, ψ=1-3, ϖ=0-2;

R ²⁶ in OR ²⁶ is optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH ₂ ; And

m represents an integer 1-8,

R ³ and R ⁴ in formula (XXVII) and (XXVIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH;

R ⁵ , R ⁶ , R ⁷ and R ⁸ in formula (XXVII) and (XXVIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

R ³¹ in formulas (XXVII) and (XXVIII) is selected from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, optionally further substituted, preferably selected from the group consisting of And

X in formulas (XXVII) and (XXVIII) is selected from -(CR ⁸¹ R ⁸² ) _m -, optionally substituted heteroaryl or heterocyclyl,

Z in formulas (XXVII) is selected from C=O, -O-, -NR, -CONH-, -NHCO- or may be absent;

R ⁸¹ and R ⁸² in -(CR ⁸¹ R ⁸² ) _m are independently selected from hydrogen, halogen, alkyl or cycloalkyl, or R ⁸¹ and R ⁸² can be taken together to form a carbocyclic ring;

R ¹⁰ and R ¹¹ in independently selected from hydrogen, halogen or alkyl;

R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ in independently selected from hydrogen, halogen or optionally substituted alkyl or OR ¹⁷ ;

R ¹⁷ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

m and n in -(CR ²¹ R ²² ) _m - and independently equal to 0, 1, 2, 3 or 4;

o and r in independently equal to 0, 1, 2 or 3;

q and t in independently equal to 0, 1, 2, 3 or 4;

r in equals 0 or 1;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00109] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXIX), (XXX), (XXXI) or (XXXII), which is derived from the structure of the IAP ligands described in publ. WO No. 2014/055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or a corresponding non-natural mimetic, and a chemical linker to the linker group L, as shown

Where

R ² in formulas (XXIX) - (XXXII) is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;

or alternatively

R ¹ and R ² in formula (XXVII) and (XXVIII) are independently selected from H, optionally substituted thioalkyl -CR ⁶⁰ R ⁶¹ SR ⁷⁰ , where R ⁶⁰ and R ⁶¹ are selected from H or methyl, and R ⁷⁰ is optionally substituted alkyl , optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ;

Where

v is an integer 1-3;

R ²⁰ and R ²² in -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ in -CH ₂ CHR ²¹ COR ²² selected from NR ²⁴ R ²⁵ ;

R ²³ in -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ in NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ in NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _m CH ₃ or a polyamine chain such as spermine or spermidine,

where δ=0-2, ψ=1-3, ϖ=0-2;

R ²⁶ in OR ²⁶ represents an optionally substituted alkyl, where the optional substituents are OH, halogen or NH ₂ ,

m represents an integer 1-8;

R ⁶ and R ⁸ in formula (XXIX) - (XXXII) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; And

R ³¹ in formulas (XXIX) - (XXXII) is selected from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, optionally further substituted, preferably selected from the group consisting of

[00110] In certain embodiments, the ILM in the connection is

[00111] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXXX), which is derived from the structure of the IAP ligands described in publ. WO No. 2014/074658 and publ. WO No. 2013/071035, or its corresponding non-natural mimetic,

Where

R ² in formula (XXXIII) is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl,

R ⁶ and R ⁸ in formula (XXXX) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl,

R ³² in formula (XXXIII) is selected from (C1-C4alkylene)-R ³³ , where R ³³ is selected from hydrogen, aryl, heteroaryl or cycloalkyl, optionally further substituted,

X in the formula (ХХХШ) is chosen from

Z and Z' in formula (XXXIII) are independently selected from

where everyone represents the point of attachment to the connection, and Z and Z' cannot both represent in any given connection;

Y in formula (ХХХШ) is chosen from

where Z and Z' in formula (XXXX) are the same, and Z represents where is everyone represents the attachment point to the connection, X is selected from

And

Y in formula (XXXX) is independently selected from

Where

represents the point of attachment to the -C=O part of the compound,

represents the point of attachment to the -NH part of the compound,

represents the first attachment point to Z,

represents the second attachment point to Z,

m is an integer 0-3;

n is an integer from 1-3,

p is an integer 0-4, and

A represents -C(O)R ³ ,

R ³ in -C(O)R ³ is selected from OH, NHCN, NHSO ₂ R ¹⁰ , NHOR ¹¹ or N(R ¹² )(R ¹³ ),

R ¹⁰ and F ¹¹ in NHSO ₂ R ¹⁰ and NHOR ¹¹ are independently selected from hydrogen, optionally substituted with -C ₁ -C ₄ alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocycloalkyl,

R ¹² and R ¹³ in N(R ¹² )(R ¹³ ) are independently selected from hydrogen, -C ₁ -C ₄ alkyl, -(C ₁ -C ₄ )alkylene)-NH-(C ₁ -C ₄ alkyl) and -(C ₁ -C ₄ alkylene)-O-(C ₁ -C ₄ hydroxyalkyl), or R ¹² and R ¹³ are taken together with the nitrogen atom to which they are normally bonded to form a saturated heterocyclyl, optionally containing one additional heteroatom, selected from N, O and S, and wherein the saturated heterocycle is optionally substituted with methyl.

[00112] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXXIV) or (XXXV), which is derived from the structure of the TAP ligands described in publ. WO No. 2014/047 024, or its corresponding non-natural mimetic,

Where

X in formula (XXXIV) or (XXXV) is absent or selected from the group consisting of -(CR ¹⁰ R ¹¹ ) _m -, optionally substituted heteroaryl or optionally substituted heterocyclyl,

Y and Z in formula (XXXIV) or (XXXV) are independently selected from C=0, -0-, -NR ⁹ -, -CONH-, -NHCO- or may be absent;

R ¹ and R ² in formula (XXXIV) or (XXXV) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or

R ¹ and R ² in formula (XXXIV) or (XXXV) are independently selected from optionally substituted thioalkyl, wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH ₂ ) _v COR ²⁰ , -CH ₂ CHR ²¹ COR ²² or -CH ₂ R ²³ ; Where

v is an integer 1-3;

R ²⁰ and R ²² in -(CH ₂ ) _v COR ²⁰ and -CH ₂ CHR ²¹ COR ²² are independently selected from OH, NR ²⁴ R ²⁵ or OR ²⁶ ;

R ²¹ in -CH ₂ CHR ²¹ COR ²² selected from NR ²⁴ R ²⁵ ;

R ²³ in -CH ₂ R ²³ is selected from optionally substituted aryl or optionally substituted heterocyclyl, where optional substituents include alkyl and halogen;

R ²⁴ in NR ²⁴ R ²⁵ is selected from hydrogen or optionally substituted alkyl;

R ²⁵ in NR ²⁴ R ²⁵ is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH ₂ (OCH ₂ CH ²⁰ )mCH3 or polyamine chain;

R ²⁶ represents optionally substituted alkyl, where optional substituents are OH, halogen or NH ₂ ;

m in -(CR ¹⁰ R ¹¹ ) _m - represents an integer 1-8;

R ³ and R ⁴ in formula (XXXIV) or (XXXV) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, where the substituents are alkyl, halogen or OH,

R ⁵ , R ⁶ , R ⁷ and R ⁸ in formula (XXXIV) or (XXXV) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cyclo alkyl, and

R ¹⁰ and R ¹¹ in -(CR ¹⁰ R ¹¹ ) _m are independently selected from hydrogen, halogen or optionally substituted alkyl;

R ¹² and R ¹³ in independently selected from hydrogen, halogen or optionally substituted alkyl, or R ¹² and R ¹³ can be taken together to form a carbocyclic ring,

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ in independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁹ ,

R ¹⁹ in OR ¹⁹ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl,

m and n in -(CR ¹⁰ R ¹¹ ) _m - independently equal 0, 1, 2, 3 or 4,

o and p in -(CR ¹⁰ R ¹¹ ) _m - independently equal 0, 1, 2 or 3,

q in -(CR ¹⁰ R ¹¹ ) _m - equals 0, 1, 2, 3 or 4; g equals 0 or 1;

t in -(CR ¹⁰ R ¹¹ ) _m is 1, 2 or 3, and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00113] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XXXVI), which is derived from the structure of the IAP ligands described in publ. WO No. 2014/025759, or its corresponding non-natural mimetic,

Where

And in formula (XXXVI) is selected from where the dotted line represents an optional double bond,

X in formula (XXXVI) is selected from -(CR ²¹ R ²² ) _m -,

Y and Z in formula (XXXVI) are independently selected from -0-, -NR ⁶ - or absent,

V in formula (XXXVI) is selected from -N- or -CH-,

W in formula (XXXVI) is selected from -CH- or -N-;

R ¹ in formula (XXXVI) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl or optionally substituted aryl,

R ³ and R ⁴ in formula (XXXVI) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted hetero o arylalkyl, or optionally substituted heterocycloalkyl;

R ⁵ , R ⁶ , R ⁷ and R ⁸ in formula (XXIV), (XXV) or (XXVI) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or preferably methyl,

R ⁹ and R ¹⁰ in independently selected from hydrogen, halogen or optionally substituted alkyl, or R ⁹ and R ¹⁰ can be taken together to form a ring;

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ in independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁵ ,

R ¹⁵ in OR ¹⁵ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl,

m and n in -(CR ²¹ R ²² ) _m - and independently selected from 0, 1, 2, 3 or 4,

o and r in and independently selected from 0, 1,2 or 3;

q in selected from 0, 1, 2, 3 or 4;

r in selected from 0 or 1, and/or or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00114] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXXVII) or (XXXVIII), which is derived from the structure of the IAP ligands described in publ. WO No. 2014/011712, or its corresponding non-natural mimetic,

Where

X in formulas (XXXVII) and (XXXVIII) represents - (CR ¹⁶ R ¹⁷ ) _m ,-

or absent;

Y and Z in formula (XXXVII) and (XXXVIII) are independently selected from -0-, C=0, NR ⁶ or none;

R ¹ and R ² in formula (XXXVII) and (XXXVIII) are selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylaryl, or optionally substituted aryl;

R ³ and R ⁴ in formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl alkyl, or optionally substituted aryl;

R ⁵ and R ⁶ in formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl or optionally substituted cycloalkyl;

R ⁷ and R ⁸ in formula (XXXVII) and (XXXVIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or preferably methyl,

R ⁹ and R ¹⁰ in independently selected from hydrogen, optionally substituted alkyl, or R ⁹ and R ¹⁰ may be taken together to form a ring,

R ¹¹ - R ¹⁴ V independently selected from hydrogen, halogen, optionally substituted alkyl or OR ¹⁵ ;

R ¹⁵ in OR ¹⁵ is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl,

R ¹⁶ and R ¹⁷ in -(CR ¹⁶ R ¹⁷ ) _m are independently selected from hydrogen, halogen or optionally substituted alkyl;

^R50 and ^R51 in formula (XXXVII) and (XXXVIII) are independently selected from optionally substituted alkyl, or ^R50 and ^R51 are taken together to form a ring;

m and n in -(CR ¹⁶ R ¹⁷ ) _m - and independently represent an integer 0-4;

o and r in independently represent an integer 0-3;

q in represents an integer 0-4, and

r in represents an integer 0-1;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[00115] In one embodiment, R ¹ and R ² in an ILM of formula (XXXVII) or (XXXVIII) are tert-butyl, and R ³ and R ⁴ in an ILM of formula (XXXVII) or (XXXVIII) are tetrahydronaphthalene.

[00116] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XXXIX) or (XL), which is derived from the structure of the IAP ligands described in publ. WO No. 2013/071039, or its corresponding non-natural mimetic,

Where

R ⁴³ and R ⁴⁴ in formulas (XXXIX) and (XL) are independently selected from hydrogen, alkyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl, cyclo alkyl, cyclo alkyl alkyl, further optionally substituted, and

R ⁶ and R ⁸ in formula (XXXIX) and (XL) are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted ring o alkyl,

each X in formulas (XXXIX) and (XL) is independently selected from

each Z in formulas (XXXIX) and (XL) is selected from where is everyone represents the point of attachment to a connection; And

each Y is selected from

Where

represents the point of attachment to the -C=O portion of the compound;

represents the point of attachment to the amino part of the compound;

represents the first attachment point to Z;

represents the second attachment point to Z; And

A selected from -C(O)R ³ or

or a tautomeric form of any of the above, where:

R ³ in -C(O)R ³ is selected from OH, NHCN, NHS0 ₂ R ¹⁰ , NHOR ¹¹ or N(R ¹² )(R ¹³ );

R ¹⁰ and R ¹¹ in NHS0 ₂ R ¹⁰ and NHOR ¹⁰ are independently selected from -C ₁ -C ₄ alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, any of which is optionally substituted, and hydrogen;

each of R ¹² and R ¹³ in N(R ¹² )(R ¹³ ) is independently selected from hydrogen, -C ₁ -C ₄ alkyl, -(C ₁ -C ₄ alkylene)-NH-(C ₁ -C ₄ alkyl) , benzyl, -(C ₁ -C ₄ alkylene)-C(O)OH,

-(C ₁ -C ₄ alkylene)-C(O)CH ₃ , -CH(benzyl)-COOH, -C ₁ -C ₄ alkoxy and

-(C ₁ -C ₄ alkylene)-O-(C ₁ -C ₄ hydroxyalkyl); or R ¹² and R ¹³ in N(R ¹² )(R ¹³ ) are taken together with the nitrogen atom to which they are jointly bonded to form a saturated heterocyclyl, optionally containing one additional hetero atom selected from N, O and S, and wherein the saturated heterocycle is optionally substituted with methyl.

[00117] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XLI), which is derived from the structure of the IAP ligands described in publ. WO No. 2013/071039, or its corresponding non-natural mimetic,

Where

W ¹ in formula (XLI) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² in formula (XLI) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that W ¹ and W ² are not both O or simultaneously S,

R ¹ in formula (XLI) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ is selected from O, NR ^A , S, S(O) or S(O) ₂ , then ^{X 2} is C(R ^2a R ^2b );

or

X ¹ in formula (XLI) is selected from CR ^2c R ^2d , and X ² is CR ^2a R ^2b , and R ^2c and R ^2a together form a bond;

or

X ¹ and X ² in formula (XLI) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;

or

X ¹ in formula (XLI) is selected from CH ₂ and X ² is C=0, C=C( ^RC ) ₂ or C=NR ^C ; where each R ^c is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

R ^A in NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d in CR ^2c R ^2d and CR ^2a R ^2b are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B in -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E in NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m in formula (XLI) is selected from 0, 1 or 2;

-U- in formula (XLI) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(= O)NH-, -NH(C=O)О-, -О(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ in formula (XLI) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ in formula (XLI) is selected from -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ )3 or -OR ⁵ ;

each R ⁵ in -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ )3 and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or

R ³ and R ⁵ in formula (XLI), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or

R ³ in formula (XLI) is bonded to the nitrogen atom in U to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ in formula (XLI) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O) ₂ R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl ;

each R ⁷ in -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) , -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p in R ⁷ is selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d in C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together form a bond; or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected of S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or

R ^8c and R ^8d are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or

R ^8a and R ^8b are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ in R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C _{4 alkyl, C 1 -C 4} fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C(=O) NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)- O-(C ₁ -C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH ₂ , -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O( C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ , or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl

[00118] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XLII), which is derived from the structure of the IAP ligands described in publ. WO No. 2013/07 1 03 9, or a corresponding non-natural mimetic,

Where

W ¹ in formula (XLII) represents O, S, NR ^A or C(R ^8a )(R ^8b );

W ² in formula (XLII) represents O, S, NR ^A or C(R ^8c )(R ^8d ), provided that W ¹ and W ² are not both O or both are not S,

R ¹ in formula (XLII) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl),

if X ¹ in formula (XLII) represents NR ^A , then X ² represents C=O or CR ^2c R ^2d , and X ³ represents CR ^2a R ^2b ,

or

if X ¹ in formula (XLII) is selected from S, S(O) or S(O) ₂ , then X ² is CR ^2c R ^2d and X ³ is CR ^2a R ^2b ;

or

if X ¹ in formula (XLII) represents O, then X ² represents CR ^2c R ^2d and NR ^A and X ³ represents CR ^2a R ^2b ;

or

if X ¹ in formula (XLII) is CH ₃ , then X ² is selected from O, ^NRA , S, S(O) or S(O) ₂ , and X ³ is CR ^2a R ^2b ;

if X ¹ in formula (XLII) is CR ^2e R ^2f , then X 2 is CR ^2c R ^2d , and R ^2e and R ^2c together form a bond, and X ³ in formula (VLII) is CR ^2a R ^2b .

or

X ¹ and X ³ in formula (XLII) are both CH ₂ , and X ² in formula (XLII) is C=0, C=C( ^RC ) ₂ or C=NR ^C ; where each R ^C is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C2 - _C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted aryl) or C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl);

or

X ¹ and X ² in formula (XLII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ³ is CR ^2a R ^2b ;

or

X ² and X ³ in formula (XLII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ¹ in formula (VLII) represents CR ^2e R ^2f ;

R ^A in NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f in CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₁ - C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B in -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E in NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m in formula (XLII) is selected from 0, 1 or 2;

-U- in formula (XLII) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(= O)NH-, -NH(C=O)О-, -О(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ in formula (XLII) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ in formula (XLII) is selected from -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ in -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or

R ³ and R ⁵ in formula (XLII), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or

R ³ in formula (XLII) is bonded to the nitrogen atom in U to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ in formula (XLII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O) ₂ R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ in -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O)2NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)2NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl) ₂ , -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl ), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p in R ⁷ is selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d in C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together form a bond; or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected of S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or

R ^8c and R ^8d are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or

R ^8a and R ^8b are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N,

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ , and

each R ⁹ in R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C _{4 alkyl, C 1 -C 4} fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C(=0) NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)- O-(C ₁ -C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH ₂ , -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O( C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ , or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl

[00119] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XLIII), which is derived from the structure of the IAP ligands described in publ. WO No. 2013/07 1 03 9, or a corresponding non-natural mimetic,

Where

W ¹ in formula (XLIII) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² in formula (XLIII) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that W ¹ and W ² are not both O or both S;

R ¹ in formula (XLIII) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl (substituted or unsubstituted C ₃ -C ₆ dicloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ in formula (XLIII) is selected from NR ^A , S, S(O) or S(O) ₂ , then X ² in formula (XLIII) represents CR ^2c R ^2d , and X ³ in formula (XLIII) represents is CR ^2a R ^2b ;

or

if X ¹ in formula (XLIII) is O, then X ² in formula (XLIII) is selected from O, ^NRA , S, S(O) or S(O) ₂ , and X ³ in formula (XLIII) is CR ^2a R ^2b ;

or

if X ¹ in formula (XLIII) represents CR ^2e R ^2f , then X ² in formula (XLIII) represents CR ^2c R ^2d , and R ^2e and R ^2c together form a bond, and X ³ in formula (XLIII) represents is CR ^2a R ^2b ;

or

X ¹ and X ² in formula (XLIII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ³ in formula (XLIII) represents CR ^2a R ^2b ;

or

X ² and X ³ in formula (XLIII) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ¹ in formula (VLII) represents CR ^2e R ^2f ;

R ^A in NR ^A is H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f in CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B in -C(=O)R ^B is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl), or -NR ^D R ^E ;

R ^D and R ^E in NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl (substituted or unsubstituted heteroaryl);

m in formula (XLIII) is equal to 0, 1 or 2;

-U- in formula (XLIII) represents -NHC(=O)-, -C(=O)NH-, -NHS(=O) ₂ -, -S(=O) ₂ NH-, -NHC(= O)NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ in formula (XLIII) represents C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ in formula (XLIII) is -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ in -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or

R ³ and R ⁵ in formula (XLIII), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or

R ³ in formula (XLIII) is bonded to the nitrogen atom in U to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ in formula (XLIII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O) ₂ R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ , substituted or unsubstituted C2-Cyheterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ in -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O) ₂ R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) , -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl) ₂ , -( _CH2 ) _p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p in R ⁷ is 0, 1 or 2;

R ^8a , R ^8b , R ^8c and R ^8d in C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together form a bond; or

R ^8a and R ^8d are defined above, and R ^8b and R ^8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected of S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

or

R ^8c and R ^8d are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

or

R ^8a and R ^8b are 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 3-7 membered spirocycle or heterospirocycle containing 1-3 heteroatoms selected from S, O and N;

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ in R ^8a , R ^8b , R ^8c and R ^8d is independently selected from halogen, -OH, -SH, (C=O), CN, C ₁ -C _{4 alkyl, C 1 -C 4} fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -G(=O)OH, -C(=O) NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)- O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH ₂ ; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ , or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl

[00120] In any of the compounds described herein, the ILM may be characterized by the structure of formula (XLIV), which is derived from the structure of the IAP ligands described in publ. WO No. 2013/07 1 03 9, or a corresponding non-natural mimetic,

Where

W ¹ in formula (XLIV) is selected from O, S, NR ^A or C(R ^8a )(R ^8b );

W ² in formula (XLIV) is selected from O, S, NR ^A or C(R ^8c )(R ^8d ); provided that W ¹ and W ² are not both O or both S;

W ³ in formula (XLIV) is selected from O, S, NR ^A or C(R ^8e )(R ^8f ), provided that the ring containing W ¹ , W ² and W ³ does not contain two adjacent oxygen atoms or atoms sulfur;

R ¹ in formula (XLIV) is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alkyl (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl) or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

if X ¹ in formula (XLIV) is O, then X ² in formula (XLIV) is selected from CR ^2c R ^2d and ^NRA , and X ³ in formula (XLIV) is CR ^2a R ^2b ;

or

if X ¹ in formula (XLIV) represents CH ₂ , then X ² in formula (XLIV) is selected from O, ^NRA , S, S(O) or S(O) ₂ , and X ³ in formula (XLIV) represents is CR ^2a R ^2b ;

or

if X ¹ in formula (XLIV) represents CR ^2e R ^2f , then X ² in formula (XLIV) represents CR ^2c R ^2d , and R ^2e and R ^2c together form a bond, and X ³ in formula (VLIV) represents is CR ^2a R ^2b ;

or

X ¹ and X ³ in formula (XLIV) are both CH ₂ , and X ² in formula (XLII) is C=0, C=C(RC) ₂ or C=NR ^C ; where each R ^C is independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), or -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl);

or

X ¹ and X ² in formula (XLIV) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ³ in formula (XLIV) represents CR ^2a R ^2b ;

or

X ² and X ³ in formula (XLIV) are independently selected from C and N and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring , a fused substituted or unsubstituted 5-10 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X ¹ in formula (VLIV) represents CR ^2e R ^2f ;

R ^A in NR ^A is selected from H, C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ^2a , R ^2b , R ^2c , R ^2d , R ^2e and R ^2f in CR ^2c R ^2d , CR ^2a R ^2b and CR ^2e R ^2f are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) and -C(=O)R ^B ;

R ^B in -C(=O)R ^B is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl -(substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl-(substituted or unsubstituted heteroaryl) or -NR ^D R ^E ;

R ^D and R ^E in NR ^D R ^E are independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₆ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₂ -C ₅ heterocycloalkyl), -C ₁ -C ₆ alkyl (substituted or unsubstituted aryl) or -C ₁ -C ₆ 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) ₂ NH-, -NHC(= O)NH-, -NH(C=O)О-, -О(C=O)NH- or -NHS(=O) ₂ NH-;

R ³ in formula (XLIV) is selected from C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl;

R ⁴ in formula (XLIV) is selected from -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ or -OR ⁵ ;

each R ⁵ in -NHR ⁵ , -N(R ⁵ ) ₂ , -N+(R ⁵ ) ₃ and -OR ⁵ is independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ heteroalkyl and -C ₁ -C ₃ alkyl-(C ₃ -C ₅ cycloalkyl);

or

R ³ and R ⁵ in formula (XLIV), together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered ring;

or

R ³ in formula (XLIII) is bonded to the nitrogen atom in U to form a substituted or unsubstituted 5-7 membered ring;

R ⁶ in formula (XLIII) is selected from -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O) ₂ R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O) ₂ NHR ⁷ , substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted heteroaryl;

each R ⁷ in -NHC(=O)R ⁷ , -C(=O)NHR ⁷ , -NHS(=O)2R ⁷ , -S(=O) ₂ NHR ⁷ ; -NHC(=O)NHR ⁷ , -NHS(=O) ₂ NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHC(=O)R ⁷ , -(C ₁ -C ₃ alkyl)-C(= O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ R ⁷ , -(C ₁ -C ₃ alkyl)-S(=O) ₂ NHR ⁷ ; -(C ₁ -C ₃ alkyl)-NHC(=O)NHR ⁷ , -(C ₁ -C ₃ alkyl)-NHS(=O) ₂ NHR ⁷ independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₆ alkyl- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted C2-C10 heterocycloalkyl), -C1-C6 alkyl- (substituted or unsubstituted aryl), -C ₁ -C ₆ alkyl- (substituted or unsubstituted heteroaryl) , -(CH2)p-CH(substituted or unsubstituted aryl)2, -( _CH2 ) _p -CH(substituted or unsubstituted heteroaryl)2, -( _CH2 ) _P -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl) or -( substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p in R ⁷ is selected from 0, 1 or 2;

R ^8a , R ^8b , R ^8c , R ^8d , R ^8e and R ^8f in C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are independently selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl and substituted or unsubstituted aryl;

or

R ^8a , R ^8d , R ^8e and R ^8f in C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above, and R ^8b and R ^8c together form a bond;

or

R ^8a , R ^8b , R ^8d and R ^8f in C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above, and R ^8c and R ^8e together form a bond;

or

R ^8a , R ^8d , R ^8e and R ^8f in C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above, and R ^8b and R ^8c together with the atoms to which they are attached, form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, substituted or unsubstituted fused 5-10 -membered aryl ring or substituted or unsubstituted fused 5-10 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from S, O and N;

or

R ^8a , R ^8b , R ^8d and R ^8f in C(R ^8a )(R ^8b ), C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above, and R ^8c and R ^8e together with the atoms to which they are attached, form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic ring or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, substituted or unsubstituted fused 5-10 -membered aryl ring or substituted or unsubstituted fused 5-10 membered heteroaryl ring containing from 1 to 3 heteroatoms selected from S, O and N;

or

R ^8c , R ^8d , R ^8e and R ^8f in C(R ^8c )(R ^8d ) and C(R ^8e )(R ^8f ) are defined above, and R ^8a and R ^8b together with the atoms to which they are attached form substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing from 1 to 3 heteroatoms selected from S, O and N;

or

R ^8a , R ^8b , R ^8e and R ^8f in C(R ^8a )(R ^8b ) and C(R ^8e )(R ^8f ) are defined above, and R ^8c and R ^8d together with the atoms to which they are attached form substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing from 1 to 3 heteroatoms selected from S, O and N;

or

R ^8a , R ^8b , R ^8c and R ^8d in C(R ^8a )(R ^8b ) and C(R ^8c )(R ^8d ) are defined above, and R ^8e and R ^8f together with the atoms to which they are attached form substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle containing from 1 to 3 heteroatoms selected from S, O and N;

or

wherein each substituted alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R ⁹ ; And

each R ⁹ in R ^8a , R ^8b , R ^8c , R ^8d , R ^8e and R ^8f is independently selected from halogen, -OH, -SH, (C=O), CN, C 1 -C ₄ alkyl, C ₁ -C 4 fluoroalkyl , C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, -NH ₂ , -NH(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl) ₂ , -C(=O)OH, -C(=0)NH ₂ , -C(=O)C ₁ -C ₃ alkyl, -S(=O) ₂ CH ₃ , -NH(C ₁ -C ₄ alkyl)-OH, -NH(C ₁ -C ₄ alkyl)-O-(C-C ₄ alkyl), -O(C ₁ -C ₄ alkyl)-NH2; -O(C ₁ -C ₄ alkyl)-NH-(C ₁ -C ₄ alkyl) and -O(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl) ₂ , or two R ⁹ together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring substituted or unsubstituted with halogen, -OH or C ₁ -C ₃ alkyl.

[00121] In any of the compounds described herein, the ILM may be characterized by a structure of formula (XLV), (XLVI) or (XLVII), which is derived from the structure of the IAP ligands described in Varnos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACS Chern. Biol., 8(4), 725-32 (2013), or its corresponding non-natural mimetic,

Where

R ² , R ³ and R ⁴ in formula (XLV) are independently selected from H or Me;

X in formula (XLV) is independently selected from O or S, and

R ¹ in formula (XLV) is selected from

[00122] In a specific embodiment, the ILM is characterized by a structure in accordance with formula (XLVIII),

where R ³ and R ⁴ in formula (XLVEI) are independently selected from H or ME;

is a 5-membered heterocycle selected from

[00123] In a specific embodiment in formula (XLVIII) represents

[00124] In a specific embodiment, the ILM is characterized by the structure and attached to the clinker group L, as shown below

[00125] In a specific embodiment, the ILM is characterized by a structure in accordance with formula (XLIX), (L) or (LI),

Where

R ³ in formula (XLIX), (L) or (LI) is independently selected from H or ME;

is a 5-membered heterocycle selected from

L in formula (XLIX), (L) or (LI) is selected from

[00126] In a specific embodiment, L in formula (XLIX), (L) or (LI) is

[00127] In a specific embodiment, the ILM is characterized by a structure in accordance with formula (LII),

[00128] In a specific embodiment, LM in accordance with the formula (LIT) is chemically connected to the linker group L in the region indicated and as shown below.

[00129] In any of the compounds described herein, the ILM may be characterized by a structure of formula (LIE) or (LIV), which is based on the structure of the IAP ligands described in Hermessy, EJ, et al., Discovery of aminopiperidine-based Smac mimelics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 19604 (2012), or a corresponding non-natural mimetic,

Where

R ¹ in formulas (LIII) and (LIV) is selected from

R ² in formulas (LIII) and (LIV) is selected from H or Me;

R ³ in formulas (LIII) and (LIV) is selected from

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

[00130] In any of the compounds described herein, the ILM may be structured and chemically coupled to a linker as shown in formula (LV) or (LVI), or a corresponding non-natural mimetic,

[00131] In any of the compounds described herein, the ILM may be characterized by a structure of formula (LVII), which is based on the structure of the IAP ligands described in Cohen, F, et al., Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6), 1723-30 (2009), or a corresponding non-natural mimetic,

Where

R ¹ in formula (LVII) is selected from

X in selected from H, fluorine, methyl or methoxy.

[00132] In a specific embodiment, the ILM is represented by the following structure:

[00133] In a specific embodiment, the ILM is selected from the group consisting of the following, and a chemical bond between the ILM and the linker group L is shown,

[00134] In any of the compounds described herein, the ILM is selected from the group consisting of the structures presented below, which are based on the structure of 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), or their corresponding non-natural mimetics,

[00135] In a specific embodiment, the ILM is selected from the group consisting of the following, and a chemical bond between the ILM and the linker group L is shown,

[00136] In any of the compounds described herein, the ILM may be characterized by a structure of formula (LVIII), which is based on the structure of 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), or its corresponding non-natural mimetic,

where X in formula (LVIII) represents one or two substituents independently selected from H, halogen or cyano.

[00137] In any of the compounds described herein, the ILM may be structured and chemically coupled to a linker group L as shown in formula (LIX) or (LX), or a corresponding non-natural mimetic,

where X in formula (LIX) and (LX) represents one or two substituents independently selected from H, halogen or cyano, and; and L in formulas (LIX) and (LX) represents a linker group as described herein.

[00138] In any of the compounds described herein, the ILM may be characterized by a structure of formula (LXI), which is based on the structure of the IAP ligands described in Ardecky, RJ, et al., Design, sysnthesis and evaluation of inhibitor of apoptosis (IAP ) antagonists that are highly selective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013), or its corresponding non-natural mimetic,

Where

in formula (LXI) is a natural or unnatural amino acid; And

R ² in formula (LXI) is selected from

[00139] In any of the compounds described herein, the ILM may be structured and chemically coupled to a linker group L as shown in formula (LXII) or (LLXIII), or a corresponding non-natural mimetic,

in formula (LXI) is a natural or unnatural amino acid; And

L in formula (LXI) represents a linker group as described herein.

[00140] In any of the compounds described herein, the ILM may be characterized by a structure selected from the group consisting of the following, which is based on the structure of the IAP ligands 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), or its corresponding non-natural mimetic,

[00141] In any of the compounds described herein, the ILM is characterized by a structure according to formula (LXIX), which is based on the structure of the IAP ligands described in Hird, AW, et al., Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem. Lett., 24(7): 1820-4 (2014), or its corresponding non-natural mimetic,

where R in the LIX formula is selected from the group consisting of

R1 in selected from H or Me;

R2 in selected from alkyl or cycloalkyl;

X in represents 1-2 substituents independently selected from halogen, hydroxy, methoxy, nitro and trifluoromethyl;

Z in represents O or NH;

No in is a mono- or fused bicyclic heteroaryl; And

--- in the formula (LEX) represents an optional double bond.

[00142] In a specific embodiment, the ILM in a compound is characterized by a chemical structure represented by

[00143] In a specific embodiment, the ILM in the compound is characterized by a chemical structure selected from the group consisting of

[00144] The term “independently” is used herein to indicate that a variable that is applied independently varies from application to application.

[00145] The term "alkyl" in its appropriate context is understood to mean a linear, branched or cyclic fully saturated hydrocarbon radical or alkyl group, preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ , alternatively C ₁ -C ₃ an alkyl group which may be optionally substituted. Examples of alkyl groups include, among others, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl methyl, ring o butyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl. In certain embodiments, the alkyl group is terminated with a halogen-containing group (At, Br, Cl, F or I). In some preferred embodiments, the compounds of the present invention can be used to covalently bind to dehalogenase enzymes. These compounds typically contain a side chain (often linked by a polyethylene glycol group) that is terminated by an alkyl group that contains a halogen (often chlorine or bromine) substituent at its distal end that provides covalent binding to the compound containing such a fragment with protein.

[00146] The term "alkenyl" refers to linear, branched or cyclic hydrocarbon radicals C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) containing at least one C=C bond.

[00147] The term "alkynyl" refers to linear, branched or cyclic hydrocarbon radicals C ₂ -C ₁₀ (preferably C ₂ -C ₆ ) containing at least one C≡C bond.

[00148] The term "alkylene", when used, refers to the group -(CH ₂ ) _n - (n is an integer, typically 0-6), which may be optionally substituted. If the group is substituted, the alkylene group is preferably substituted on one or more methylene groups with a C ₁ -C ₆ alkyl group (including a cyclopropyl group or tert-butyl group), but may also be substituted with one or more halogen-containing groups, preferably 1 -3 halogen-containing groups, or one or two hydroxyl groups, O-(C ₁ -C ₆ alkyl) groups or amino acid side chains, as further disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or an alkoxy group (or other group) that is further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) that is substituted (preferably, but not exclusively at the distal end of the polyethylene glycol chain) with an alkyl chain substituted by one halogen-containing group, preferably a chlorine-containing group. In other further embodiments, the alkylene (often methylene) group may be replaced by an amino acid side chain group, such as a natural or unnatural amino acid side chain group, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, series, threonine, valine, tryptophan or tyrosine.

[00149] By “unsubstituted” we mean substituted only with hydrogen atoms. The range of carbon atoms that includes C ₀ means that carbon is missing and is replaced by H. Thus, the range of carbon atoms that is C ₀ -C ₆ includes 1, 2, 3, 4, 5 and 6 carbon atoms, and in the case of Co, there is H instead of carbon.

[00150] The term "substituted" or "optionally substituted" will mean independently (i.e., if more than one substituent occurs, each substituent is independent with respect to the other substituent) one or more substituents (independently no more than five substituents, preferably no more than three substituents , often 1 or 2 substituents on a moiety in a compound of the present invention and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere in the molecule in the appropriate context, and by substituents is meant hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO ₂ ), halogen (preferably 1, 2 or 3 halogen, especially on an alkyl, especially on a methyl group, such as trifluoromethyl), alkyl group (preferably C ₁ -C ₁₀ , more preferably C ₁ -C ₆ ), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C ₁ -C ₆ alkyl or aryl, including phenyl and substituted phenyl), simple thioester (C ₁ -C ₆ alkyl or aryl), acyl (preferably C ₁ -C ₆ acyl), ester or thioester (preferably C ₁ -C ₆ alkyl or aryl), including an alkylene ester (so that the attachment occurs at the alkylene group rather than at the ester functionality, which is preferably substituted with a C ₁ -C ₆ alkyl or aryl group), preferably C ₁ -C ₆ alkyl or aryl, halogen (preferably F or Cl), amine (including a five- or six-membered cyclic alkyleneamine, including additionally a C ₁ -C ₆ alkylamine or a C ₁ -C ₆ dialkylamine, wherein the alkyl groups may be substituted by one or two hydroxyl groups) or an optionally substituted -N(C ₀ -C ₆₎ group alkyl)C(O)(O-C ₁ -C ₆ alkyl) (which may optionally be substituted by a polyethylene glycol chain to which is additionally attached an alkyl group containing one halogen atom, preferably a substituent representing a chlorine atom), hydrazine, amido, preferably substituted with one or two C ₁ -C ₆ alkyl groups (including a carboxamide which is optionally substituted with one or two C ₁ -C ₆ alkyl groups), an alkanol (preferably a C ₁ -C ₆ alkyl or aryl) or an alkanoic acid (preferably C ₁ -C ₆ alkyl or aryl). Substituents in accordance with the present invention may include, for example, -SiR ₁ R ₂ R ₃ groups, wherein each of R ₁ and R ₂ is described later herein, and R ₃ represents H or a C ₁ -C ₆ alkyl group, preferably R ₁ , R ₂ , R ₃ in this context represent a C ₁ -C ₃ alkyl group (including isopropyl or tert-butyl group). Each of the above groups may be directly linked to a substituted moiety, or alternatively a substituent may be linked to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted ( _CH2 ) _m- group or alternatively optionally substituted -( _OCH2 ) groups. _m -, -(OSH ₂ CH ₂ ) _m - or -(CH ₂ CH ₂ O) _m -, which may be substituted by any one or more of the substituents described above. Alkylene groups -(CH ₂ ) _m -, or -(CH ₂ ) _n - groups, or other chains, such as ethylene glycol chains, as defined above, may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogen or C ₁ -C ₆ alkyl (preferably C ₁ -C ₃ ) groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (OC ₁ -C ₆ groups), not more than three halogen-containing groups (preferably F), or an amino acid side chain as further described herein, and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane groups (often with one or two substituents representing is a C ₀ -C ₆ alkyl, and the group(s) may be additionally substituted(s)). In certain embodiments, the alkylene group (often one methylene group) is substituted with one or two optionally substituted C ₁ -C ₆ alkyl groups, preferably a C ₁ -C ₄ alkyl group, most often a methyl or O-methyl group or an amino acid side chain, as follows described in this document. In the present invention, a moiety in a molecule may optionally be substituted with no more than five substituents, preferably no more than three substituents. Most often in the present invention, moieties that are substituted are substituted with one or two substituents.

[00151] The term “substituted” (each substituent is independent of any other substituent) in the context of its use should also be understood as C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C ₁ -C ₆ ester (hydroxy ester or carbonyl ester), C ₁ -C ₆ keto, urethane -OC(O)-NR ₁ R ₂ or -N(R ₁ )-C( O)-OR ₁ , nitro, cyano and amine (including, in particular, C ₁ -C ₆ alkylene-NR ₁ R ₂ , mono- or disubstituted C ₁ -C ₆ alkyl amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains, unless otherwise indicated in the appropriate context, from 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -( _CH2 ) _m- (in this context, m and n are 1, 2, 3, 4, 5 or 6), -S-, -S(O)-, SO ₂ - or -NH-C(O)-NH-, -(CH ₂ ) _n OH, -(CH ₂ ) _n SH, - (CH ₂ ) _n COOH, C ₁ -C ₆ alkyl, -(CH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl) , -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n C(O)O-(C ₁ -C ₆ alkyl), -(CH ₂ ) _n NHC( O)-R ₁ , -(CH ₂ ) _n C(O)-NR ₁ R ₂ , -(OSH ₂ ) _n OH, -(CH ₂ O) _n COOH, C ₁ -C ₆ alkyl, -(OSH ₂ ) _n O-(C ₁ -C ₆ alkyl), -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), -(OCH ₂ ) _n NHC(O)-R ₁ , -( CH ₂ O) _n C(O)-NR ₁ R ₂ , -S(O) ₂ -R _S , -S(O)-R _S (R _S represents a C ₁ -C ₆ alkyl or a -(CH ₂ ) _m -NR ₁ R ₂ ), NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of use of the substituent. Each of R ₁ and R ₂ in the appropriate context represents an H or a C ₁ -C ₆ alkyl group (which may optionally be substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluorine). In the chemical context of the particular compound and the substituent used, the term “substituted” also includes an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group, as described later herein. Alkylene groups may also be substituted, as further disclosed herein, preferably with optionally substituted C ₁ -C ₆ alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), a group representing a side chain an amino acid as further described herein, an amido group as described above herein, or a urethane group, the OC(O)-NR ₁ R ₂ group, wherein R ₁ and R ₂ are as described hereinafter, although Numerous other groups can also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably 1 or 2 substituents. It should be noted that in cases where a substitution is required in a compound at a particular position of the molecule (mainly due to valence), but the substitution is not specified, then the substituent is interpreted or understood as H, unless the context of the substitution suggests otherwise.

[00152] The term "aryl" or "aromatic" as used herein refers to a substituted (as further described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl , anthracenyl, phenanthrenyl, etc.), and may be linked to a compound of the present invention at any available stable position on the ring(s), or otherwise as indicated by the chemical structure provided. Other examples of aryl groups in the appropriate context may include, among others, heterocyclic aromatic ring systems, "heteroaryl" groups containing one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiene , thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be optionally substituted as described above. Heteroaryl groups that may be mentioned include, but are not limited to, nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolysine, azaindolysine , purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolysine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carba zol, carbazoline, pyrimidine, phenanthroline, phenacene , oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; as well as aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadizole, 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.

[00153] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or more fused rings, at least one of which is aromatic, wherein the ring(s) is(are) substituted ) with one or more substituents. For example, the aryl group may contain substituent(s) selected from -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)(C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)O (C ₀ -C ₆ )alkyl, -(CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group is amine is optionally substituted with 1 or 2 hydroxyl groups or with no more than three halogen groups (preferably F, Cl), OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or CN groups (substitution of each of which may occur at the ortho, meta and/or para positions of the phenyl ring, preferably para), optionally substituted phenyl group (the phenyl group as such is preferably connected to a PTM group, including a ULM group, to using a linker group) and/or from at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or a CN group (in ortho, meta and/or para positions a phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole, an optionally substituted oxazole, including a methyl-substituted oxazole, an optionally substituted thiazole, including a methyl-substituted thiazole, optionally substituted isothiazole, including methyl substituted isothiazole, optionally substituted pyrrole, including methyl substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, not necessarily substituted diazole group, including including a methyldiazole group, an optionally substituted triazole group, including a methyl-substituted triazole group, an optionally substituted pyridine group, including a halo- (preferably F-) or methyl-substituted pyridine group or an oxapyridine group (wherein the pyridine group is connected to the phenyl group by an oxygen atom ), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2-, 3- or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[00154] "Carboxyl" means a --C(O)OR group wherein R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, such exemplary substituents having meanings that are identical to the definitions of the corresponding groups , defined in this document.

[00155] The term “heteroaryl” or “hetaryl” can mean, without limitation, an optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom on the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, optionally substituted azaindolysine (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, optional substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or an optionally substituted -(CH ₂ ) _m -C(O)-O-C ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3- or 4-pyridine) or group according to chemical structure:

Where

^SC represents CHR ^SS , NR ^URE or O;

R ^HET is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups (e.g. CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups);

R ^URE is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which is optionally substituted with one or two hydroxyl groups or no more than three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C is N or CR ^YC where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted by one or two hydroxyl groups or no more than three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

[00156] The terms “aralkyl” and “heteroarylalkyl” refer to groups that contain both aryl and heteroaryl, as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems as defined above.

[00157] The term “arylalkyl” as used herein refers to an aryl group, as defined above, attached to an alkyl group, as defined above. The arylalkyl group is attached to the parent moiety via an alkyl group, where the alkyl group contains from one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[00158] The term “heterocycle” refers to a cyclic group that contains at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included in the definition of heterocycle, depending on the context of their use. Exemplary heteroaryl groups are described above herein.

[00159] Illustrative heterocyclic groups include, among others, an azetidinyl, gasymidazolil, 1.4-benzodioxanil, 1.3-benzodioxolil, benzosasolil, benzotyenil, dihydromidazolil, dihydrine, dihydrofuranil, dijot. Evina, 1.3-deioxlan , 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyr rolidon , pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, those trahydrothiophene, ocean, oxetanil, oxathiolanil , tian.

[00160] Heterocyclic groups may optionally be substituted by a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido , cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic group, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O) and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of nitrogen-containing heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolysine, isoindole, indole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine , carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as heterocycles containing N-alkoxynitrogen. The term “heterocyclic group” also includes bicyclic groups in which any of the heterocyclic rings are fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[00161] The term “cycloalkyl” can mean, without limitation, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes as defined herein, for example, saturated monocyclic hydrocarbon groups containing from three to twenty carbon atoms in the ring, including without limitations cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can mean, without limitation, a monocyclic or polycyclic alkyl group and contemplates substitution with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, such exemplary substituent groups having meanings that are identical to the definitions of the corresponding groups defined in this designation.

[00162] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one carbon atom in the ring of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. “Substituted heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one carbon atom in the ring of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and wherein the group contains one or more substituents selected from the group, consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto or sulfo, such exemplary substituent groups having meanings that are identical to the definitions of the corresponding groups defined herein.

[00163] The term "hydrocarbon radical" is understood to mean a compound that contains carbon and hydrogen atoms and which may be fully saturated, partially unsaturated or aromatic, and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.

[00164] The term “independently” is used herein to indicate that a variable that is applied independently varies from application to application.

[00165] The term "lower alkyl" refers to methyl, ethyl or propyl.

[00166] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[00167] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A, and Rn may be independently covalently linked to the linker and/or a linker to which one or more PTM, ULM, ILM or ILM' groups are attached.

[00168] Illustrative MLM

[00169] In certain additional embodiments, the MLM of the bifunctional compound contains chemical moieties such as substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazoline, substituted pyrrolopyr. rolidinones and substituted isoquinolinones.

[00170] In additional embodiments, MLM provides the basic structures noted above with adjacent bis-aryl substitutions arranged in a cis or trans configuration.

[00171] In still further embodiments, the MLM comprises a portion of the structural features as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242 and NVP-CGM-097 and analogs or derivatives thereof.

[00172] In certain preferred embodiments, MLM is a derivative of a substituted imidazoline, represented by formula (A-1), or a thiazoloimidazoline, represented by formula (A-2), or spiroindolinone, represented by formula (A-3) , or pyrollidine represented by formula (A-4), or piperidinone/morpholinone represented by formula (A-5), or isoquinolinone represented by formula (A-6), or pyrollopyrimidine/imidazolopyridine represented by formula (A-7), or pyrrolopyrrolidinone/imidazolopyrrolidinone represented by formula (A-8).

where in the above formula (A-1) - formula (A-8)

X in formula (A-1) to formula (A-8) is selected from the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone and NR ^a ;

R ^a independently represents H or an alkyl group with 1-6 carbon atoms;

Y and Z in formula (A-1) to formula (A-8) independently represent carbon or nitrogen;

A, A' and A'' in formula (A-1) - formula (A-8) are independently selected from C, N, O or S, and may also represent one or two atoms forming a fused bicyclic ring or 6,5 - and a 5,5-fused aromatic bicyclic group;

R ₁ , R ₂ in formula (A-1) - formula (A-8) are independently selected from the group consisting of an aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms independently selected from sulfur or nitrogen, wherein an aryl or heteroaryl group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of

halogen, -CN, C1-C6alkyl group, C3-C6cycloalkyl, -OH, alkoxy with 1-6 carbon atoms, fluorinated alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 carbon atoms, ketone with 2-6 carbon atoms, amides with 2-6 carbon atoms and dialkylamine with 2-6 carbon atoms;

R ₃ , R ₄ in formula (A-1) - formula (A-8) are independently selected from the group consisting of H, methyl and C1-C6 alkyl;

R ₅ in formula (A-1) - formula (A-8) is selected from the group consisting of an aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of

halogen, -CN, C1-C6alkyl group, C3-C6cycloalkyl, -OH, alkoxy with 1-6 carbon atoms, fluorinated alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 carbon atoms, ketone with 2-6 carbon atoms, amides with 2-6 carbon atoms, dialkylamine with 2-6 carbon atoms, alkyl ether (C2-C6), alkyl ketone (C3-C6), morpholinyl, alkyl ester (C3-C6), alkyl cyanide (C3-C6);

R ₆ in formula (A-1) - formula (A-8) represents H or -C(=O)R ^b , where

R ^b formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1- piperidinyl, 4- ^NRc -morpholinyl, 4-Rc- ¹ -piperidinyl and 3- ^Rc -1-piperidinyl, where

R ^c in formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, fluoro-alkyl, cyanoalkyl, hydroxyl-alkyl, cycloalkyl, alkoxyalkyl, amidalkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, mono- , bis- and trisubstituted aryl or heteroaryl, CH ₂ CH ₂ R ^d and CH ₂ CH ₂ CH ₂ R ^d , where

R ^d in formula (A-1) - formula (A-8) is selected from the group consisting of alkoxy, alkyl sulfone, alkyl sulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO ₂ -alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl;

R ₇ in formula (A-1) - formula (A-8) is selected from the group consisting of H, C1-C6 alkyl, cyclic alkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or 5-substituted aryl or 6-membered heteroaryl or aryl;

R ₈ in formula (A-1) - formula (A-8) is selected from the group consisting of -R ^e -C(O)-R ^f , -R ^e -alkoxy, -R ^e -aryl, -R ^e - heteroaryl and -R ^e -C(O)-R ^f -C(O)-R ^g , where:

R ^e in formula (A-1) - formula (A-8) represents an alkylene with 1-6 carbon atoms or a bond;

R ^f in formula (A-1) - formula (A-8) represents a substituted 4-7 membered heterocycle;

R ^g in formula (A-1) - formula (A-8) is selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl and a 4-7 membered heterocycle;

R ₉ in formula (A-1) through formula (A-8) is selected from the group consisting of mono-, bis-, or tri-substitution with substituents on the fused bicyclic aromatic ring in formula (A-3), wherein the substituents are independently selected from the group, consisting of halogen, alkene, alkyne, alkyl, unsubstituted or substituted with Cl or F;

R ₁₀ in formula (A-1) - formula (A-8) is selected from the group consisting of an aryl or heteroaryl group, where the heteroaryl group may contain one or two heteroatoms such as sulfur or nitrogen, and the aryl or heteroaryl group may be monocyclic or bicyclic, the aryl or heteroaryl group can be unsubstituted or substituted with one to three substituents, including halogen, F, Cl, -CN, alkene, alkyne, C1-C6alkyl group, C1-C6cycloalkyl, -OH, alkoxy with 1 -6 carbon atoms, fluorinated alkoxy with 1-6 carbon atoms, sulfoxide with 1-6 carbon atoms, sulfone with 1-6 carbon atoms, ketone with 2-6 carbon atoms;

R ₁₁ in formula (A-1) - formula (A-8) is -C(O)-N(R ^h )(R ⁱ ), where R ^h and R ⁱ are selected from the group consisting of the following groups:

H, C1-C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heteroaryl, mono-, bis- or tri-substituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted alkylcarboxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl; Where

R ^h and R ⁱ in formula (A-1) - formula (A-8) are independently selected from the group consisting of H, and they are connected to form a ring, 4-hydroxycyclohexane; mono- and dihydroxy-substituted alkyl (C3-C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid and substituted phenyl-4-carboxylic acid;

R ₁₂ and R ₁₃ in formula (A-1) - formula (A-8) are independently selected from H, lower alkyl (C1-C6), lower alkenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl ( 4-, 5- and 6-membered ring), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl, R12 and R13 can be combined to form a 5- and 6-membered ring with substitution in the ring or without him;

R ₁₄ in formula (A-1) - formula (A-8) is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;

R ₁₅ in formula (A-1) - formula (A-8) represents CN;

R ₁₆ in formula (A-1) - formula (A-8) is selected from the group consisting of C1-6alkyl, C1-6cycloalkyl, C2-6alkenyl, C1-6alkyl or C3-6cycloalkyl with one or more hydrogen atoms replaced by fluorine , alkyl or cycloalkyl with one CH ₂ group replaced by S(=O), -S or -S(=O) ₂ , alkyl or cycloalkyl with a terminal CH ₃ group replaced by S(=O) ₂ N(alkyl)(alkyl) ), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O) ₂ (alkyl), -C(=O)2(alkyl), -O(alkyl), C1- 6alkyl or alkylcycloalkyl with a hydron replaced by a hydroxyl group, a 3-7-membered cycloalkyl or heterocycloalkyl, optionally containing a -(C=0)- group, or a 5-6-membered aryl or heteroaryl group, wherein heterocycloalkyl or heteroaryl group may contain from one to three heteroatoms independently selected from O, N or S, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be unsubstituted or substituted by one to three substituents independently selected from halogen, C1-6 alkyl groups, hydroxylated C1-6alkyl, C1-6alkyl thioether, ether, sulfone, sulfoxide, fluoroether or cyano group;

R ₁₇ in formula (A-1) - formula (A-8) is selected from the group consisting of (CH ₂ ) _n C(O)NR ^k R ^l , where R ^k and R ^l are independently selected from H, C1-6 alkyl , hydroxylated C1-6alkyl, C1-6alkoxyalkyl, C1-6alkyl with one or more hydrogen atoms replaced by fluorine, C1-6alkyl with one carbon atom replaced by S(O), S(O)(O), C1-6alkoxyalkyl with one or several hydrogen atoms replaced by fluorine, a C1-6 alkyl with a hydrogen atom replaced by a cyano group, a 5- and 6-membered aryl or heteroaryl, an alkylaryl with an alkyl group containing 1-6 carbon atoms, and an alkylheteroaryl with an alkyl group containing 1-6 carbon atoms, where the aryl or heteroaryl group may be further substituted;

R ₁₈ in formula (A-1) to formula (A-8) is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution preferably being -N(C1-4alkyl)(cycloalkyl), -N( C1-4alkyl)alkylcycloalkyl and -N(C1-4alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];

R ₁₉ in formula (A-1) to formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and such aryl or heteroaryl groups may be substituted with halogen, C1-6alkyl, C1-6cycloalkyl, CF ₃ , F, CN, alkyne, alkyl sulphate, wherein substitution with a halogen atom may involve mono-, bi- or tri-substitution;

R ₂₀ and R ₂₁ in formula (A-1) - formula (A-8) are independently selected from C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy, hydroxylated C1-6alkoxy and fluoro-substituted C1-6alkoxy, wherein R ₂₀ and R ₂₁ may additionally be joined to form a 5-, 6-, and 7-membered cyclic or heterocyclic ring, which may be further substituted;

R ₂₂ in formula (A-1) to formula (A-8) is selected from the group consisting of H, C1-balkyl, C1-6cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acyl urea containing nitrogen of a 5-membered heterocycle, wherein the 5-membered heterocycles can be additionally substituted with C1-6alkyl, alkoxy, fluoro-alkyl, CN and alkylsulfone;

R ₂₃ in formula (A-1) - formula (A-8) is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkylcycloalkyl, -NH-alkyl, -NH- alkylcycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl)-heteroaryl, wherein aryl or heteroaryl groups can be replaced by halogen, C1-6alkyl, hydroxylated C1-6alkyl, cycloalkyl, fluorine-substituted C1-6alkyl, CN, alkoxy, alkylsulfone, amide and sulfonamide;

R ₂₄ in formula (A-1) - formula (A-8) is selected from the group consisting of -CH2-(C1-6alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl, aryl and heteroaryl may be substituted with halogen, alkoxy, hydroxylated alkyl, cyanoalkyl, cycloalyl and substituted cycloalkyl;

R ₂₅ in formula (A-1) - formula (A-8) is selected from the group consisting of C1-balkyl, C1-6alkylcycloalkyl, 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 such saturated heterocycles may be substituted with C1-6alkyl, fluoro-substituted C1-balkyl, alkoxy, aryl and heteroaryl group;

R ₂₆ in formula (A-1) - formula (A-8) is selected from the group consisting of C1-6alkyl, C3-bcycloalkyl, wherein alkyl or cycloalkyl may be substituted by OH, alkoxy, fluoroalkoxy, fluoroalkyl, -NH ₂ , -NH-alkyl, NH-C(O)alkyl, -NH-S(O) ₂ -alkyl and -S(O) ₂ -alkyl;

R ₂₇ in formula (A-1) - formula (A-8) is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, where the aryl or heteroaryl groups may be substituted with C1-6alkyl, alkoxy, NH2, NH-alkyl, halogen or -CN, and the substitution may independently include mono-, bis- and tri-substitution;

R ₂₈ in formula (A-1) to formula (A-8) is selected from the group consisting of aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidinone, tetrahydropyran, N- acylpiperidine, wherein cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further substituted with -OH, alkoxy, wherein mono-, bi- or tri-substitution involves substitution with halogen, -CN, alkylsulfone and fluoro-alkyl groups; And

R _1'' in formula (A-1) to formula (A-8) is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

[00173] In certain embodiments, the heterocycles in R ^f and R ^g in Formula (A-1) through Formula (A-8) are substituted pyrrolidine, substituted piperidine, substituted piperazine.

[00174] More specifically, non-limiting examples of MLMs include the MLMs shown below, as well as “hybrid” MLM molecules that are formed by the combination of 1 or more different features shown in the molecules below.

[00175] Using the MLM of Formula A-1 to A-8, the following PROTACs can be prepared to target a specific protein for destruction, where "L" represents a connecting molecule (i.e., a linker group), and "RTM" is a ligand that binds to the target protein.

[00176] In certain embodiments, the disclosure provides a bifunctional molecule characterized by a structure selected from the group consisting of

where X, R ^a , Y, Z, A, A', A'', R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ^b , R ^c , R ^d , R ₇ , R ^e , R ^f , R ^g , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ^k , R ^l , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ and R _1'' are defined herein with respect to formulas (A-1) - (A-8).

[00177] In certain embodiments, the disclosure describes bifunctional or chimeric molecules with the structure PTM-L-MLM, wherein PTM is a target protein binding moiety linked to the MLM by L, wherein L is a linkage (i.e. missing) or chemical linker. In certain embodiments, the MLM is characterized by a structure selected from the group consisting of A-1-1, A-1-2, A-1-3 and A-1-4:

Where

R1' and R2' in formulas A-1-1 to A-1-4 (i.e. A-1-1, A-1-2, A-1-3 and A-1-4) are independently selected from a group consisting of F, Cl, Br, I, acetylene, CN, CF ₃ and NO ₂ ;

R3' is selected from the group consisting of -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ F, -OCH ₂ CH ₂ OCH ₃ and -OCH(CH ₃ ) ₂ ;

R4' in formulas A-1-1 - A-1-4 is selected from the group consisting of H, halogen, -CH ₃ , -CF ₃ , -OCH ₃ , -C(CH ₃ ) ₃ , -CH(CH ₃ ) ₂ , -cyclopropyl, -CN, -C(CH ₃ ) ₂ OH, -C(CH ₃ ) ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₂ OH, -C(CH ₃ ) ₂ CH ₂ OCH ₂ CH ₃ , -C(CH ₃ ) ₂ CN, -C(CH ₃ ) ₂ C(O)CH ₃ , -C(CH ₃ ) ₂ C(O)NHCH ₃ , -C(CH ₃ ) ₂ C(O)N(CH ₃ ) ₂ , -SCH ₃ , -SCH ₂ CH ₃ , - S(O) ₂ CH ₃ , -S(O ₂ )CH ₂ CH ₃ , -NHC(CH ₃ ) ₃ , -N(CH ₃ ) ₂ , pyrrolidinyl and 4-morpholinyl;

R5' in formulas A-1-1 to A-1-4 is selected from the group consisting of halogen, -cyclopropyl, -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , 1-pyrrolidinyl, -NH ₂ , -N(CH ₃ ) ₂ and -NHC(CH ₃ ) ₃ ; And

R6' in formulas A-1-1 to A-1-4 is selected from the structures presented below, where the point of connection with the linker is indicated as "*".

In addition to R6' as a linker attachment point, R4' can also serve as a linker attachment position. In case R4' is the junction site of a linker, the linker will be connected to the terminal atom of the R4' groups shown above.

[00178] In certain embodiments, the position of the linker compound in Formulas A-1-1 through A-1-4 is at at least one of R4' or R6', or both.

[00179] In certain embodiments, R6' in formulas A-1-1 through A-1-4 is independently selected from the group consisting of H,

and, where "*" indicates the point of attachment of the linker.

[00180] In certain embodiments, the linker in formula A-4-1 to A-4-6 is attached to at least one of R1', R2', R3', R4', R5', R6', or a combination thereof.

[00181] In certain embodiments, the disclosure describes bifunctional or chimeric molecules with the structure PTM-L-MLM, wherein PTM is a target protein binding moiety linked to the MLM by L, wherein L is a linkage (i.e. missing) or chemical linker. In certain embodiments, the MLM is characterized by a structure selected from the group consisting of A-4-1, A-4-2, A-4-3, A-4-4, A-4-5 and A-4-6:

Where

R7' in formulas A-4-1 - 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 a radical selected from the group consisting of halogen, mono- and di- or tri-halogen;

R8' in formulas A-4-1 to A-4-6 is selected from the group consisting of H, -F, -Cl, -Br, -I, -CN, _-NO2 , ethylene, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C1-6alkyl, other C1-6alkenyl and C1-6alkynyl, mono-, di- or trisubstituted;

R9' in formulas A-4-1 to A-4-6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl , alkenyl and substituted cycloalkenyl;

Z in formulas A-4-1 to A-4-6 is selected from the group consisting of H, -OSH ₃ , -OSH ₂ CH ₃ and halogen;

each of R10' and R11' in formulas A-4-1 to A-4-6 is independently selected from the group consisting of H, (CH ₂ ) _n -R', (CH ₂ ) _n -NR'R'', (CH ₂ ) _n -NR'COR'', (CH ₂ ) _n -NR'SO ₂ R'', (CH ₂ ) _n -COOH, (CH ₂ ) _n -COOR', (CH) _n -CONR'R'', (CH ₂ ) _n -OR', (CH ₂ ) _n -SR', (CH ₂ ) _n -SOR', (CH ₂ ) _n -CH(OH)-R, (CH ₂ ) _n - COR', (CH ₂ ) _n -SO ₂ R', (CH ₂ ) _n -SONR'R'', (CH ₂ ) _n -SO ₂ NR'R'', (CH ₂ CH ₂ O) _m -( CH ₂ ) _n -R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OR', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'COR'', (CH ₂ CH ₂ O) _m (CH ₂ ) _n -NR 'SO ₂ R'', (CH ₂ CH ₂ O) _m (CH ₂ ) _n -COOH, (CH ₂ CH ₂ O) _m (CH ₂ ) _n -COOR', (CH ₂ CH ₂ O)m-( CH ₂ ) _n -CONR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ R', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COR', ( CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SONR'R'', (CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ NR'R'', (CH ₂ ) _p -( CH ₂ CH ₂ O) _m -(CH ₂ ) _n R', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OH, (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -OR', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'COR'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -NR'SO ₂ R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COOH, (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COOR', (CH ₂ ) _p -( CH ₂ CH ₂ O) _m -(CH ₂ ) _n -CONR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ R', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -COR', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SONR'R'', (CH ₂ ) _p -(CH ₂ CH ₂ O) _m -(CH ₂ ) _n -SO ₂ NR'R'', aryl-(CH ₂ ) _n -COOH and heteroaryl-alkyl-CO-alkyl-NR'R''m , where alkyl may be substituted with OR', and heteroaryl-(CH ₂ ) _n -heterocycle, where the heterocycle may optionally be substituted with alkyl, hydroxyl, COOR' and COR'; where R' and R'' are selected from H, alkyl, halogen-substituted alkyl, hydroxyl, NH2, NH(alkyl), N(alkyl) ₂ , oxo, carboxy, cycloalkyl and heteroaryl;

m, n and p are independently 0-6;

R12' in formulas A-4-1 to A-4-6 is selected from the group consisting of -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl), -C( OH)-alkylalkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl) ₂ , -S(O)-(alkyl), S(O) ₂ -(alkyl), -C(O)-(cyclic amine) and -O-aryl-(alkyl), -O-aryl-(alkoxy);

R1'' in formulas A-4-1-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.

[00182] In any of the aspects or embodiments described herein, alkyl, alkoxy, or the like. may be lower alkyl or lower alkoxy.

[00183] In certain embodiments, the position of the linker compound in formulas A-4-1 through A-4-6 is at least one of Z, R8', R9', R10', R11'', R12'', or R1 ''.

[00184] The method used to develop the chimeric molecules presented in A-1-1 - A-1-4, A-4-1 - A-4-6 can be applied to MLM with formula A-2, A- 3, A-5, A-6, A-7 and A-8, where the hydrophilic region in the MLM can be connected to a linker “L”, which will be attached to “PTM”, a protein targeting ligand, to construct a PROTAC.

[00185] Exemplary MDM2 binding fragments include, but are not limited to, the following:

[00186] 1. HDM2/MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004) and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or additionally) the compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized) described below, as well as all derivatives and analogs thereof:

(derivatized, where a linker group L or a -(L-MLM) group is attached, for example, at a methoxy group or hydroxyl group);

(derivatized, where a linker group L or a -(L-MLM) group is attached, for example, at a methoxy group or hydroxyl group);

(derivatized, where the linker group L or group -(L-MLM) is attached, for example, through a methoxy group or hydroxyl group); And

[00187] 2. Trans-4-iodo-4'-boranyl-chalcone

[00188]

[00189] (derivatized, wherein the linker group L or the linker group L or the -(L-MLM) group is attached, for example, through a hydroxy group).

[00190] Illustrative CLMs

[00191] Neoimide compounds

[00192] In one aspect, the disclosure provides compounds useful for binding and/or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of chemical structures:

Where

W in formulas (a)-(f) is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

X in formulas (a)-(f) is independently selected from the group consisting of O, S and H ₂ ;

Y in formulas (a)-(f) is independently selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z in formulas (a)-(f) is independently selected from the group consisting of O and S or H ₂ except that X and Z cannot both be H ₂ ;

G and G' in formulas (a)-(f) are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optional substituted with R' and benzyl, optionally substituted with R';

Q1-Q4 in formulas (a)-(f) represent a C carbon substituted by a group independently selected from R', N or N-oxide;

A in formulas (a)-(f) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl and F;

R in formulas (a)-(f) includes, without limitation, -CONR'R'', -OR', -NR'R'', -SR', -SO ₂ R', -SO ₂ NR'R'', -CR'R''-, -CR'NR'R''-, (-CR'O) _n R'', -aryl, -heteroaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, - heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR'SO ₂ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C (=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ₂ )NR'R'', -SO ₂ NR'COR'', -NO ₂ , -CO ₂ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ₅ and -OCF ₃ ;

R' and R'' in formulas (a)-(f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R, heterocyclyl, each of which is optionally substituted;

n in formulas (a)-(f) is an integer from 1 to 10 (for example, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

in formulas (a)-(f) represents a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

R _n in formulas (a)-(f) contains 1 4 independent functional groups or atoms.

[00193] Illustrative CLMs

[00194] In any of the compounds described herein, the CLM provides a chemical structure selected from the group:

Where

W in formulas (a)-(f) is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

X in formulas (a) - (f) is independently selected from the group consisting of O, S and H ₂ ;

Y in formulas (a) - (f) is independently selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z in formulas (a)-(f) is independently selected from the group consisting of O and S or H ₂ except that X and Z cannot both be H ₂ ;

G and G' in formulas (a)-(f) are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', CH ₂ -heterocyclyl, optional substituted with R' and benzyl, optionally substituted with R';

Q1-Q4 in formulas (a)-(f) represent a C carbon substituted by a group independently selected from R', N or N-oxide;

A in formulas (a)-(f) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl and F;

R in formulas (a)-(f) includes, without limitation, -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, -CF ₃ , -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 formulas (a)-(f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R, heterocyclyl, each of which is optionally substituted;

n in formulas (a)-(f) is an integer from 1 to 10 (for example, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

in formulas (a)-(f) represents a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

Rn in formulas (a)-(f) provides 1 to 4 independent functional groups or atoms, and optionally one of them is modified so as to covalently bind to a PTM, a chemical linker group (L), a ULM, CLM (or CLM') or a combination thereof.

[00195] In certain embodiments described herein, the CLM or ULM provides a chemical structure selected from the group:

Where

W in formula (g) is independently selected from the group consisting of CH ₂ , C=O, NH and N-alkyl;

R in formula (g) is independently selected from H, methyl, or optionally substituted linear, branched, optionally substituted alkyl [eg, optionally substituted C1-C6alkyl (linear, branched, optionally substituted)];

in formula (g) represents a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

Rn in formula (g) provides 1-4 independently selected functional groups or atoms, and optionally one of them is modified so as to covalently bind to the PTM, chemical linker group (L), ULM, CLM ( or CLM') or a combination thereof.

[00196] 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) may be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, CLM or CLM' groups are attached.

[00197] In any of the aspects or embodiments described herein, Rn contains from 1 to 4 functional groups or atoms, for example, O, OH, N, C1-C6alkyl, C1-C6alkoxy, amine, amide or carboxy, and optionally one of them is modified with covalent attachment to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[00198] More specifically, non-limiting examples of CLMs include the CLMs shown below, as well as “hybrid” CLM molecules that are formed by the combination of 1 or more different features shown in the molecules below.

[00199] In any of the compounds described herein, the CLM provides a chemical structure selected from the group:

Where

W in formulas (h)-(ab) is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ in formulas (h)-(ab) independently represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

R ¹ in formulas (h)-(ab) is selected from H, CN, C1-C3-alkyl;

R ² in formulas (h)-(ab) is selected from the group consisting of H, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO;

R ³ in formulas (h)-(ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R ⁴ in formulas (h)-(ab) is selected from H, alkyl, substituted alkyl;

R ⁵ in formulas (h)-(ab) represents H or lower alkyl;

X in formulas (h)-(ab) represents C, CH or N;

R' in formulas (h)-(ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R in formulas (h)-(ab) represents H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;

in formulas (h)-(ab) represents a single or double bond; And

CLM is covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[00200] In any aspect or embodiment described herein, CLM or CLM' is covalently linked to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via an R group (such as R, R ¹ , R ² , R ³ , R ⁴ or R'), W, X or Q groups (such as Q ₁ , Q ₂ , Q ₃ , Q ₄ or Q ₅ ) from formulas (h)-(ab).

[00201] In any of the embodiments described herein, CLM or CLM' is covalently linked to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof via W, X, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R', Q ₁ , Q ₂ , Q ₃ , Q ₄ and Q ₅ from formulas (h)-(ab).

[00202] In any of the embodiments described herein, W, X, R ¹ , R ² , R ³ , R ⁴ , R', Q _{1 , Q 2 ,} Q ₃ , Q ₄ , and Q ₅ from formulas ( h)-(ab) may be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[00203] More specifically, non-limiting examples of CLMs include the CLMs shown below, as well as “hybrid” molecules or compounds that are formed by combining 1 or more features of the following compounds:

Where

W in formulas (ac)-(an) is independently selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

R ¹ in formulas (ac)-(an) is selected from the group consisting of H, CN, C1-C3 alkyl;

R ³ in formulas (ac)-(an) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R in formulas (ac)-(an) represents H;

represents a single or double bond; And

Rn in formulas (ac)-(an) provides a functional group or atom.

[00204] In any of the embodiments described herein, W, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q _{4 ,} and Rn in formulas (ac)-(an) may be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[00205] In any of the embodiments described herein, R ¹ , R ² , Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn in formulas (ac)-(an) can be independently covalently linked to the linker and /or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[00206] In any of the embodiments described herein, Q ₁ , Q ₂ , Q ₃ , Q ₄ and Rn in formulas (ac)-(an) may be independently covalently linked to a linker and/or a linker to which one or more PTM, ULM, ULM', CLM or CLM' groups are attached.

[00207] In any aspect or embodiment described herein, _Rn in formulas (ac)-(an) is modified to covalently bind to a linker group (L), PTM, ULM, a second CLM having the same chemical a structure such as CLM, CLM', a second linker, or any plurality or combination thereof.

[00208] In any aspect or embodiment described herein, the CLM is selected from:

where R' represents halogen, and R ¹ is described above in relation to formulas (h)-(ab) or (ac)-(an).

[00209] In certain cases, CLM may be imides that bind to the cereblon of the E3 ligase complex. Such imides and the point of attachment of the linker can be represented, without limitation, by the following structures:

is a halogen.

[00210] Illustrative VLMs

[00211] In certain embodiments of the compounds described herein, the ULM is a VLM and has a chemical structure selected from the group ULM-a:

Where

the dotted 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 moiety linking at least one PTM, ULM', or VLM', or CLM', or ILM', or MLM' to the other end of the linker;

each of X ¹ , X ² in formula ULM-a is independently selected from the group consisting of bond, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, OS, SO and SO ₂ ;

each of R ^Y3 , R ^Y4 in formula ULM-a is independently selected from the group consisting of H, straight or branched C _1-6 alkyl, optionally substituted with 1 or more halogen atoms, optionally substituted C _1-6 alkoxy (e.g., optionally substituted 0-3 groups R ^P );

R ^P in formula ULM-a represents 0, 1, 2 or 3 groups, each independently selected from the group consisting of H, halogen, -OH, C _1-3 alkyl, C=O;

W ³ in formula ULM-a is selected from the group consisting of optionally substituted TN(R ^1a R ^1b )X ³ , optionally substituted TN(R ^1a R ^1b ), optionally substituted T-aryl, optionally substituted T-heteroaryl, optionally substituted T -biheteroaryl, optionally substituted T-heterocycle, optionally substituted -T-biheterocycle, optionally substituted -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ -T-heterocycle;

X ³ in the formula ULM-a represents C=O, R ¹ , R ^1a , R ^1b ;

each of R ¹ , R ^1a , R ^1b is independently selected from the group consisting of an H, straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C=S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 )SO ₂ ;

T in formula ULM-a is covalently bonded to X ¹ and is selected from the group consisting of an optionally substituted alkyl, the group -(CH ₂ ) _n -, wherein each of the methylene groups is optionally substituted with one or two substituents selected from the group consisting of halogen , methyl, a linear or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, or an optionally substituted amino acid side chain;

W ⁴ in formula ULM-a represents an optionally substituted -NR1-T-aryl, an optionally substituted -NR1-T-heteroaryl group, or an optionally substituted -NR1-T-heterocycle, where -NR1 is covalently bonded to X ² and R1 is H or CH3, preferably N.

[00212] In any of the embodiments described herein, T is selected from the group consisting of an optionally substituted alkyl group, -(CH ₂ ) _n -, wherein each of the methylene groups is optionally substituted with one or two substituents selected from the group, consisting of a halogen, methyl, linear or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, or an optionally substituted amino acid side chain; and n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1.

[00213] In certain embodiments, W ⁴ in formula ULM-a is wherein each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl.

[00214] In any of the embodiments, W ⁵ in formula ULM-a is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ in the formula ULM-a is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted).

[00215] In additional embodiments, W ⁴ substituents for use in the present invention also specifically include (and without limitation to the specific compound disclosed) W ⁴ substituents that are found in certain compounds disclosed herein. Each of these W ⁴ substituents may be used in conjunction with any number of W ³ substituents also disclosed herein.

[00216] In certain additional embodiments, ULM-a is optionally substituted with 0-3 ^R3 groups on the pyrrolidine moiety. Each R ^P is independently H, halogen, -OH, C1-3 alkyl, C=O.

[00217] In any of the embodiments described herein, W ³ , W ⁴ in formula ULM-a can be independently covalently linked to a linker to which one or more PTM groups are attached,

and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[00218] In certain embodiments, the ULM is a VHL and is represented by the structure:

,

Where

W ³ in formula ULM-b is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ and R ₁₀ in formula ULM-b are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R ₉ , R ₁₀ and the carbon atom to which they are attached optionally form substituted cycloalkyl;

R ₁₁ in formula ULM-b is selected from the group consisting of optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R ₁₂ in formula ULM-b is selected from the group consisting of H or optionally substituted alkyl;

R ₁₃ in formula ULM-b is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted Each of R _14a , R _14b in formula ULM-b is independently selected from the group consisting of from H, haloalkyl or optionally substituted alkyl;

W5 in formula ULM-b is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ in formula ULM-b is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted);

R ₁₆ in formula ULM-b is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o in the ULM-b formula equals 0, 1, 2, 3 or 4;

R ₁₈ in formula ULM-b is independently selected from the group consisting of H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p in formula ULM-b is 0, 1, 2, 3 or 4, and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety binding the at least one PTM, or ULM', or both, to ULM.

[00219] In certain embodiments, R ₁₅ in formula ULM-b is where R ₁₇ represents H, halogen, 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 represents S or O.

[00220] In certain embodiments, R ₁₇ in formula ULM-b is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl.

[00221] In certain additional embodiments, R ₁₅ in formula ULM-b is selected from the group consisting of

And

[00222] In certain embodiments, R ₁₁ in formula ULM-b is selected from the group consisting of

[00223] In certain embodiments, the ULM has a chemical structure selected from the group consisting of

Where

R ₁ in formulas ULM-c, ULM-d and ULM-e is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a in formulas ULM-c, ULM-d and ULM-e is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₁₅ in formulas ULM-c, ULM-d and ULM-e is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl (each optionally substituted);

X in formulas ULM-c, ULM-d and ULM-e represents C, CH ₂ or C=O;

R ₃ in formulas ULM-c, ULM-d and ULM-e is absent or represents an optionally substituted 5- or 6-membered heteroaryl; And

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[00224] In certain embodiments, the ULM provides a group according to chemical structure:

Where

R _14a in formula ULM-f is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₉ in formula ULM-f represents H;

R ₁₀ in formula ULM-f is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R ₁₁ in the ULM-f formula is or optionally substituted heteroaryl;

p in the ULM-f formula is 0, 1, 2, 3 or 4;

each R ₁₈ in formula ULM-f independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R ₁₂ in the formula ULM-f represents H, C=O;

R ₁₃ in formula ULM-f is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl,

R ₁₅ in formula ULM-f is selected from the group consisting of H, halogen, Cl, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl;

And

wherein the dotted line in formula ULM-f indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[00225] In certain embodiments, the ULM is selected from the following structures:

where n is 0 or 1.

[00226] In certain embodiments, the ULM is selected from the following structures:

wherein the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15 and ULM-d1-ULM-d9 is optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM3), or a chemical linker moiety linking at least one PTM, or ULM', or both, to ULM-a.

[00227] In one embodiment, the phenyl ring in ULM-a1-ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15 and ULM-d1-ULM-d9 can be functionalized as an ester to make part of the prodrug.

[00228] In certain embodiments, the hydroxyl group a on the pyrrolidine ring in ULM-al -ULM-a15, ULM-b1-ULM-b12, ULM-c1-ULM-c15, and ULM-d1-ULM-d9, respectively, contains an ester linkage prodrug fragment.

[00229] In any of the aspects or embodiments described herein, each of ULM and ULM', when present, independently represents a group according to chemical structure:

R ^1' in ULM-g is an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted -(CH ₂ ) _n OH, optionally substituted -(CH ₂ ) _n SH, optionally substituted (CH ₂ ) _n -O-( a C ₁ -C ₆ )alkyl group, an optionally substituted (CH ₂ ) _n -WCOCW-(C ₀ -C ₆ )alkyl group containing a WCOCW epoxy moiety, where each W independently represents an H or a C ₁ -C ₃ alkyl group, optionally substituted -(CH ₂ ) _n COOH, optionally substituted -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ ) _n C(O)-NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n OC(O)-NR ₁ R ₂ , -(CH ₂ O) _n H, optionally substituted -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n COOH, optionally substituted -(OSH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(OCH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted -(CH ₂ CH ₂ O) _n COOH , optionally substituted -(OSH ₂ CH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted - (OCH ₂ CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ CH ₂ O) _n C(O)-NR ₁ R ₂ , optionally substituted -SO ₂ R _S , optionally substituted with S(O) _RS , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl);

each of R ₁ and R ₂ in ULM-g independently represents an H or a C ₁ -C ₆ alkyl group, which may be optionally substituted by one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

Rs in ULM-g represents a C ₁ -C ₆ alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group;

each of X and X' in ULM-g independently represents C=O, C=S, -S(O), S(O) ₂ (preferably both X and X' represent C=O);

R ^2' in ULM-g represents an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, an optionally substituted -(CH ₂ ) _n - (C= O) _u (NRi) _v (SO ₂ ) _w NR _1N R _2N , optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SCO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -(C=O) _u )NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or an optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, an optionally substituted -X ^R2' -alkyl group; an optionally substituted -X ^R2' -aryl group; an optionally substituted -X ^R2' -heteroaryl group; an optionally substituted -X ^R2' -heterocyclic group; optionally substituted;

R ^3' in ULM-g is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n -(O _)n (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -(CH ₂ ) _n -C( O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O) R _1N , optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n -C(O) _u (NRi) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ )w-heteroaryl, optionally substituted -(CH ₂ ) _n -C (O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted - NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v ( SO ₂ ) _w -heterocycle, optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ ) _n -(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -O-(CH ₂ )n-(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n -(C =O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle; -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' - heterocyclic group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -heterocyclic group, optionally substituted -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' heterocyclic group; optionally substituted;

each of R _1N and R _2N in ULM-g independently represents H, C ₁ -C ₆ alkyl, which is optionally substituted with one or two hydroxyl groups and no more than three halogen-containing groups, or optionally substituted -(CH ₂ ) _n -aryl , -(CH ₂ ) _n -heteroaryl or -(CH ₂ ) _n -heterocyclic group;

V in ULM-g is O, S or NR ₁ ;

R ₁ in ULM-g is the same as above;

each of R ¹ and R _1' in ULM-g independently represents an H or a C ₁ -C ₃ alkyl group;

each of X ^R2' and X ^R3' in ULM-g is independently optionally substituted -(CH ₂ ) _n -, -(CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans) , -(CH ₂ ) _n -CH≡CH-, -(CH ₂ CH ₂ O) _n - or C ₃ -C ₆ cycloalkyl group, where X _v represents H, halogen or C ₁ -C ₃ alkyl group, which optionally substituted;

each m in ULM-g is independently equal to 0, 1,2, 3, 4, 5, 6;

each m' in ULM-g is independently 0 or 1;

each n in ULM-g is independently equal to 0, 1,2, 3, 4, 5, 6;

each n' in ULM-g is independently 0 or 1;

each u in ULM-g is independently 0 or 1;

each v in ULM-g is independently 0 or 1;

each w in ULM-g is independently 0 or 1; And

any one or more of R ¹ , R ^2' , R ^3' , X and X' in ULM-g are optionally modified to be covalently linked to a PTM group via a linker group if PTM is not ULM', or if PTM is is ULM', then any one or more of R ^1' , R ^2' , R ^3' , X and X' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[00230] In any of the aspects or embodiments described herein, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

each of R ^1' , R ^2' and R ^3' in ULM-h is the same as above, and X represents a C=O group, C=S, -S(O) or an S(O) ₂ group , more preferably a C=O group, and

any one or more of R ^1' , R ^2' and R ^3' in ULM-h are optionally modified to bind to a linker group to which a PTM group is further covalently linked, if PTM is not ULM', or if PTM is is ULM', then any one or more of R ^1' , R ^2' , R ^3' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or

a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[00231] In any of the aspects or embodiments described herein, each of the ULM and ULM', when present, independently corresponds to the chemical structure:

Where

any one or more of R ^1' , R ^2' and R ^3' in ULM-I are optionally modified to bind to a linker group to which a PTM group is further covalently linked if PTM is not ULM', or if PTM is is ULM', then any one or more of R ¹ , R ^2' , R ^3' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or

a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[00232] In further preferred aspects of the present invention, R ^1' in ULM-g - ULM-i preferably represents a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group, whereby the compound is a prodrug form of the active compound. Exemplary preferred R ^1' groups include, for example, -(CH ₂ ) _n OH, (CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl group, -(CH ₂ ) _n COOH, -(CH ₂ 0) _n H, optionally substituted -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl) or optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), where n is 0 or 1. If R ^1' is or contains a carboxylic acid group, a hydroxyl group, or an amino group, then the hydroxyl group, carboxylic acid group, or amino group (each of which may be optionally substituted) may be further chemically modified to provide a covalent bond with a linker group to which the PTM group is linked (including the LUM'group);

[00233] X and X', when present in ULM-g and ULM-h, are preferably a C=O, C=S, -S(O) group or an S(O) ₂ group, more preferably a C=O group ;

[00234] R ^2' in ULM-g - ULM-i is preferably an optionally substituted -NR ¹ -T-aryl group, an optionally substituted -NR ¹ -T-heteroaryl group, or an optionally substituted -NR ¹ -T-heterocycle, wherein R ¹ represents H or CH ₃ , preferably H, and T represents an optionally substituted (CH ₂ ) _n group, wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, of the amino acid side chain, as further described herein, or a C ₁ -C ₃ alkyl group, preferably 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 may also be a -(CH ₂ O) _n - group, a -(OCH ₂ ) _n - group, a -(CH ₂ CH ₂ O)] _n -, group (OSH ₂ CH ₂ ) _n -, all groups of which are optionally substituted.

[00235] Preferred aryl groups for R ^2' in ULM-g - ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups wherein the phenyl or naphthyl group is optionally connected to a PTM group (including a ULM' group) via a linker groups and/or optionally substituted with halogen (preferably F or Cl), amine, monoalkyl or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C ₁ -C ₆ alkyl, preferably CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or a CN group (substitution of each of which may occur at the ortho, meta and/or para positions of the phenyl ring, preferably para), an optionally substituted phenyl group (the phenyl group as such is optionally connected to the PTM group, in including a ULM' group via a linker group), and/or wherein it is optionally substituted with at least one of F, Cl, OH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ or a CN group (in ortho -, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole, an optionally substituted oxazole, including a methyl-substituted oxazole, optionally substituted thiazole, including methyl substituted thiazole, optionally substituted isothiazole, including methyl substituted isothiazole, optionally substituted pyrrole, including methyl substituted pyrrole, optionally substituted imidazole, including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxymidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methyl-substituted triazole group, an optionally substituted pyridine group, including a halo- (preferably F) or methyl-substituted pyridine group or an oxapyridine group (wherein pyridine group is connected to the phenyl group by an oxygen atom), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2-, 3- or 4-azaindolizine), optionally substituted quinoline, optionally substituted group in according to chemical structure:

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (e.g., CF ₃ ), an optionally substituted O(C ₁ -C ₈ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups), or an optionally substituted acetylene group C≡CR _a , where R _a is H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups), or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or _{C 1i} -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which is optional substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted phenyl group, an optionally substituted heteroaryl or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran);

R ^PRO in ULM-g - ULM-i is H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group; And

each n in ULM-g - ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), or is an optionally substituted heterocycle, preferably tetradrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (each group of which, if substituted, is preferably substituted with methyl or halogen (F, Br, Cl)), each group of which may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[00236] In certain preferred aspects in ULM-g - ULM-i represents a group

where R ^PRO and n in ULM-g - ULM-i are the same as above.

[00237] Preferred heteroaryl groups for R ^2' in ULM-g - ULM-i include optionally substituted quinoline (which may be attached to a pharmacophore or substituted at any carbon atom on 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 group according to chemical structure:

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ )), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a in ULM-g - ULM-i represents an H or a C ₁ -C ₆ alkyl group (preferably a C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or C1), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups), or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted an acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl), each group of which may optionally be connected to a PTM group (including a ULM' group ) via a linker group.

[00238] Preferred heterocyclic groups for R ^2' in ULM-g - ULM-i include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, ocean or tian, each group of which may be optionally substituted, or a group according to with chemical structure:

preferably a group

Where

R ^PRO in ULM-g - ULM-i is H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group; And

each n in ULM-g - ULM-i is independently equal to 0, 1,2, 3, 4, 5 or 6 (often 0 or 1), each group of which may optionally be connected to a PTM group (including a ULM' group ) via a linker group.

[00239] Preferred R ^2' substituents in ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^2' substituents that are found in certain compounds disclosed herein (which include specific compounds that are disclosed in this description and the accompanying graphic materials). Each of these R ^2' substituents may be used in conjunction with any number of R ^3' substituents also disclosed herein.

[00240] R ^3' in ULM-g - ULM-i is preferably optionally substituted -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-heterocycle, where R ¹ represents H or a C ₁ -C ₃ alkyl group, preferably H or CH ₃ , T represents an optionally substituted -(CH ₂ ) _n group wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a C ₁ -C ₃ alkyl group or an amino acid side chain as further described herein, preferably methyl, which may be optionally substituted; and n is 0-6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be a -(CH ₂ O) _n - group, a -(OCH ₂ ) _n - group, a -(CH ₂ CH ₂ O) _n -, a group (OCH ₂ CH ₂ ) _n -, each group of which is optionally substituted.

[00241] Preferred aryl groups for R ^3' in ULM-g - ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups wherein the phenyl or naphthyl group is optionally connected to a PTM group (including a ULM' group) via a linker group and/or optionally substituted with at least one of a halogen (preferably F or Cl), an amine, a monoalkyl or dialkylamine (preferably a dimethyl amine), an amido group (preferably a -(CH ₂ ) _m -NR ₁ C(O) group R ₂ where m, R ₁ and R ₂ are the same as above), halogen (often F or Cl), OH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or S(O ) ₂ Rs (Rs represents a C ₁ -C ₆ alkyl group, optionally substituted with an aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group), each of which may be ortho-, meta-, or /or para-positions of the phenyl ring, preferably para-, or aryl (preferably phenyl), heteroaryl or heterocycle. Preferably, said phenyl substituent group is an optionally substituted phenyl group (i.e., the phenyl substituent itself is preferably substituted by at least one of F, Cl, OH, SH, COOH, CH ₃ , CF ₃ , OMe, OCF ₃ , NO ₂ , CN or a linker group to which is attached a PTM group (including a ULM' group), where the substitution occurs at the ortho, meta and/or para positions of the phenyl ring, preferably para), a naphthyl group which may be optionally substituted, including as described above, optionally substituted heteroaryl, preferably optionally substituted isoxazole, including methyl substituted isoxazole, optionally substituted oxazole, including methyl substituted oxazole, optionally substituted thiazole, including methyl substituted thiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, optionally substituted imidazole, including methylimidazole, benzylimidazole or methoxybenzylimidazole, oxymidazole or methyloximidazole, optionally substituted diazole group, including methyldiazole group, optionally substituted triazole group, including methyl-substituted triazole group, pyridine group, in including a halogen (preferably F) or methyl substituted pyridine group or oxapyridine group (where the pyridine group is connected to the phenyl group by an oxygen atom), or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, ocean or tian. Each of the aryl, heteroaryl or heterocyclic groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[00242] Preferred heteroaryl groups for R ^3' in ULM-g - ULM-i include optionally substituted quinoline (which can be attached to a pharmacophore or substituted at any carbon atom on 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 and/or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, triisopropylsilyl group, optionally substituted -(CH ₂ ) _m -OC ₁ -C ₆ alkyl group or an optionally substituted -(CH ₂ ) _m -C(O)-O-C ₁ -C ₆ alkyl group), optionally substituted pyridine (2-, 3- or 4-pyridine) or group according to the chemical structure:

or

Where

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (eg, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a where Ra is H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or C1), optionally substituted C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups), or optionally substituted -C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ )), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted an acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl). Each of these heteroaryl groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[00243] Preferred heterocyclic groups for R ^3' in ULM-g - ULM-i include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, ocean and tian, each group of which may be optionally substituted, or a group according to with chemical structure:

preferably a group

Where

R ^PRO in ULM-g - ULM-i is H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolysine, azaindo-lysine;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n in ULM-g - ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), where each of said heterocyclic groups may optionally be connected to a PTM group (including a ULM group ') via a linker group.

[00244] Preferred R ^3' substituents in ULM-g - ULM-i also specifically include (and without limitation to the specific compound disclosed) R ^3' substituents that are found in certain compounds disclosed herein (which include specific compounds that are disclosed in this description and the accompanying graphic materials). Each of these R ^3' substituents may be used in conjunction with any number of R ^2' substituents also disclosed herein.

[00245] In certain alternative preferred embodiments, R ^2' in ULM-g - ULM-i is an optionally substituted -NR ₁ -X ^R2' alkyl group, -NR ₁ -X ^R2' aryl group; optionally substituted -NR ₁ -X ^R2' -HET, optionally substituted -NR ₁ -X ^R2' -aryl-HET or optionally substituted -NR ₁ -X ^R2' -HET-aryl.

Where

R ₁ in ULM-g - ULM-i represents H or a C ₁ -C ₃ alkyl group (preferably H);

X ^R2' in ULM-g - ULM-i is optionally substituted -(CH ₂ ) _n -, -(CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans), -( CH ₂ ) _n -CH≡CH-, -(CH ₂ CH ₂ O)) _n - or C ₃ -C ₆ cycloalkyl group; And

X _v in ULM-g - ULM-i represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or no more than three halogen-containing groups;

the alkyl in ULM-g - ULM-i is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen-containing group, often Cl or Br);

the aryl in ULM-g - ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO in ULM-g - ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine , benzofuran, indole, indolizine, azaindolizine, quinoline (wherein, if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl) or group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or optionally substituted - C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₁ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran a, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolysine, azaindo-lysine;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group, and

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1).

[00246] Each of these groups may optionally be connected to a PTM group (including a ULM' group) via a liner group.

[00247] In certain alternative preferred embodiments of the present invention, R ^3' in ULM-g - ULM-i is an optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n' -(V) group _n' -R ^S3' , optionally substituted -(CH ₂ ) _n -N(Rr)(C=O) _m' -(V) _n' -R ^S3' , optionally substituted -X ^R3' -alkyl group, optional a substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -NO group, an optionally substituted -X ^R3' -aryl-NO group or an optionally substituted -X ^R3' -NO-aryl group,

Where

R ^S3' represents an optionally substituted alkyl group (C ₁ -C ₁₀ , preferably C ₁ -C ₆ alkyl), an optionally substituted aryl group or a NO group;

R _1' represents H or a C ₁ -C ₃ alkyl group (preferably H);

V represents O, S or NR _1' ;

X ^R3' represents -(CH ₂ ) _n -, -(CH ₂ CH ₂ O) _n -, -(CH ₂ ) _n -CH(X _v )=CH(X _v )- (CIS or trans), - (CH ₂ ) _n -CH≡CH- or C ₃ -C ₆ cycloalkyl group, all of which are optionally substituted;

X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups;

alkyl is an optionally substituted C ₁ -C ₁₀ alkyl (preferably C ₁ -C ₆ alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen-containing group, often Cl or Br);

aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); And

NO represents an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine , quinoline (wherein, if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl) or a group in accordance with the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or optionally substituted - C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably C1 or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

every m' in ULM-g - ULM-i is 0 or 1; And

every n' in ULM-g - ULM-i is 0 or 1;

wherein each of these compounds, preferably with alkyl, aryl or Het groups, is optionally connected to a PTM group (including a ULM' group) via a linker group.

[00248] In alternative embodiments, R ^3' in ULM-g - ULM-i is -(CH ₂ ) _n -aryl, -(CH ₂ CH ₂ O) _n -aryl, -(CH ₂ ) _n -NO, or -(CH ₂ CH ₂ O) _n -NO,

Where

said aryl in ULM-g - ULM-i is phenyl which is optionally substituted with one or two substituents, where said substituent(s) are preferably selected from -(CH ₂ ) _n OH, C ₁ -C ₆ alkyl, which itself is optionally further substituted with CN, halogen (not more than three halogen-containing groups), OH, -(CH ₂ ) _n O(C ₁ -C ₆ )alkyl, amine, mono- or di-( a C ₁ -C ₆ alkyl)amine, wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or no more than three halogen-containing groups (preferably F, Cl), or

the specified aryl group in ULM-g - ULM-i is replaced by -(CH ₂ ) _n OH, -(CH ₂ ) _n -O-(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -O-(CH ₂ ) _n -(C ₁ -C ₆ )alkyl, -(CH ₂ ) _n -C(O)(C ₀ -C ₆ )alkyl, (CH ₂ ) _n -C(O)O(C ₀ -C ₆ ) alkyl, -(CH ₂ ) _n -OC(O)(C ₀ -C ₆ )alkyl, amine, mono- or di-(C ₁ -C ₆ alkyl)amine, where the alkyl group on the amine is optionally replaced by 1 or 2 hydroxyl groups or no more than three halogen-containing groups (preferably F, Cl), CN, NO ₂ , optionally substituted -(CH ₂ ) _n -(V) _m' -CH ₂ ) _n -(V) _m' -(C ₁ - With _{a 6} )alkyl group, a group -(V) _m' -(CH ₂ CH ₂ O) _n -R ^PEG , where V represents O, S or NR _1' , R _1' represents H or C ₁ -C ₆ an alkyl group (preferably H), and R ^PEG is an H or a C ₁ -C ₆ alkyl group that is optionally substituted (including optionally substituted with a carboxyl group), or

said aryl group in ULM-g - ULM-i is optionally substituted with a heterocycle, including a heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolysine, azaindolysine (wherein, if substituted, each is preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen containing group, preferably F or Cl) or group according to chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or optionally substituted - C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^c in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i is H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

each of R ^PRQ1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

NO in ULM-g - ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C ₁ -C ₃ alkyl group, preferably a methyl group or a halogen-containing group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine or group according to the chemical structure:

S ^c in ULM-g - ULM-i represents CHR ^SS , NR ^URE or O;

R ^HET in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups (for example, CF ₃ ), an optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen-containing groups) or an optionally substituted acetylene group -C≡CR _a , where R _a is H or C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^SS in ULM-g - ULM-i is H, CN, NO ₂ , halogen (preferably F or Cl), optionally substituted with C ₁ -C ₆ alkyl (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups ), optionally substituted O-(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups) or optionally substituted - C(O)(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or no more than three halogen-containing groups);

R ^URE in ULM-g - ULM-i is H, C ₁ -C ₆ alkyl (preferably H or C ₁ -C ₃ alkyl) or -C(O)(C ₀ -C ₆ alkyl), each group of which optionally substituted with one or two hydroxyl groups or at most three halogen-containing groups, preferably fluorine, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

Y ^C in ULM-g - ULM-i is N or CR ^YC , where R ^YC is H, OH, CN, NO ₂ , halogen (preferably Cl or F), optionally substituted C ₁ -C ₆ alkyl (preferably substituted one or two hydroxyl groups or at most three halogen-containing groups (for example, CF ₃ ), optionally substituted O(C ₁ -C ₆ alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen-containing groups) or optionally substituted acetylene group -C≡CR _a , where R _a represents H or a C ₁ -C ₆ alkyl group (preferably C ₁ -C ₃ alkyl);

R ^PRO in ULM-g - ULM-i represents H, an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;

each of R ^PRO1 and R ^PRO2 in ULM-g - ULM-i independently represents an H, optionally substituted C ₁ -C ₃ alkyl group or together form a keto group;

each m' in ULM-g - ULM-i is independently 0 or 1; And

each n in ULM-g - ULM-i is independently equal to 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

wherein each of said compounds, preferably with said aryl or NET groups, is optionally connected to a PTM group (including a ULM' group) via a linker group.

[00249] In yet further embodiments, preferred compounds include those based on chemical structure:

Where

R ^1' in ULM-i represents OH or a group that is metabolized in the patient or subject to OH;

R ^2' in ULM-i is -NH-CH ₂ -aryl-NET (preferably phenyl coupled directly to a methyl-substituted thiazole);

R ^3' in ULM-i is a -CHR ^CR3' -NH-C(O)-R ^3P1 group or a -CHR ^CR3' -R ^3P2 group;

R ^CR3' in ULM-i represents a C ₁ -C ₄ alkyl group, preferably methyl, isopropyl or tert-butyl;

R ^3P1 in ULM-i is a C ₁ -C ₃ alkyl (preferably methyl), an optionally substituted oxetane group (preferably a methyl substituted group (CH ₂ ) _n OCH ₃ where n is 1 or 2 (preferably 2), or a

(the ethyl ether group is preferably substituted on the phenyl moiety in the meta position), a morpholine group (connected to a carbonyl at the 2 or 3 position;

R ^3P2 in ULM-i represents the group

aryl in ULM-i is phenyl;

NO in ULM-i is an optionally substituted thiazole or isothiazole; And

R ^HET in ULM-i represents H or a halogen containing group (preferably H);

or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of these compounds is optionally connected to a PTM group (including a ULM' group) via a linker group.

[00250] In certain aspects, the bifunctional compounds contain an E3 ubiquitin ligase binding moiety (ULM), wherein ULM is a group according to the chemical structure:

Where

each of R ₅ and R ₆ in ULM-j independently represents OH, SH or optionally substituted alkyl, or R ₅ , K ₆ and the carbon atom to which they are attached form a carbonyl;

R ₇ in ULM-j is H or optionally substituted alkyl;

E in ULM-j represents a bond, C=O or C=S;

G in ULM-j represents a bond, optionally substituted alkyl, -COOH or C=J;

J in ULM-j represents O or NR ₈ ;

R ₈ in ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

M in ULM-j represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic group, or

R ₉ and R ₁₀ in ULM-j are each independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R ₁₁ in ULM-j is an optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R ₁₂ in ULM-j represents H or optionally substituted alkyl;

R ₁₃ in ULM-j is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,

each R ₁₄ in ULM-j independently represents H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

R ₁₅ in ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;

each R ₁₆ in ULM-j independently represents halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN or optionally substituted haloalkoxy;

each R ₂₅ in ULM-j independently represents H or optionally substituted alkyl; or both R25 groups can be taken together to form an oxo or optionally substituted cycloalkyl group;

R ₂₃ in ULM-j is H or OH;

Z ₁ , Z ₂ , Z ₃ and Z ₄ in ULM-j are independently C or N; And

o in ULM-j is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[00251] In certain embodiments, where G in ULM-j is C=J, J is O, _R7 is H, each _R14 is H, and o is 0.

[00252] In certain embodiments, where G in ULM-j is C=J, J is O, R7 is H, each _R14 is H, _R15 is optionally substituted heteroaryl, and O is 0. In other cases, E represents C=O, and M represents

[00253] In certain embodiments, where E in ULM-j is C=O, R ₁₁ is an optionally substituted heterocyclic group, or and M represents

[00254] In certain embodiments, where E in ULM-j is C=O, M is and R ₁₁ represents each R ₁₈ independently represents halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy; and p equals 0, 1, 2, 3 or 4.

[00255] In certain embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

G in ULM-k represents C=J, J represents O;

R ₇ in ULM-k is H;

each R ₁₄ in ULM-k represents H;

o in ULM-k is 0;

R ₁₅ in ULM-k represents

R ₁₇ in ULM-k is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[00256] In other cases, R ₁₇ in ULM-k is alkyl (eg, methyl) or cycloalkyl (eg, cyclopropyl).

[00257] In other embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

G in ULM-k represents C=J, J represents O;

R ₇ in ULM-k is H;

each R ₁₄ in ULM-k represents H;

o in ULM-k is 0; And

R ₁₅ in ULM-k is selected from the group consisting of:

where R ₃₀ in ULM-k represents H or optionally substituted alkyl.

[00258] In other embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

E in ULM-k represents C=O;

The M in ULM-k represents

R ₁₁ in ULM-k is selected from the group consisting of:

[00259] In yet other embodiments, the compound has the chemical structure:

where E in ULM-k represents C=O;

R ₁₁ in ULM-k represents

The M in ULM-k represents

q in ULM-k is 1 or 2;

R ₂₀ in ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

R ₂₁ in ULM-k represents H or optionally substituted alkyl; And

R ₂₂ in ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[00260] In any embodiment described herein, R ₁₁ in ULM-j or ULM-k is selected from the group consisting of:

[00261] In certain embodiments, R ₁₁ in ULM-j or ULM-k is selected from the group consisting of:

[00262] In certain embodiments, the ULM (or ULM' when present) is a group according to the chemical structure:

Where

X in ULM-1 represents O or S;

Y in ULM-1 is H, methyl or ethyl;

R ₁₇ in ULM-1 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

M in ULM-1 is optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ in _ULM-1 is H;

R ₁₀ in ULM-1 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;

R ₁₁ in ULM-1 is an optionally substituted heteroaromatic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or

R ₁₂ in ULM-1 represents H or optionally substituted alkyl; And

R ₁₃ in ULM-1 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

[00263] In some embodiments, each of ULM and ULM', when present, independently represents a group according to chemical structure:

Where

Y in ULM-m is H, methyl or ethyl;

R ₉ in ULM-m is H;

R ₁₀ is isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl;

R ₁₁ in ULM-m represents an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isooxazole, an optionally substituted heterocycle.

[00264] In other preferred embodiments of the present invention, each of ULM and ULM', when present, is independently a group according to chemical structure:

Where

R ₁₇ in ULM-n is methyl, ethyl or cyclopropyl; And

R ₉ , R ₁₀ and R ₁₁ in ULM-n are defined above. In other cases, R ₉ represents H; And

R ₁₀ in ULM-n is H, alkyl or cycloalkyl (preferably isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[00265] In any of the aspects or embodiments described herein, ULM (or ULM' when present) as described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any of the aspects or embodiments described herein, the ULM (or ULM' when present) as described herein may be linked to the PTM directly via a bond or chemical linker.

[00266] In certain aspects of the present invention, the ULM fragment is selected from the group consisting of

And

wherein the VLM may be linked to the PTM by a linker as described herein at any suitable position, including, for example, an aryl, heteroaryl, phenyl, or phenyl indole group, optionally by any suitable functional group, such as an amine, a complex ether, ether, alkyl or alkoxy.

Illustrative Linkers

[00267] In certain embodiments, the compounds described herein include one or more PTMs chemically coupled to or linked to one or more ULMs (e.g., at least one of CLM, VLM, MLM, ILM, or a combination thereof) through chemical linker (L). In certain embodiments, a linker group L is a group containing one or more covalently linked structural units (for example, -A ^L ₁ ...(A ^L ) _q - or -(A ^L ) _q -), where A ^L ₁ is a group , associated with RTM, and (A ^L ) _q represents the group associated with ULM.

[00268] In certain embodiments, the linker group L is -(A ^L ) _q -:

(A ^L ) _q represents a group that is connected to at least one of ULM (such as VLM, VLM', CLM, CLM', ILM, ILM', MLM and/or MLM'), RTM (such as RTM and RTM') or a combination thereof; And

q in the linker is an integer that is greater than or equal to 1;

each A ^L is independently selected from the group consisting of a link, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡С, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN) , NR ^L3 C(=CNO ₂ )NR ^L4 , C _3-11 cycloalkyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , C _5-13 spirocycloalkyl, optionally substituted with 0-9 groups ^RL1 and/or R ^L2 , C _3-11 heterocyclyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , C _5-13 spiroheterocycloalkyl, optionally substituted with 0-8 groups ^RL1 and/or ^RL2 , aryl, optionally substituted with 0-6 groups R ^L1 and/or R ^L2 , heteroaryl, optionally substituted with 0-6 groups of R ^L1 and/or R ^L2 , where each of R ^L1 or R ^L2 is independently optionally linked to other groups to form a cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0 -4 groups R ^L5 ; And

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _1-8 alkyl), C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OS _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N(C _1-8 cycloalkyl)(C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P(O)(OS _1-8 alkyl)(C _1-8 alkyl), P(O)(OS _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH=CH(C _1-8 alkyl), C(C _1-8 alkyl)=CH(C _1-8 alkyl ), C(C _1-8 alkyl)=C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , SOS _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl) ₂ , CONHC _1-8 alkyl, CON(C _1-8 alkyl) ₂ , N(C _1-8 alkyl)CONH(C _1-8 alkyl), N (C _1-8 alkyl)CON(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH (C _1-8 alkyl), N(C _1-8 alkyl)SO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH(C _1-8 alkyl), NHSO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

[00269] In certain embodiments, q in the linker is an integer that is greater than or equal to 0. In certain embodiments, q is an integer that is greater than or equal to 1.

[00270] For example, in certain embodiments, if the q in the linker is greater than 2, (A ^L ) _q is a group that is connected to the ULM, and A ^L ₁ and (A ^L ) _q are connected through linker structural units (L) .

[00271] For example, in certain embodiments, if q in

linker is 2, (A ^L ) _q represents the group that is connected to A ^L ₁ and to ULM.

[00272] For example, in certain embodiments, if q in the linker is 1, the structure of the linker group L is -A ^L ₁ -, and A ^L ₁ is a group that is connected to a ULM moiety and a PTM moiety.

[00273] In certain embodiments, the linker (L) includes a group represented by a general structure selected from the group consisting of

-NR(CH ₂ ) _n -(lower alkyl)-, -NR(CH ₂ ) _n -(lower alkoxy)-, -NR(CH ₂ ) _n -(lower alkoxy)-OSH ₂ -, -NR(CH ₂ ) _n -(lower alkoxy)-(lower alkyl)-OSH ₂ -, -NR(CH ₂ ) _n -(cycloalkyl)-(lower alkyl)-OSH ₂ -, -NR(CH ₂ ) _n -(heterocycloalkyl)- , NR(CH ₂ CH ₂ O) _n -(lower alkyl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(heterocycloalkyl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O _n -(heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O-( heteroaryl)-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(cycloalkyl)-O-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl)- NH-aryl-O-CH ₂ -, -NR(CH ₂ CH ₂ O) _n -(lower alkyl)-O-aryl-CH ₂ , -NR(CH ₂ CH ₂ O) _n- cycloalkyl-O-aryl- , -NR(CH ₂ CH ₂ O) _n -cycloalkyl-O-(heteroaryl)-, -NR(CH ₂ CH ₂ ) _n -(cycloalkyl)-O-(heterocycle)-CH ₂ , -NR(CH ₂ CH ₂ ) _n -(heterocycle)-(heterocycle) _-CH2 , -N(R1R2)-(heterocycle) _-CH2 ; where

n in the linker can be 0-10;

R in the linker may be H, lower alkyl;

R1 and R2 in the linker can form a ring with the connecting N.

[00274] In certain embodiments, the linker (L) includes a group represented by a general structure selected from the group consisting of

-N(R)-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -OCH ₂ - ,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-,

-O-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-N(R)-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -O-;

-(CH2) _m -O(CH2) _n -O(CH2) _o -O(CH2) _p -O(CH2) _q -O(CH2) _r -OCH2-;

Where

m, n, o, p, q and r in the linker are independently equal to 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19 or 20;

if the number is zero, then there is no N-O or O-O bond;

R in the linker is H, methyl and ethyl;

X in the linker represents H and F;

where m in the linker can be 2, 3, 4, 5;

where each of n and m in the linker can independently be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[00275] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

And where each type is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[00276] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

, where each of m, n, o, p, q or r is independently equal to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19 or 20.

[00277] In any aspect or embodiment described herein, L is selected from the group consisting of

[00278] In additional embodiments, the linker (L) provides a structure selected, without limitation, from the structures shown below, where the dotted line indicates the point of attachment to the PTM or ULM moieties.

Where

each of W ^L1 and W ^L2 is independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with R ^Q , with each R ^Q independently representing H, halogen, OH, CN, CF ₃ , C ₁ -C ₆ alkyl (linear, branched, optionally substituted), C ₁ -C ₆ alkoxy (linear, branched, optionally substituted), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 4-8 membered ring system , containing 0-4 heteroatoms;

each Y ^L1 independently represents a bond, C ₁ -C ₆ alkyl (straight, branched, optionally substituted), and optionally one or more C atoms are replaced by O; or C ₁ -C ₆ alkoxy (linear, branched, optionally substituted); And

n is 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[00279] In additional embodiments, the linker (L) provides a structure selected, without limitation, from the structures shown below, wherein the dotted line indicates the point of attachment to the PTM or ULM moieties.

Where

each of W ^L1 and W ^L2 is independently aryl, heteroaryl, cyclic group, heterocyclic group, C _1-6 alkyl, bicyclic group, biaryl, biheteroaryl or biheterocyclic group, each optionally substituted with R ^Q , with each R ^Q independently represents H, halogen, OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (linear, branched, optionally substituted), C ₁ -C ₆ alkoxy (linear, branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 R ^Q groups taken together with an atom , to which they are attached, form a 4-8-membered ring system containing 0-4 heteroatoms;

each Y ^L1 independently represents a bond, NR ^YL1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, SO ₂ , C ₁ -C ₆ alkyl (linear, branched, optionally substituted) , and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (linear, branched, optionally substituted);

^QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 ^RQ , wherein each ^RQ is independently H, _C1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

each of R ^YL1 , R ^YL2 independently represents H, OH, C _1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or R ¹ , R ² together with an atom, k to which they are attached form a 3-8-membered ring system containing 0-2 heteroatoms);

n is 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[00280] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol containing from 1 to about 100 ethylene glycol units, from about 1 to about 50 ethylene glycol units, from 1 to about 25 ethylene glycol units, from about 1 to 10 ethylene glycol units units, from 1 to about 8 ethylene glycol units and from 1 to 6 ethylene glycol units, from 2 to 4 ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[00281] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group with a size ranging from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units.

[00282] In another embodiment, the present invention is directed to a compound that provides a PTM group described above that binds to a target protein or polypeptide (eg, estrogen receptor) that is ubiquitinated by a ubiquitin ligase and directly chemically linked to the ULM group or via a linker moiety L, or alternatively PTM is a ULM' group, which is also a ubiquitin ligase binding moiety, which may be identical or different from the ULM group described above, and is directly connected to the ULM group directly or through a linker moiety; and wherein L represents a linker moiety as described above, which may or may not be present, that chemically (covalently) links ULM to PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

[00283] In certain embodiments, the linker group L is a group containing one or more covalently linked structural units independently selected from the group consisting of

X is selected from the group consisting of O, N, S, S(O) and SO ₂ ; n is an integer from 1 to 5; R ^L1 represents hydrogen or alkyl, is a mono- or bicyclic aryl or heteroaryl, optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; is a mono- or bicyclic cycloalkyl or heterocycloalkyl, optionally substituted with 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring moiety may be optionally substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy and cyano. In one embodiment, the linker group L contains no more than 10 covalently linked structural units described above.

[00284] Although the ULM group and the PTM group can be covalently linked to the linker group by any group that is suitable and stable relative to the chemical nature of the linker, in preferred aspects of the present invention the linker is independently covalently linked to the ULM group and the PTM group, preferably through an amide, ester , thioester groups, keto group, carbamate group (urethane group), carbon atom or ester group, each group of which may be included anywhere on the ULM group and PTM group to ensure maximum binding of the ULM group to the ubiquitin ligase and the PTM group to the target protein, subject to destruction. (It should be noted that in certain aspects, if the PTM group is a ULM group, the target protein to be degraded may itself be a ubiquitin ligase). In certain preferred aspects, the linker may be connected to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group on ULM and/or PTM groups.

Illustrative RTMs

[00285] In preferred aspects of the present invention, the PTM group is a group that binds to target proteins. PTM group targets are numerous in nature and are selected from proteins that are expressed in a cell such that at least a portion of the sequences occur in the cell and can bind to the PTM group. The term "protein" includes oligopeptides and polypeptide sequences of sufficient length so that they can bind to the PTM group in accordance with the present invention. Any protein in a eukaryotic system or microbial system, including a virus, bacteria or fungi, as described later herein, are targets for ubiquitination mediated by the compounds of the present invention. Preferably, the target protein is a eukaryotic protein.

[00286] PTM groups of the present invention include, for example, any moiety that specifically binds to a protein (binds to a target protein), and includes the following non-limiting examples of small molecule protein-targeting moieties: Hsp90 inhibitors, selective estrogen receptor modulators, inhibitors kinases, HDM2 and MDM2 inhibitors, compounds targeting human bromodomain BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, compounds targeting nuclear hormone receptors, immunosuppressive compounds and compounds targeting the aromatic hydrocarbon receptor (AHR), among numerous others. The compositions described below illustrate some of the low molecular weight moieties that bind the target protein. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of such compositions, as well as other small molecules that can target the protein of interest. Such binding moieties are linked to the ubiquitin ligase binding moiety, preferably by linker to place the target protein (to which the protein targeting moiety is bound) in close proximity to the ubiquitin ligase for ubiquitination and degradation.

[00287] Any protein that can bind to a protein targeting moiety or PTM group and can be exposed to or degraded by a ubiquitin ligase is a target protein in accordance with the present invention. In general, target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins related to general cellular function, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, regulatory enzyme activity, signal transporter activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, involved in cell motility, membrane synthesis, cellular communication, regulation of biological processes, development, cellular differentiation, response to stimulus, proteins associated with cell behavior, proteins associated with cell adhesion, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear-cytoplasmic transport, ion transporter activity, transport channel activity, transport activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Proteins of interest may include proteins from eukaryotes and prokaryotes, including humans as targets for drug therapy, other animals, including domestic animals, microorganisms to identify targets for antibiotics and other antimicrobials, and plants and even viruses, among numerous others .

[00288] The present invention can be used to treat a variety of disease states and/or conditions, including any disease state and/or condition in which proteins are dysregulated and in which a patient would benefit from the destruction and/or inhibition of proteins.

[00289] In a further aspect, the disclosure provides therapeutic compositions comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient and optionally an additional biologically active agent. Therapeutic compositions modulate protein degradation and/or inhibition in a patient or subject, for example, an animal such as a human, and can be used to treat or alleviate disease states or conditions that are modulated by protein degradation/inhibition. In certain embodiments, the therapeutic compositions described herein can be used to promote the destruction of proteins of interest to treat or alleviate a disease, such as cancer. In certain further embodiments, the disease is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof.

[00290] In alternative aspects, the present invention provides a method of treating a disease state or alleviating the symptoms of a disease or condition in a subject in need thereof by disrupting a protein or polypeptide by which the disease state or condition is modulated, comprising administering to said patient or subject an effective amount , for example, a therapeutically effective amount of at least one compound described herein above, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally an additional biologically active agent, wherein the composition is effective in treating or alleviating a disease or disorder or their symptom in the subject. The method in accordance with the present invention can be used to treat a wide variety of disease states or conditions, including cancer, by administering an effective amount of at least one compound described herein. The disease state or condition may be a disease caused by a microbial organism or other exogenous organism, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease condition that is caused by overexpression of a protein, resulting in a disease state and/or condition.

[00291] In another aspect, the disclosure provides methods for identifying the effects of disruption of proteins of interest in a biological system using compounds of the present invention.

[00292] The term “target protein” is used herein to describe a protein or polypeptide that is a target for binding to a compound of the present invention and degradation by a ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of such compositions, as well as other small molecules that can target the protein of interest. These linking moieties are linked to at least one ULM group (e.g., VHL, CLM, ILM, and/or MLM) by at least one L linker group.

[00293] Target proteins that can be bound to the protein targeting moiety and degraded by the ligase to which the ubiquitin ligase binding moiety is bound include any protein or peptide, including fragments thereof, analogs thereof and/or homologues thereof . Target proteins include proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport and signal transduction. More specifically, a number of drug targets for human therapeutics are protein targets that a protein targeting moiety can bind to and incorporate into compounds of the present invention. These include proteins that can be used to restore function in numerous polygenic diseases, including, for example, B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA- reductase, phosphodiesterase type PDE V, phosphodiesterase type 4 PDE IV, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptors, dopamine receptors, G-proteins, those. Gq, histamine receptors, 5-lipoxygenase, tryptase, which is a serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosome GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza virus neuraminidase , hepatitis B reverse transcriptase, sodium channel, multidrug resistance protein (MDR), P-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, p56 lck tyrosine kinase, CD4, CD5, IL-2 receptor, receptor, IL-1 TNF -alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, nevokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, RNA helicase HCV NS3, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitors, angiotensin-11, glycine receptor, norepinephrine reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptor (ER), androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferase, TrkA receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Additional target proteins include, for example, ecdysone 20 monooxidase, ER, GABA ligand-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, cell calcium release channel, and chloride channels. Still other additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvyl shikimate phosphate synthase.

[00294] These various protein targets can be used in screens to identify fragments of a compound that bind to the protein, and by incorporating the fragment into compounds of the present invention, the level of activity of the protein can be altered to achieve the ultimate therapeutic outcome.

[00295] The term “protein targeting moiety,” or PTM, is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and places the protein or polypeptide in close proximity to a ubiquitin ligase such such that protein or polypeptide degradation can occur via ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include selective estrogen receptor modulators, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human bromodomain-containing BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds and compounds targeting aromatic hydrocarbon receptor (AHR), among numerous others. The compositions described below illustrate some of the small molecular target proteins.

[00296] Exemplary protein-targeting moieties in accordance with the present invention include haloalkanghalogenase inhibitors, selective estrogen receptor modulators, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human bromodomain-containing BET proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, inhibitors angiogenesis, immunosuppressive compounds and compounds targeting the aromatic hydrocarbon receptor (AHR).

[00297] The compositions described herein illustrate some of these types of small molecular moieties that bind a target protein. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of such compositions, as well as other small molecules that can target the protein of interest. The sources cited below in this document are incorporated herein by reference in their entirety.

[00298] In any embodiment or aspect described herein, a PTM may be represented by the formula PTM-I:

Where

X _RTM represents O or C=O;

each of X _PTM1 and X _PTM2 is independently selected from N or CH;

R _PTM1 is independently selected from OH, O(CO)R _PTM , lower O-alkyl, where R _PTM represents an alkyl or aryl group in an ester;

each of at least one R _PTM2 is independently selected from H, OH, halogen, CN, CF ₃ , SO ₂ -alkyl, lower O-alkyl;

each of the at least one R _PTM3 is independently selected from H, halogen;

ULM is an E3 ligase binding fragment described herein; And

L represents a bond or linker moiety as described herein.

[00299] In any embodiment or aspect described herein, a PTM may be represented by the formula PTM-I:

Where

X _RTM represents O or C=O;

each of X _PTM1 and X _PTM2 is independently selected from N or CH;

R _PTM1 is independently selected from OH, O(CO)R _PTM , lower O-alkyl, where R _PTM represents an alkyl or aryl group in an ester;

each R _PTM2 is independently selected from H, OH, halogen, CN, CF ₃ , SO ₂ -alkyl, lower O-alkyl;

each R _PTM3 is independently selected from H, halogen;

ULM is an E3 ligase binding fragment described herein;

L represents a bond or linker moiety as described herein;

PTM-I contains at least one _PTM2 R, at least one _PTM3 R, or a combination thereof on appropriate rings.

[00300] In any embodiment or aspect described herein, PTM-I comprises at least one of: two _PTM2 R's, two _PTM3 R's, or combinations thereof.

[00301] In any embodiment or aspect described herein, the PTM may be represented by the formula PTM-II:

Where

X _RTM represents O or C=O;

each of X _PTM1 and X _PTM2 is independently selected from N or CH;

R _PTM1 is independently selected from OH, O(CO)R _PTM , lower O-alkyl, where R _PTM represents an alkyl or aryl group in an ester;

R _PTM2 and R _PTM4 are independently selected from H, OH, halogen, CN, CF ₃ , 80 g-alkyl, lower O-alkyl;

R _PTM3 and R _PTM5 are independently selected from H, halogen;

ULM is an E3 ligase binding fragment described herein; And

L represents a bond or linker moiety as described herein.

[00302] In some embodiments, the O(CO)R _PTM functions as a prodrug for the corresponding phenol of formula PTM-I or PTM-II.

[00303] In any embodiment or aspect described herein, the lower O-alkyl in PTM-I or PTM-II is an alkyl chain having 1 to 3 carbon atoms.

Therapeutic compositions

[00304] Pharmaceutical compositions containing combinations of an effective amount of at least one bifunctional compound described herein and one or more of the compounds described later herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive, or excipients constitute a further aspect of the present invention.

[00305] Included in the present invention, where applicable, are compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. Acids that are used to prepare pharmaceutically acceptable acid addition salts of the above basic compounds useful in this aspect are acids that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as, among others, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salt.

[00306] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of the compounds or derivatives of the present invention. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the present invention that are acidic in nature are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble addition salts amine, such as N-methylglucamine (meglumine) and lower alkanolammonium, as well as other basic salts of pharmaceutically acceptable organic amines.

[00307] The compounds described herein in accordance with the present invention can be administered in a single dose or in divided doses by the oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous infusion) to multiple oral administrations per day (e.g., Q.I.D.) and may include, among other routes of administration, oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer ), buccal, sublingual and suppository administration. Enteric-coated oral tablets can also be used to increase the bioavailability of compounds via the oral route. The most effective dosage form will depend on the pharmacokinetic characteristics of the particular agent chosen, as well as the severity of the patient's disease. Administration of the compounds of the present invention in the form of sprays, mists or aerosols for intranasal, intratracheal or inhalation administration may also be used. Accordingly, the present invention is also directed to pharmaceutical compositions containing an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. The compounds of the present invention may be administered in immediate release, timed release, or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form can also be used to control or slow the release of the compound at the injection site.

[00308] The compositions described herein can be formulated in conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered as controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, block copolymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

[00309] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally or intravenously.

[00310] Sterile injectable forms of the compositions described herein may be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent suitable for parenteral administration, for example, a solution in 1,3-butanediol. Acceptable carrier media and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are traditionally used as a solvent or suspending medium. For this purpose, any light, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a diluent or dispersant which is a long chain alcohol such as that specified in the Swiss Pharmacopoeia or a similar alcohol.

[00311] The pharmaceutical compositions described herein can be administered orally in any dosage form acceptable for oral administration, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For oral tablets, conventional carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweeteners, flavorings, or colors may also be added if desired.

[00312] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00313] The pharmaceutical compositions described herein can also be administered topically. Suitable topical formulations are readily available for each of these areas or organs. Topical application to the lower intestine can be achieved using a rectal suppository formulation (see above) or a suitable douche formulation. Transdermal patches that are acceptable for topical use may also be used.

[00314] For topical applications, pharmaceutical compositions can be formulated in the form of a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, a propylene glycol compound, polyoxyethylene, polyoxypropylene, emulsified wax and water. In certain preferred aspects of the present invention, the compounds can be coated on a stent that is surgically implanted in a patient to prevent or reduce the likelihood of occlusion of the stent in the patient.

[00315] Alternatively, the pharmaceutical compositions may be formulated in the form of a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00316] For ophthalmic use, the pharmaceutical compositions can be formulated as fine suspensions in isotonic, sterile, pH-adjusted saline, or preferably as solutions in isotonic, sterile, pH-adjusted saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutical compositions can be formulated in the form of an ointment, such as with Vaseline.

[00317] The pharmaceutical compositions described herein can also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. .

[00318] The amount of compound in the pharmaceutical composition described herein that can be combined with carrier materials to form a single dosage form will vary depending on the organism and disease being treated and the particular route of administration. Preferably, the compositions will be formulated to contain from about 0.05 milligrams to about 750 milligrams or more, more preferably from about 1 milligram to about 600 milligrams, and even more preferably from about 10 milligrams to about 500 milligrams of the active ingredient alone or in combination with at least one other compound according to the present invention.

[00319] It should also be understood that the specific dosage regimen and treatment regimen for any particular patient will depend on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate excretion, drug combinations and the judgment of the treating physician, as well as the severity of the particular disease or condition being treated.

[00320] A patient or subject in need of therapy using compounds in accordance with the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound in accordance with the present invention, including pharmaceutically acceptable salts, solvates or polymorphs, optionally in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known therapeutic agents as defined hereinafter.

[00321] These compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, including transdermally, in the form of a liquid, cream, gel or solid or aerosol form.

[00322] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication without causing serious toxic effects to the patient receiving treatment. The preferred dose of the active compound for all conditions listed herein is in the range from about 10 ng/kg to 300 mg/kg, preferably from 0.1 to 100 mg/kg per day, in general from 0.5 to about 25 mg per day. kilogram of recipient/patient body weight per day. A typical dose for topical application will be in the range of 0.01 to 5% w/w in a suitable vehicle.

[00323] The compound is conveniently administered in any suitable unit dosage form, including, but not limited to, a dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of approximately 25-250 mg is often appropriate.

[00324] The active ingredient is preferably administered to achieve maximum plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous media, or by administration of the active ingredient as a bolus. Oral administration is also suitable to achieve effective plasma concentrations of the active agent.

[00325] The concentration of active compound in a drug formulation will depend on the rates of absorption, distribution, inactivation and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage levels will also vary depending on the severity of the condition being alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time in accordance with individual need and the professional judgment of the specialist administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are illustrative only and are not intended to limitations on the scope or practical application of the claimed composition. The active ingredient may be administered at one time or may be divided into several smaller doses to be administered at various time intervals.

[00326] Compositions for oral administration will generally include an inert diluent or edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or a prodrug derivative thereof can be combined with excipients and administered in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or auxiliary materials can be included as part of the composition.

[00327] Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of similar origin: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint flavor, methyl salicylate, or orange flavor. If the unit dosage form is a capsule, it may contain, in addition to the above type of material, a liquid carrier such as a fatty oil. In addition, unit dosage forms may contain various other materials that alter the physical form of the dosage form, such as coatings of sugar, shellac, or enteric agents.

[00328] The active compound or a pharmaceutically acceptable salt thereof may be administered as a component of a tincture, suspension, syrup, cachet, chewing gum, or the like. The syrup may contain, in addition to the active compounds, sucrose as a sweetener and certain preservatives, dyes and coloring agents, and flavoring agents.

[00329] The active compound or pharmaceutically acceptable salts thereof may also be mixed with other active materials that do not adversely affect the desired action, or with materials that complement the desired action, such as anticancer agents, among others. In some preferred aspects of the present invention, one or more compounds of the present invention are co-administered with another biologically active agent, such as an anticancer agent or a wound healing agent, including an antibiotic, described later herein.

[00330] Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical use may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents to regulate tonicity such as sodium chloride or dextrose. The drug for parenteral administration may be contained in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[00331] When administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[00332] In one embodiment, the active compounds are formulated with carriers that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for preparing such compositions will be apparent to those skilled in the art.

[00333] Liposomal suspensions may also be pharmaceutically acceptable carriers. They can be prepared in accordance with methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving a suitable lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, which is then evaporated, leaving a thin film of dried lipid on the surface of the container. The aqueous solution of the active compound is then added to the container. The container is then manually rotated to separate the lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

Therapeutic methods

[00334] In a further aspect, the disclosure provides therapeutic compositions containing an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. Therapeutic compositions modulate protein degradation in a patient or subject, such as an animal such as a human, and may be used to treat or alleviate disease states or conditions that are modulated by protein degradation.

[00335] The terms “treat,” “treat,” and “treat,” etc., as used herein, refer to any action that provides benefit to a patient to whom the compounds of the present invention may be administered, including treatment of any a disease state or condition modulated by a protein to which the compounds of the present invention bind. Disease conditions or conditions, including cancer, that can be treated with the compounds of the present invention are set forth herein above.

[00336] The description provides therapeutic compositions described herein for promoting the destruction of proteins of interest to treat or alleviate a disease, such as cancer. In certain additional embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof. Accordingly, in another aspect, the disclosure provides a method for causing ubiquitination/degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein, comprising, for example, a ULM and a PTM, preferably linked through a linker moiety described later herein, wherein the ULM is linked to the PTM and wherein the ULM recognizes a ubiquitin pathway protein ( for example, a ubiquitin ligase, such as an E3 ubiquitin ligase, including cereblon, VHL, IAP and/or MDM2), and PTM recognizes the target protein such that when the target protein is placed in close proximity to the ubiquitin ligase, destruction of the target protein will occur, thus thus leading to the destruction of the target protein/suppression of its effects and control of protein levels. The control of protein levels provided by the present invention provides treatment for a disease state or condition modulated by a target protein by reducing the level of that protein in a cell, such as a patient's cell. In certain embodiments, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, excipient, other biologically active agent, or a combination thereof.

[00337] In additional embodiments, the disclosure provides methods of treating or alleviating a disease, disorder, or symptom thereof in a subject or patient, such as an animal such as a human, comprising administering to the subject in need thereof a composition containing an effective amount, such as a therapeutic amount an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, excipient, other biologically active agent, or combination thereof, wherein the composition is effective for treating or alleviating a disease or disorder or a symptom thereof in a subject .

[00338] In another aspect, the specification provides methods for identifying the effects of disruption of proteins of interest in a biological system using compounds of the present invention.

[00339] In another embodiment, the present invention is directed to a method of treating a human patient in need of modulation of a disease state or condition by a protein, wherein disruption of the protein will have a therapeutic effect in the patient, the method comprising administering to the patient in need an effective amount of a compound in in accordance with the present invention, optionally in combination with another biologically active agent. The disease state or condition may be a disease caused by a microbial organism or other exogenous organism, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease condition that is caused by overexpression of a protein, resulting in a disease state and/or condition.

[00340] The term "disease or condition" is used to describe any disease or condition in which a protein is dysregulated (i.e., the amount of protein expressed in a patient is increased) and wherein one or more proteins are destroyed in patient may provide beneficial therapy or symptomatic relief to a patient in need of it. In certain cases, a disease or condition can be cured.

[00341] Disease conditions or conditions that can be treated using the compounds of the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various types of cancer, ciliopathies, cleft palate, diabetes, cardiovascular disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria , polycystic kidney disease, Prader-Willi syndrome (PKD1) or 4 (PKD2), sickle cell disease, Tay-Sachs disease, Turner syndrome.

[00342] The term “neoplasia” or “cancer” is used throughout this specification to describe a pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e. abnormal tissue that grows through cell proliferation, often more rapidly than normal tissue, and continues to grow after the stimulus that initiated new growth has ceased. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissue and most spread into surrounding tissues, metastasize to multiple sites and are likely to recur after attempted removal and cause the death of the patient if not sufficiently treated. As used herein, the term “neoplasia” is used to describe all cancer disease states and includes or covers the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary types of cancer that can be treated with the compounds of the present invention either alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma types and renal cell carcinoma types, bladder cancer, colorectal, breast, cervical, colon, esophageal, head, kidney, liver, lung, neck, ovarian, pancreatic, prostate and stomach cancer; types of leukemia; types of benign and malignant lymphoma, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; types of benign and malignant melanoma; myeloproliferative diseases; types of sarcoma, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, types of myosarcoma, peripheral neuroepithelioma, synovial sarcoma, types of glioma, types of astrocytoma, types of oligodendroglioma, types of ependymoma, types of gliobastoma, types of neuroblastoma, types of ganglioneuroma, types of ganglioglioma , species medulloblastomas, pineal cell tumors, types of meningioma, types of meningeal sarcoma, types of neurofibroma and types of schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor and types of teratocarcinoma. Additional types of cancer that can be treated using the compounds of the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, T -adult cell leukemia, pre-B ALL, types of pre-B lymphoma, large B cell lymphoma, Burkitt's lymphoma, B cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[00343] The term "biologically active agent" is used to describe an agent, other than a compound of the present invention, that is used in combination with the compounds of the present invention as an agent with biological activity to assist in the intended therapy, inhibition and/or prevention /prophylaxis for which the compounds of the present invention are used. Preferred biologically active agents for use herein include those that have pharmacological activity similar to that for which the compounds of the present invention are used or administered and include, for example, anticancer agents, antiviral agents, especially including anti-HIV and anti-HCV agents, antimicrobial agents, antifungal agents, etc.

[00344] The term "additional anticancer agent" is used to describe an anticancer agent that can be combined with the compounds of the present invention for the treatment of cancer. Such agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258 , GSK461364, AZD 1152, enzastaurine, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, Aurora kinase inhibitor, PIK modulator -1, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1/2 inhibitor, JAK inhibitor STAT, checkpoint inhibitor 1 or 2, focal junction kinase inhibitor, Mark kinase inhibitor (tec), anti-VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan , IL13 -PE38QQR, FNO 1001, IPdR ₁ KRX-0402, Lucanton, LY317615, neuradiab, vitesan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etopoise d, gemcitabine , doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR -258); 3-[5-(methylsulfonylpiperadinemethyl)indolylquinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutami d, nilutamide, megestrol acetate, SR -724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, anti-ABX-EGF, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, bacillus Calmette-Guerin vaccine (BCG), adriamycin, bleu omycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubi cin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin , teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithrami cin, vinblastine, vinorelbine , topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, Vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortesimibe, paclitaxel, cremophore-free paclitaxel, docetaxel, epitilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifene, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE- 424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl) rapamycin, temsirolimus, AR-23573, RAD001, AVT-578, VS-210 , LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuxime ab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a , interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2 , megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritugumomub tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina asparaginase, strontium 89, casopitant, netupitant, NK receptor antagonist -1, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, PEG-filgrastim, erythropoietin, epoetin alfa, darbepo ethin alpha and them mixtures.

[00345] The term "anti-HIV agent" or "additional anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., inhibitors that are exemplary of the present invention) , protease inhibitors, fusion inhibitors, among others, exemplary compounds which may include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), Tenofovir (PMPA), D-D4FC (Reverset), D4T (stavudine), Racivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV ( ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), fusion inhibitors such as T20, among others, fuzeon and mixtures thereof, including anti-HIV compounds, currently in clinical trials or in development.

[00346] Other anti-HIV agents that may be coadministered with the compounds of the present invention include, for example, other NNRTIs (i.e., other than the NNRTI of the present invention) and may be selected from the group consisting of from nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl] -2-methyl-3-furancarbothiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKS-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC -278), MSC-127, HBY 097, DMP266, baicalin (TJN-151) ADAM-II (methyl-3',3'-dichloro-4',4''-dimethoxy-5',5''-bis (methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate (alkenyldiarylmethane analogue , analogue of Adam), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-VHAR (U-104489 or PNU-104489), capravirine (AG-1549, S-1153), atevirdine (U- 87201E), aurintri carboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N -(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2 -indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indoyl )carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl- 2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscavir), HEPT (1-[(2- hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2- hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothimine), inophyllum P, L-737,126, mishelamine A (NSC650898), mishelamine B (NSC649324), mishelamine F, 6-(3,5-dimethylbenzyl)-1- [(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), oltipraz (4-methyl-5 -(pyrazinyl)-3H-1,2-dithiol-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (Cl, F derivative of PETT), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2- (5-methylpyridyl)]thiourea {pyridyl derivative of PETT), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6 -ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697.639, L-697.593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pipridin-2(1H)-thione (2-pyridinone derivative), 3-[[ (2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pipridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (loviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a ]isoindol-5(9bH)-one, tivirapine (R86183), UC-38 and UC-84, among others.

[00347] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, as applicable, a salt form of one or more of the compounds described herein that is present to increase the solubility of the compound in the gastric juices of the gastrointestinal tract of a patient to promote dissolution and bioavailability of compounds. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids, as appropriate. Suitable salts include salts derived from alkali metals, such as potassium and sodium salts, alkaline earth metals, such as calcium, magnesium and ammonium salts, among a number of other acids and bases well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred as phosphate neutralizing salts in accordance with the present invention.

[00348] The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable form of prodrug (such as an ester, amide, other prodrug group) that, when administered to a patient, provides directly or indirectly a compound of the present invention or an active metabolite of a compound of the present invention. the present invention.

General approaches to synthesis

[00349] To practice the synthesis and optimization of the bifunctional molecules described herein, a solution can be found in a stepwise or modular manner. For example, the identification of compounds that bind to target molecules may involve high- or medium-throughput screening operations if suitable ligands are not immediately available. It is not uncommon for initial ligands to require cycles of iterative design and optimization to improve suboptimal aspects identified using data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR operation will be to test ligand positions that are substitutable and that may be suitable sites for attachment of linker chemical groups previously identified herein. If crystallographic or NMR structural data are available, they can be used to focus such synthetic efforts.

[00350] In a very similar manner, ligands for E3 ligase can be identified and optimized, i.e. ULM/ILM/VLM/CLM/ILM.

[00351] Given the PTM and ULM (eg, ILM, VLM, CLM and/or ILM), one skilled in the art can use known synthetic methods to combine them with or without a linker moiety. Linker moieties can be synthesized in a range of compositions, lengths and elasticities and functionalized so that PTM and ULM groups can be attached sequentially to the distal ends of the linker. In this way, a library of bifunctional molecules can be generated and profiled in pharmacological studies and ADMET/PK assays in vitro and in vivo. As with the PTM and ULM groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with the desired properties.

[00352] In some cases, protecting group and/or functional group interconversion (FGI) strategies may be necessary to facilitate the production of the desired substances. These chemical methods are widely known to the organic synthesis chemist, and many methods can be found in manuals such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M. Wuts and Theodora W. Greene (Wiley) and "Organic Synthesis: The Disconnection Approach" by Stuart Warren and Paul Wyatt (Wiley).

Protein level control

[00353] Also provided herein are methods for monitoring protein levels in a cell. They rely on the use of compounds described herein that are known to interact with a specific target protein such that disruption of the target protein in vivo will result in control of the amount of protein in the biological system, preferably with a specific therapeutic benefit.

[00354] The following examples are used to help describe the present invention, but should not be construed as limiting the present invention in any way.

General approaches to synthesis

[00355] To practice the synthesis and optimization of the bifunctional molecules described herein, a solution can be found in a stepwise or modular manner. For example, the identification of compounds that bind to target molecules may involve high- or medium-throughput screening operations if suitable ligands are not immediately available. It is not uncommon for initial ligands to require cycles of iterative design and optimization to improve suboptimal aspects identified using data from suitable in vitro and pharmacological and/or ADMET assays. Part of the optimization/SAR operation will be to test ligand positions that are substitutable and that may be suitable sites for attachment of linker chemical groups previously identified herein. If crystallographic or NMR structural data are available, they can be used to focus such synthetic efforts.

[00356] In a very similar manner, ligands for E3 ligase can be identified and optimized, i.e. ULM/VLM/CLM/ILM/MLM.

[00357] Given the PTM and ULM (eg, VLM, CLM, ILM and/or MLM), one skilled in the art can use known synthetic methods to combine them with or without a linker moiety. Linker moieties can be synthesized in a range of compositions, lengths and elasticities and functionalized so that PTM and ULM groups can be attached sequentially to the distal ends of the linker. In this way, a library of bifunctional molecules can be generated and profiled in pharmacological studies and ADMET/PK assays in vitro and in vivo. As with the PTM and ULM groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with the desired properties.

[00358] The compounds of the present invention [eg, of the general formulas PTM-I or PTM-II] can be prepared using methods known in the field of organic synthesis, as presented in the specific examples described herein. In all methods, it is well understood that, if necessary, protecting groups can be applied to sensitive or reactive groups in accordance with general principles of chemistry. Protecting groups are manipulated according to standard organic synthesis techniques (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, ^3rd edition, John Wiley & Sons). These groups are removed at a suitable stage in the synthesis of the compound using methods that are readily understood by those skilled in the art. The choice of methods, as well as the reaction conditions and the order in which they are carried out will be consistent with the preparation of the compounds of the present invention, including the compounds of formula (I). The schemes described below illustrate general methods for preparing compounds with the structure represented by formula (I) and formula (II).

[00359] Abbreviations

[00360] ACN: Acetonitrile

[00361] ADDP: 1,1'-(azodicarbonyl)dipiperidine

[00362] BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[00363] DCE: 1,2-dichloroethane

[00364] DCM: dichloromethane

[00365] DEAD: diethyl azodicarboxylate

[00366] DIEA or DIPEA: N,N-diisopropylethylamine

[00367] DMA: N,N-dimethylacetamide

[00368] DME: dimethoxyethane

[00369] DMF: N,N-dimethylformamide

[00370] DMP: Dess-Martin periodinane

[00371] ES+: electrospray in positive ion mode

[00372] h: hour

[00373] HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[00374] HPLC: High Performance Liquid Chromatography

[00375] LC-MS: liquid chromatography with mass spectrometry

[00376] min: minutes

[00377] NBS: N-bromosuccinimide

[00378] NMP: N-methylpyrrolidone

[00379] NMR: nuclear magnetic resonance

[00380] RT or t _R : holding time

[00381] SFC: supercritical fluid chromatography

[00382] TVAS: tetrabutylammonium chloride

[00383] TCCA: trichloroisocyanuric acid

[00384] TFA: trifluoroacetic acid

[00385] THF: tetrahydrofuran

[00386] TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide

[00387] XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl

[00388] General conditions and analytical methods

[00389] All solvents used were purchased from commercial sources and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert nitrogen atmosphere. Flash column chromatography was typically performed using silica gel 60 (particle size 0.035-0.070 mm).

[00390] The synthesis of the claimed compounds can be carried out in accordance with the following schemes. Synthetic routes in such schemes are described as illustrative methods. Other methods known to those skilled in the art of synthesis may also be used.

[00391] General Synthesis Scheme 1 for the Preparation of Intermediates

[00392] General synthesis scheme 2 for the preparation of intermediates

[00393] General synthesis scheme 3 for the preparation of intermediates

[00394] General Synthesis Scheme 4 for the Preparation of Intermediates

[00395] General Synthesis Scheme 5 for the Preparation of Intermediates

[00396] General Synthesis Scheme 6 for the Preparation of Intermediates

[00397] General Synthesis Scheme 7 for the Preparation of Intermediates

[00398] General Synthesis Scheme 8 for the Preparation of Intermediates

[00399] General Synthesis Scheme 9 for the Preparation of Intermediates

[00400] General Synthesis Scheme 10 for the Preparation of Intermediates

[00401] General Synthesis Scheme 11 for the Preparation of Intermediates

[00402] General Synthesis Scheme 12 for the Preparation of Intermediates

[00403] General Synthesis Scheme 13 for the Preparation of Intermediates

[00404] General synthesis scheme 14

[00405] General synthesis scheme 15

[00406] General synthesis scheme 16

[00407] General synthesis scheme 17

[00408] General synthesis scheme 18

[00409] General synthesis scheme 19

[00410] General synthesis scheme 20

[00411] General synthesis scheme 21

[00412] General synthesis scheme 22

[00413] General synthesis scheme 23

[00414] General synthesis scheme 24

[00415] General synthesis scheme 25

[00416] General synthesis scheme 26

[00417] General synthesis scheme 27

[00418] General synthesis scheme 28

[00419] General synthesis scheme 29

[00420] General synthesis scheme 30

[00421] General synthesis scheme 31

[00422] General synthesis scheme 32

[00423] General synthesis scheme 33

[00424] General Scheme 1A for Preparation of Intermediates

[00425] General Scheme 2A for Preparation of Intermediates

[00426] General Scheme 3A for Preparation of Intermediates

[00427] General Scheme 4A for Preparation of Intermediates

[00428] General Scheme 5A for Preparation of Intermediates

[00429] General Scheme 6A for Preparation of Intermediates

[00430] General Scheme 7A for Preparation of Intermediates

[00431] General scheme 8A for preparing intermediates

[00432] General Scheme 9A for Preparation of Intermediates

[00433] General circuit 10A for obtaining intermediate compounds

[00434] General scheme 11A for preparing intermediate compounds

[00435] General circuit 12A for obtaining intermediate compounds

[00436] General scheme 13A for preparing intermediate compounds

[00437] General scheme 14A for preparing intermediate compounds

[00438] General scheme 15A for obtaining intermediate compounds

[00439] General circuit 16A for producing intermediates

[00440] General scheme 17A for preparing intermediate compounds

[00441] General connection acquisition circuit 18A for connection 111

[00442] General connection acquisition circuit 19A for connection 140

[00443] General scheme 20A for preparing the compound in Examples 161, 162, 163, 164, 165 and 166

[00444] General circuit 1B for obtaining connection 170

[00445] General circuit 2B for obtaining connection 174

[00446] General circuit 3B for obtaining connection 175

[00447] General circuit 4B for obtaining connection 177

[00448] General circuit 5B receiving connection 178

[00449] General circuit 6B for obtaining connection 180

[00450] General circuit 7B for obtaining connection 182

[00451] General circuit 8B for obtaining connection 183

[00452] General circuit 9B for obtaining connection 184

[00453] General circuit 10B receiving connection 185

[00454] General circuit 11B for obtaining an intermediate connection for connection 186

[00455] General circuit 12V receiving connection 187

[00456] General circuit 13B for obtaining an intermediate connection for connection 188

[00457] General circuit 14V receiving connection 189

[00458] General circuit 15B for obtaining an intermediate connection for connection 190

[00459] General circuit 16B for obtaining an intermediate connection for connection 192

[00460] General circuit 17B for obtaining an intermediate for connection 193

[00461] General circuit 18B for obtaining an intermediate connection for connection 197

[00462] General circuit 19B for obtaining an intermediate connection for connection 198

[00463] General circuit 20B to obtain an intermediate connection for connection 206

[00464] General circuit 21B for obtaining an intermediate connection for connection 204

[00465] General circuit 22V receiving connection 207

[00466] General circuit 23B receiving connection 209

[00467] General 24V circuit for receiving connection 211

[00468] General circuit 25V receiving connection 212

[00469] General circuit 26B receiving connection 213

[00470] General 27V circuit to obtain connections 214 and 216

[00471] General circuit 28V to obtain an intermediate connection for connection 218

[00472] General circuit 29B for obtaining an intermediate connection for connection 222

[00473] General circuit 30V receiving connection 223

[00474] General circuit 31B for receiving connection 224

[00475] General circuit 32B for obtaining an intermediate connection for connection 225

[00476] General circuit 33B for obtaining connection 226

[00477] General circuit 34B for obtaining an intermediate connection for connection 230

[00478] General circuit 35B for obtaining connection 231

[00479] General circuit 36B for obtaining an intermediate connection for connection 232

[00480] General circuit 37B for obtaining an intermediate connection for connection 238

[00481] General circuit 38B receiving connection 240

[00482] General circuit 39B for obtaining an intermediate connection for connection 241

[00483] General circuit 40B receiving connection 242

[00484] General circuit 41B for obtaining connections 243, 244 and 245

[00485] Experimental procedures for the synthesis of PROTACs targeting the ER

[00486] Preparation of 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl ]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide (compound 11 )

[00487] Step 1: Preparation of 1-(4-benzyloxyphenoxy)propan-2-one

[00488] To a solution of 4-benzyloxyphenol (3 g, 14.98 mmol, 1.00 eq.) in acetone (30 mL), add potassium carbonate (2.48 g, 17.98 mmol, 1.20 eq.) and 1-bromopropan-2-one (2.46 g, 17.98 mmol, 1.20 eq.) under nitrogen. The reaction mixture was stirred at 60°C for 5 hours. LC/MS demonstrated that most of the starting material was consumed. Water (150 ml) was added to the mixture, and the resulting mixture was extracted with petroleum ether (50 ml x 3). The combined organic phase was washed with brine (80 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 30/1 to 3/1) to give 1-(4-benzyloxyphenoxy)propan-2-one (3.3 g, crude) as a white solid .

[00489] LC/MS: MS (ESI) mass/charge: 257.0 [M+1] ⁺ ; ^1H NMR: (400 MHz, CDCl ₃ )

[00490] δ: 7.44-7.33 (m, 5H), 6.94-6.90 (m, 2H), 6.84-6.82 (m, 2H), 5.03 (s, 2H), 4.50 (s, 2H), 2.28 (s, 3H).

[00491] Step 2: Preparation of tert-butyl 4-[2-(4-benzyloxyphenoxy)-1-methylethyl]piperazine-1-carboxylate

[00492] To a solution of 1-(4-benzyloxyphenoxy)propan-2-one (1.8 g, 7.02 mmol, 1.00 eq.) in 1,2-dichloroethane (30 ml) was added tert-butylpiperazine-1 -carboxylate (1.05 g, 5.62 mmol, 0.80 eq.) and acetic acid (421 mg, 7.02 mmol, 0.41 ml, 1.00 eq.). The mixture was stirred at 20°C for 1 hour. Sodium triacetoxyborohydride (2.23 g, 10.53 mmol, 1.50 eq.) was then added to the mixture and the reaction mixture was stirred at 20°C for 5 hours. LC/MS demonstrated that most of the starting material had been consumed. Water (150 ml) and dichloromethane (80 ml) were added to the mixture and the layers were separated. The organic layer was washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1 to 1/1) to give tert-butyl 4-[2-(4-benzyloxyphenoxy)-1-methylethyl]piperazine-1-carboxylate (1 .4 g, 3.28 mmol, 47% yield) as a light yellow oil.

[00493] LCMS: MS (ESI) mass/charge: 427.1 [M+1] ⁺ ; ^1H NMR: (400 MHz, CDCl ₃ ) δ: 7.44-7.30 (m, 5H), 6.94-6.90 (m, 2H), 6.85-6.82 (m, 2H ), 5.02 (s, 2H), 4.02-3.98 (m, 1H), 3.85-3.81 (m, 1H), 3.43 (t, J=4.8 Hz, 4H), 3.05-2.97 (m, 1H), 2.65-2.55 (m, 4H), 1.46 (s, 9H), 1.16 (d, J=6.8 Hz , 3H).

[00494] Step 3: Preparation of tert-butyl 4-[2-(4-hydroxysphenoxy)-1-methylethyl]piperazine-1-carboxylate

[00495] A solution of tert-butyl 4-[2-(4-benzyloxyphenoxy)-1-methylethyl]piperazine-1-carboxylate (1.4 g, 3.28 mmol, 1.00 eq.) in methanol (40 ml) Pd/C (200 mg, 10%) was added under nitrogen atmosphere. The suspension was degassed in vacuum and purged with hydrogen several times. The reaction mixture was stirred at 20°C for 16 hours under a hydrogen atmosphere (50 psi). TLC (petroleum ether/ethyl acetate = 1/1) demonstrated that most of the starting material had been consumed. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 4-[2-(4-hydroxyphenoxy)-1-methylethyl]piperazine-1-carboxylate (1 g, 2.97 mmol, 91% yield) as a yellow oil .

[00496] ¹ H NMR: (400 MHz, CDCl ₃ ) δ: 8.78-8.73 (m, 4H), 4.00-3.96 (m, 1H), 3.84-3.80 ( m, 1H), 3.44 (t, J=4.8 Hz, 4H), 3.03-2.99 (m, 1H), 2.64-2.58 (m, 4H), 1.46 (s, 9H), 1.17 (d, J=6.8 Hz, 3H).

[00497] Step 4: Preparation of tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium-3-yl]oxyphenoxy]-1-methylethyl ]piperazine-1-carboxylate

[00498] Stage 4-1. Preparation of 3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene

[00499] To a solution of KOH (25 g, 10 eq.) in ethanol (1 L) at 15-25°C, 3-methoxybenzenethiol (54 g, 1.1 eq.) was added and the mixture was stirred at 15-25°C for 30 min. The mixture was then cooled to 0°C and ethyl acetate (700 ml) and 2-bromo-1-(4-bromophenyl)ethanone (80 g, 1.0 eq.) were added sequentially at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was heated to room temperature. and stirred for 4 hours. Then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (500 ml×2), washed with brine (300 ml) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure. The residue was recrystallized from CH ₃ OH (500 ml) to give 1-(4-bromophenyl)-2-(3-methoxyphenylthio)ethanone as a yellow solid (100 g, 87%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.80 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.91 (t, J=2.0 Hz, 1H), 6.77 (dd, J= 8.0, 1.6 Hz, 1H), 4.23 (s, 2H), 3.78 (s, 3H).

[00500] To a stirred PPA solution (1 L) at 80°C (continued stirring as quickly as possible), 1-(4-bromophenyl)-2-(3-methoxyphenylthio)ethanone (100 g, 1.0 eq.) was added in portions. within 40 min. (temperature control below 95°C). The reaction mixture was then heated to 90°C and stirred for 2 hours. The solution was stirred at 130-135°C for another 16 hours. The mixture was cooled to 50-70°C. The reaction mixture was poured into ice water (1.5 L) and stirred for 1 hour. The crude product was collected by filtration and the solid was washed with water and recrystallized with EA to give 2-(4-bromophenyl)-6-methoxybenzo[b] thiophene as a pale solid, 51 g (yield: 52.6%). ^1H NMR (400 MHz, DMSO) δ: 7.86 (s, 1H), 7.57-7.82 (m, 6H), 7.01-7.03 (m, 1H), 3.84 ( s, 3H).

[00501] To a suspended mixture of 2-(4-bromophenyl)-6-methoxybenzo[b]thiophene (46 g, 1.0 eq.) in dried DCM (1 L) was added N-bromosuccinimide (26 g, 1.02 eq. .) at 20°C. The reaction mixture was stirred at room temperature for 5 hours and then quenched by adding water (500 ml). The mixture was extracted with DCM and the combined organic layers were dried over anhydrous sodium sulfate and the solution was concentrated in vacuo. The residue was recrystallized with EA to give 3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene as a light purple solid (50.0 g, 88%). ¹ H NMR (400 MHz, DMSO) δ: 7.67-7.77 (m, 6H), 77.18 (d, J=7.2 Hz, 1H), 3.87 (s, 3H).

[00502] Stage 4-2. Preparation of tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-yl-3-yl]oxyphenoxy]-1-methylethyl]piperazine-1-carboxylate

[00503] To a solution of 3-bromo-2-(4-bromophenyl)-6-methoxybenzothiophene (1.80 g, 4.52 mmol, 1.00 eq.) in dichloromethane (18 ml) was added dropwise trifluoroacetic acid (15 ml). Hydrogen peroxide (769 mg, 6.78 mmol, 0.65 mL, 30% aq. solution, 1.50 eq.) was added. The mixture was stirred at 18°C for 2 hours. TLC (petroleum ether:ethyl acetate = 3:1, _Rf = 0.24) demonstrated that the reaction was complete and a new spot had formed. The reaction mixture was quenched by adding saturated sodium sulfite solution (5 ml) and the mixture was stirred at 18°C for 10 minutes, then pH of the mixture to = (7-8) using saturated sodium bicarbonate solution (150 ml). The solution was extracted with dichloromethane (50 ml x 3). The combined organic phase was washed with brine (50 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give 3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium (1 .10 g, 2.66 mmol, 59% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.73-7.63 (m, 4H), 7.59 (d, J=8.4 Hz, 1H), 7.50 (d, J=2 ,4 Hz, 1H), 7.16 (dd, J=2.4, 8.4 Hz, 1H), 3.94 (s, 3H).

[00504] A solution of tert-butyl 4-[2-(4-hydroxyphenoxy)-1-methylethyl]piperazine-1-carboxylate (1.0 g, 2.97 mmol, 1.00 eq.) in N,N -dimethylformamide (10 ml) was added sodium hydride (143 mg, 3.57 mmol, 60% in mineral oil, 1.20 eq.) at 0°C. The mixture was stirred at 20°C for 0.5 h. Then 3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium (1.23 g, 2.97 mmol, 1 00 eq), the reaction mixture was stirred at 20°C for 1 hour. TLC (dichloromethane/methanol = 20/1) demonstrated that most of the starting material was consumed. A saturated ammonium chloride solution (100 ml) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1- oxidobenzothiophene-1-yl-3-yl]oxyphenoxy]-1-methylethyl]piperazine-1-carboxylate (2 g, crude material) as a yellow oil. LC/MS: MS (ESI) mass/charge: 668.8, 670.8 [M, M+2] ⁺ .

[00505] Step 5: Preparation of tert-butyl 4-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]-1-methyl-ethyl]piperazine-1-carboxylate

[00506] Into a solution of tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium-3-yl]oxyphenoxy]-1-methylethyl]piperazine -1-carboxylate (2 g, 2.54 mmol, 1.00 eq.) in acetonitrile (20 ml) was added sodium iodide (1.14 g, 7.62 mmol, 3.00 eq.) and trimethylchlorosilane (552 mg , 5.08 mmol, 2.00 eq.). The reaction mixture was stirred at 20°C for 3 hours. LC/MS demonstrated that most of the starting material was consumed. The reaction mixture was quenched with saturated sodium thiosulfate solution (50 ml), the resulting mixture was extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with brine (40 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1 to 0/1) to give tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophene-3 -yl]oxyphenoxy]-1-methylethyl]piperazine-1-carboxylate (1.5 g, 2.29 mmol, 90% yield) as a yellow solid. LC/MS: MS (ESI) mass/charge: 653.1, 655.1 [M, M+2] ⁺ . ¹ H NMR: (400 MHz, CD ₃ Cl ₃ ) δ: 7.64-7.61 (m, 2H), 7.30-7.26 (m, 3H), 6.90-6.88 (m , 3H), 6.80-6.78 (m, 2H), 3.99-3.95 (m, 1H), 3.88 (d, J=1.6 Hz, 3H), 3.82- 3.79 (m, 1H), 3.42 (t, J=4.0 Hz, 4H), 3.02-2.97 (m, 1H), 2.63-2.58 (m, 4H) , 1.46 (d, J=8.0 Hz, 9H), l.15 (d, J=5.6 Hz, 3H).

[00507] Step 6: Preparation of 1-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]-1-methylethyl]piperazine

[00508] In a solution of tert-butyl 4-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]-1-methylethyl]piperazine-1-carboxylate (800 mg, 1.22 mmol, 1.00 eq.) in dichloromethane (5 ml), a mixture of hydrochloric acid/dioxane (4 M, 3 ml, 9.51 eq.) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove dichloromethane and dioxane to give 1-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]-1-methylethyl]piperazine (700 mg , 1.19 mmol, 97% yield, hydrochloride) as a white solid. LCMS: MS (ESI) mass/charge: 555.0 [M+1] ⁺ .

[00509] Step 7: Preparation of methyl 2-(4-(1-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)propane-2- yl)piperazin-1-yl)acetate

[00510] Into a solution of 1-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]-1-methylethyl]piperazine (720 mg, 1.22 mmol, 1.00 eq., hydrochloride) in N,N-dimethylformamide (10 ml) was added potassium carbonate (506 mg, 3.66 mmol, 3.00 eq.) and methyl 2-bromoacetate (224 mg, 1.46 mmol, 0. 14 ml, 1.20 eq.). The mixture was stirred at 20°C for 16 hours. LC/MS demonstrated that the reaction was complete and the required MS was determined. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with brine (40 ml x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1 to 1:1) to give methyl-2-{4-[1-(4-{[2-(4-bromophenyl)-6- methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate (500 mg, 0.8 mmol, 66% yield) as a yellow oil. LCMS: MS (ESI) mass/charge: 627.1 [M+1] ⁺ .

[00511] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.65-7.58 (m, 2H), 7.49-7.45 (m, 2H), 7.30-7.23 (m, 2H), 6.91-6.83 (m, 3H), 6.81-6.74 (m, 2H), 4.03-3.94 (m, 1H), 3.87 (s , 3H), 3.85-3.76 (m, 1H), 3.74-3.71 (m, 3H), 3.22 (s, 2H), 3.05-2.98 (m, 1H ), 2.82-2.59 (m, 8H), 2.05 (s, 1H), 1.21-1.16 (m, 3H).

[00512] Step 8: Preparation of 2-(4-(1-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)propan-2-yl) piperazin-1-yl)acetic acid

[00513] Into a solution of methyl 2-4-[1-(4-{[2-(4-bromophenyl)-6-methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazine -1-yl}acetate (500 mg, 0.8 mmol, 1.00 eq.) in dichloromethane (10 ml) was added boron tribromide (600 mg, 2.40 mmol, 0.23 ml, 3.00 eq.) at -70°C. The mixture was stirred at 20°C for 16 hours. LC/MS demonstrated that the reaction was complete and the desired product was formed. The reaction mixture was quenched with methanol (10 ml) at 0°C and concentrated under reduced pressure to remove methanol and dichloromethane to give 2-(4-(1-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b ]thiophen-3-yl)oxy)phenoxy)propan-2-yl)piperazin-1-yl)acetic acid (380 mg, crude) as a yellow oil, which was directly used for the next step without further purification. LCMS: MS (ESI) mass/charge: 599.0 [M+1] ⁺ .

[00514] Step 9: Preparation of methyl 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy) propan-2-yl]piperazin-1-yl}acetate

[00515] Into a solution of 2-{4-[1-(4-{[2-(4-bromophenyl)-6-methoxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin- 1-yl} acetic acid (380 mg, 0.64 mmol, 1.00 eq.) in methanol (10 ml) was added sulfuric acid (184 mg, 1.88 mmol, 0.1 ml, 2.95 eq.) . The mixture was stirred at 70°C for 12 hours. LC/MS demonstrated that the reaction was complete and the desired product was formed. The pH of the reaction mixture was adjusted to (8~9) with sodium bicarbonate (2 M, 4 ml) and it was diluted with water (30 ml), and extracted with ethyl acetate (20 ml × 2). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain the desired compound (200 mg, 51% yield, 92% purity) as a white solid, which was further separated by chiral SFC (AD column, 250 mm × 30 mm, 10 µm, 0.1% NH ₃ -H ₂ O in IPA) to give methyl-2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-

[00516] hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate (90 mg, 0.15 mmol, 23% yield) as a yellow oil and methyl 2-{4-[(2S)-1-(4-{[2-(4-bromophenyl)-6-

[00517]hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetate (90 mg, 0.15 mmol, 23% yield) as a yellow oil. LCMS: MS (ESI) mass/charge: 613.0 [M+1] ⁺ .

[00518] Step 10: Preparation of 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan- 2-yl]piperazin-1-yl}acetic acid

[00519] Into a solution of methyl 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan- 2-yl]piperazin-1-yl}acetate (90 mg, 0.15 mmol, 1.00 eq.) in tetrahydrofuran (1 ml) and methanol (2 ml) was added lithium hydroxide monohydrate (2 M, 0.5 ml , 6.79 eq.). The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with hydrochloric acid (2 M, 0.6 ml). The mixture was concentrated under reduced pressure to remove methanol, tetrahydrofuran and water to give 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophene-3- yl]oxy}phenoxy)propan-2-yl]piperazin-1-yl}acetic acid (95 mg, crude) as a white solid, which was directly used for the next step without further purification. ICMS: MS (ESI) mass/charge: 598.9 [M+1] ⁺ .

[00520] Step 11: Preparation of 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan- 2-yl]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide

[00521] Into a solution of 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2- yl]piperazin-1-yl} acetic acid (85 mg, 0.14 mmol, 1.00 eq.) and 3-[5-(aminomethyl)-1-oxoisoindolin-2-yl]piperidin-2,6-dione (64 mg, 0.14 mmol, 1.00 eq.) in N,N-dimethylformamide (3 ml) was added (7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (65 mg, 0.17 mmol, 1.20 eq.) and diisopropylethylamine (92 mg, 0.7 mmol, 0.1 ml, 5.00 eq.). The mixture was stirred at 20°C for 12 hours. LC/MS demonstrated that the reaction was complete and the desired product was formed. The reaction mixture was purified by preparative HPLC (column: Boston Green ODS 150 mm × 30 mm, 5 μm; mobile phase: water with 0.225% TFA as solvent A and acetonitrile as solvent B; gradient: 27% B to 57% in 10 minutes). The collected fraction was then concentrated to remove most of the acetonitrile and hydrochloric acid (1 M, 2 ml) was added. The solution was lyophilized to give 2-{4-[(2R)-1-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)propan-2-yl ]piperazin-1-yl}-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}acetamide (54 mg , 0.06 mmol, 43% yield, 98% purity, hydrochloride) as a yellow solid. LCMS: MS (ESI) mass/charge: 852.2 and 854.2 [M+1] ⁺ ; ^1H NMR (400 MHz, DMSO-d) δ: 10.99 (s, 1H), 9.98 (s, 1H), 9.14-8.78 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.61 (s, 4H), 7.51 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.99-6.89 (m, 4H), 6.84 (dd, J=2.0 , 8.8 Hz, 1H), 5.11 (dd, J=5.2, 13.2 Hz, 1H), 4.56-4.11 (m, 7H), 4.02-3.53 ( m, 10H), 2.96-2.87 (m, 1H), 2.65-2.55 (m, 1H), 2.43-2.35 (m, 1H), 2.05-1, 95 (m, 1H), 1.53 (br d, J=6.4 Hz, 1H), 1.38 (s, 2H).

[00522] Preparation of 5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl]piperazin-1-yl}- 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (compound 61)

[00523] Step 1: Preparation of 4-(5-hydroxypentyloxy)phenol

[00524] To a solution of 4-hydroxyphenol (3.0 g, 27.3 mmol) in water (30 ml) was added sodium hydroxide (1.45 g, 36.4 mmol) and 5-bromopentan-1-ol (4, 5 g, 27.3 mmol). The mixture was heated to 100°C for 6 hours under an atmosphere of N ₂ gas. After cooling to room temperature. hydrochloric acid (1.0 M) was added and the pH was adjusted to 1.0. The mixture was extracted with ethyl acetate (50 ml x 3). The organic layer was washed with brine (50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified with silica gel (petroleum ether/ethyl acetate = 3:1) to give 4-(5-hydroxypentyloxy)phenol (1.5 g, 48.7%) as a white solid.

[00525] ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.51-1.54 (2H, m), 1.61-1.66 (2H, m), 1.76-1.83 (2H, m), 3.68 (2H, t, J=6.6 Hz), 3.91 (2H, t, J=6.4 Hz), 4.61 (1H, s), 6.73-6, 79 (4H, m).

[00526] Step 2: Preparation of 6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H1-benzothiophene-1-ium-1-olate

[00527] To a solution of 4-(5-hydroxypentyloxy)phenol (100 mg, 0.5 mmol) in DMF (5 ml) was added 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1H-1 -benzothiophene-1-ium-1-olate (400 mg, 0.82 mmol) and potassium carbonate (170 mg, 1.23 mmol). The mixture was heated to 60°C for 3 hours under an atmosphere of N ₂ gas. After cooling to room temperature. the reaction mixture was diluted with water (10 ml) and the mixture was extracted with ethyl acetate (10 ml x 3). The organic layer was washed with saline (10 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H-1- benzothiophene-1-ium-1-olate (200 mg, 64.9%) as a yellow oil, which was used in the next step without further purification.

[00528] Step 3: Preparation of 5-(4-{[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy}phenoxy)pentan-1-ol

[00529] In a solution of 6-(benzyloxy)-2-(4-bromophenyl)-3-{4-[(5-hydroxypentyl)oxy]phenoxy}-1H-1-benzothiophene-1-ium-1-olate (200 mg, 0.33 mmol) in acetonitrile (10 ml), chlorotrimethylsilane (30 mg, 0.3 mmol) and potassium iodide (50 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was treated with water (10.0 ml) and then extracted with dichloromethane (10.0 ml x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified by preparative TLC to give 5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo [b]thiophen-3-yloxy)phenoxy)pentan-1-ol (140 mg, 71.8%) as a yellow solid.

[00530] Step 4: Preparation of 5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentanal

[00531] Into a solution of 5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentan-1-ol (200 mg, 0.34 mmol) Dess-Martin periodinane (0.44 g, 1.02 mmol) was added in dichloromethane (20 ml). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20.0 ml) and extracted with dichloromethane (20.0 ml x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and purified by preparative TLC to give 5-(4-(6-(benzyloxy)-2-(4-bromophenyl) )benzo[b]thiophen-3-yloxy)phenoxy)pentanal (120 mg, 60.2%) as a yellow solid.

[00532] Step 5: Preparation of 5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal

[00533] A solution of 5-(4-(6-(benzyloxy)-2-(4-bromophenyl)benzo[b]thiophen-3-yloxy)phenoxy)pentanal (150 mg, 0.2 mmol) in dichloromethane (20 ml) boron tribromide (0.30 ml, 1.0 M) was added at -78°C and stirred for 30 minutes. at a given temperature. The reaction mixture was diluted with water (10 ml) and sodium bicarbonate (5 ml) and then extracted with EtOAc (10 ml x 3). The organic layer was washed with saline (20 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 3:1) to give 5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal (62 mg , 61.1%) as a white solid.

[00534] Step 6: Preparation of 5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl1piperazin-1-yl} -2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione

[00535] In a solution of 5-(4-(2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)pentanal (62 mg, 0.125 mmol) in a dry mixture of DCM/MeOH/H ₂ O (2 ml/2 ml/0.1 ml) added 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindolin-1,3-dione (43 mg, 0.125 mmol ). The mixture was stirred for 30 minutes. in an atmosphere of N ₂ gas. Sodium triacetoxyborohydride (79.5 mg, 0.375 mmol) was then added and the mixture was stirred overnight. The solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC to give 5-{4-[5-(4-{[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy}phenoxy)pentyl]piperazine-1 -yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (35 mg, 33.5%) as a yellow solid.

[00536] IC-MS: MS (ESI) mass/charge 823.2, 825.1 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSO-d6) δ 1.40-1.54 (4H, m), 1.66-1.73 (2H, m), 1.99-2.02 (1H, m) , 2.31 (2H, t, J=7.4 Hz), 2.47-2.51 (5H, m), 2.53-2.60 (1H, m), 2.83-2.93 (1H, m), 3.36-3.41 (4H, m), 3.88 (2H, t, J=6.2 Hz), 5.07 (1H, dd, J=5.2, 12 ,8 Hz), 6.82 (1H, dd, J=2.0, 8.4 Hz), 6.86 (4H, s), 7.15 (1H, d, J=8.8 Hz), 7.24 (1H, dd, J=2.0, 8.4 Hz), 7.32 (2H, dd, J=1.6, 9.6 Hz), 7.62 (4H, s), 7 .67 (1H, d, J=8.8 Hz), 9.92 (1H, s), 11.08 (1H, s).

[00537] Obtaining intermediates

[00538] Intermediate 1. (2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride

[00539] Reagents and conditions: (a) (Boc) ₂ O, NaHCO ₃ , EtOAc/H ₂ O; (b) (1) Pd(OAc) ₂ , KOAc, 90°C; (2) 4 n. HCl in MeOH; (c) (1) HATU, DIPEA, DMF; (2) LiOH, THF, H ₂ O; (d) (1) intermediate 3, HATU, DIPEA, THF; (2) 4 n. HCl in MeOH.

[00540] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate (2)

[00541] A mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) and NaHCO ₃ (1.24 g, 14.8 mmol) in H ₂ O (10 ml) and ethyl acetate (10 ml) was added (Boc) _2O (5.20 g, 23.8 mmol) at 5°C. The reaction was continued for 2 hours. TLC demonstrated completion of the reaction. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 ml) and H ₂ O (10 ml) for 0.5 h. The mixture was filtered and the solid was collected and dried in an oven at 50°C to obtain the title compound as white solid (5.9 g, 98.7%). ¹ H NMR (400 MHz, DMSO-d6): δ 1.28 (d, J=7.2 Hz, 3H), 1.36 (s, 9H), 4.55-4.60 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.39 (br, 1H), 7.49 (d, J=8.4 Hz, 2H).

[00542] Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (3)

[00543] Stir a mixture of intermediate 2 (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium(II) acetate (29.6 mg, 0.13 mmol ) and potassium acetate (2.61 g, 26.6 mmol) in N,N-dimethylacetamide (10 ml) at 90°C under N ₂ for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. H ₂ O (50 ml) was added to the filtrate and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50°C to give (S)-tert-butyl-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3% ) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4, 64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1] ⁺ : 319.5.

[00544] This solid (1.9 g, 6.0 mmol) was dissolved in 4 N. a solution of hydrochloride in methanol (5 ml, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was filtered and the solid was collected and dried in an oven at 60°C to give (S)-1 -(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid. ^1H NMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H) , 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1] ⁺ : 219.2.

[00545] Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylic acid (6)

[00546] Add HATU (2.15 g, 5.7 mmol) to a solution of (S)-1-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (1.25 g, 5.4 mol), ( 2S,4R)-methyl-4-hydroxypyrrolidine-2-carboxylate hydrochloride (0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) in DMF (10 ml) at 0°C in nitrogen atmosphere. The mixture was stirred at ambient temperature for 18 hours. TLC demonstrated completion of the reaction. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (15 ml X 4). The combined organic layer was washed with 5% citric acid (10 ml X 2), saturated NaHCO ₃ solution (10 ml X 2), brine (10 ml X 2) and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated to give (2S,4R)-methyl-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylate as pale -yellow oil (1.93 g, 100% yield). This crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were taken into THF (20 ml) and H ₂ O (10 ml). The resulting mixture was stirred at ambient temperature for 18 hours. THF was removed by concentration. The residue was diluted with ice water (10 ml) and slowly adjusted to pH 2-3 with 3N. HCI. The resulting suspension was filtered and washed with H ₂ O (6 ml x 2). The solid was collected by filtration and dried in an oven at 50°C to give the title compound as a white solid (1.4 g, 75% in two steps). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.50 (d, J=9.6 Hz, 1H), 5.19 (br s, 1H), 4.32 (br s, 1H), 4.25 (t, J=8.4 Hz, 1H), 4.16 (d, J=9.2 Hz, 1H), 3.57-3.66 (m, 2H), 2.08-2 .13 (m, 1H), 1.85-1.91 (m, 1H), 1.38 (s, 9H), 0.94 (s, 9H).

[00547] Step 4: Preparation of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (7)

[00548] Add HATU (1.6 g, 4.2 mmol) to a stirred solution of Intermediate 6 (1.21 g, 3.5 mmol), Intermediate 3 (0.9 g, 3.5 mmol) and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 ml) at 0°C. The resulting mixture was heated to ambient temperature and stirring was continued for 2 hours. TLC demonstrated completion of the reaction. THF was removed by concentration. Water (15 ml) was added to the residue and the resulting mixture was stirred for 4 hours. The resulting mixture was filtered. The solid was collected and dried in an oven at 50°C to obtain a white solid. This solid was taken into methanol (10 ml) and activated carbon (150 mg) was added. The resulting mixture was heated at 80°C and stirred for 1 hour. The mixture was filtered while it was hot. Water (5 ml) was added to the filtrate at 80°C. The resulting mixture was cooled to ambient temperature and continued stirring for 18 hours. The suspension was filtered. The solid was collected and oven dried at 50°C to give tert-butyl-{(S)-1-[(2S,4R)-4-hydroxy]-2-[(S)-1-(4-(4 -methylthiazol-5-yl)phenyl)ethylcarbamoyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-ylcarbamate (1.41 g, 74.2%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J=7.2 Hz, 3H), 2.04- 2.10 (m, 1H), 2.53 (s, 3H), 2.58-2.64 (m, 1H), 3.23 (s, 1H), 3.58 (dd, J=11, 2 Hz, 3.2 Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 4.22 (d, J=9.2 Hz, 1H), 4.51 (br, 1H ), 4.79 (t, J=8.0 Hz, 1H), 5.04-5.11 (m, 1H), 5.22 (d, J=8.8 Hz, 1H), 7.36 -7.42 (m, 4H), 7.61 (d, J=7.6 Hz 1H), 8.68 (s, 1H). This solid (1.04 g, 1.9 mmol) was dissolved in 4 N. a solution of hydrogen chloride in methanol (3.0 ml) and the mixture was stirred at ambient temperature for 3 hours. TLC demonstrated completion of the reaction. The reaction mixture was concentrated to remove all volatiles under reduced pressure to obtain a light yellow solid. The solid was added to TBME (5 ml) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered and the solid was collected and dried in an oven at 50°C to give intermediate 7 (0.92 g, 100% ). ^1H NMR (400 MHz, DMSO-d6): δ 1.03 (s, 9H), 1.38 (d, J=7.2 Hz, 3H), 1.72-1.79 (m, 1H) , 2.09-2.14 (m, 1H), 2.49 (s, 3H), 3.48-3.52 (m, 1H), 3.75-3.79 (m, 1H), 3 ,88-3.90 (m, 1H), 4.31 (br, 1H), 4.56 (t, J=8.4 Hz, 1H), 4.89-4.95 (m, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 8.20 (br, 3H), 8.67 (d, J=7 .6 Hz, 1H), 9.22 (s, 1H); ¹³ C NMR (400 MHz, DMSO-d6): δ 170.7, 167.1, 153.0, 146.5, 145.7, 132.5, 129.4, 129.3, 126.9, 69 ,4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8, 26.6, 23.0, 15.7; LC-MS [M+1] ⁺ : 445.6.

[00549] Intermediate 2. (2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride

[00550] Intermediate 2 was prepared using the same method as described in the preparation of Intermediate 1.

[00551] Intermediate 3. (2S,4R)-4-Hydroxy-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl) )benzyl)pyrrolidine-2-carboxamide

[00552] Step 1: Preparation of methyl 3-(benzyloxy)isoxazole-5-carboxylate

[00553] To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (7.20 g, 50.31 mmol, 1.00 eq.) in acetone (150 ml) was added potassium carbonate (13.91 g, 100.62 mmol , 2.00 eq.). The mixture was heated to 80°C for 1 hour, then (bromomethyl)benzene (10.33 g, 60.37 mmol, 1.20 eq.) was added. The resulting mixture was stirred at 80°C for an additional 3 hours. LC/MS demonstrated completion of the reaction. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1 to 10:1) to give methyl 3-benzyloxyisoxazole-5-carboxylate (9.50 g, 40.73 mmol, 81% yield) in the form of a colorless oil. The oil hardened after standing at 15°C for 15 hours. LC-MS (ESI) mass/charge: 256.0 [M+Na ⁺ ]; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.41 (m, 5H), 6.60 (s, 1H), 5.34 (s, 2H), 3.97 (s, 3H) .

[00554] Step 2: Preparation of (3-(benzyloxy)isoxazol-5-yl)methanol

[00555] Sodium borohydride (756 mg, 19.98 mmol, 2.00 eq.). The resulting mixture was stirred at 15°C for 3 hours. TLC (petroleum ether: ethyl acetate = 5:1) demonstrated completion of the reaction. The mixture was poured into hydrochloric acid (0.2 M, 200 ml) and extracted with ethyl acetate (150 ml x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-benzyloxyisoxazol-5-yl)methanol (1.85 g, 9.02 mmol, 90% yield %) in the form of a colorless oil. LC-MS (ESI) mass/charge: 206.1 [M+H ⁺ ].

[00556] Step 3: Preparation of 2-(3-(benzyloxy)isoxazol-5-yl)acetonitrile

[00557] To a solution of cyanide bromide (334 mg, 3.15 mmol, 1.05 eq.) and triphenylphosphine (787 mg, 3.00 mmol, 1.00 eq.) in dichloromethane (10 ml) was added a solution of (3- benzyloxyisoxazol-5-yl)methanol (616 mg, 3.00 mmol, 1.00 eq.) in dichloromethane (10 ml). The mixture was stirred at 15°C for 1 hour, then 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (480 mg, 3.15 mmol) was added at 0°C , 1.05 eq.). The resulting mixture was stirred at 0°C for another 14 hours. LC-MS demonstrated completion of the reaction. The solvent was concentrated in vacuo. The residue was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 4:1) to give 2-(3-benzyloxyisoxazol-5-yl)acetonitrile (320 mg, 1.49 mmol, 50% yield ) in the form of a colorless oil. LC-MS (ESI) mass/charge: 215.0 [M+H ⁺ ]; ^1H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.41 (m, 5H), 6.06 (s, 1H), 5.30 (s, 2H), 3.82 (s, 2H) .

[00558] Step 4: Preparation of 2-(3-(benzyloxy)isoxazol-5-yl)-3-methylbutanenitrile

[00559] To a solution of 2-(3-benzyloxyisoxazol-5-yl)acetonitrile (214 mg, 1.00 mmol, 1.00 eq.) in N,N-dimethylformamide (3 mL) was added potassium carbonate (138 mg, 1 .00 mmol, 1.00 eq.). The mixture was stirred at 15°C for half an hour, then 2-iodopropane (170 mg, 1.00 mmol, 1.00 eq.) was added. The resulting mixture was stirred at 15°C for an additional 2.5 hours. LC-MS showed no reaction. Potassium 2-methylpropan-2-olate (90 mg, 0.8 mmol, 0.80 eq.) was then added to the mixture and the mixture was stirred at 15°C for an additional 12 hours. TLC (petroleum ether: ethyl acetate = 3:1) demonstrated almost complete completion of the reaction. The mixture was poured into hydrochloric acid (0.2 M, 30 ml), extracted with ethyl acetate (30 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 8:1) to give 2-(3-benzyloxyisoxazol-5-yl)-3-methylbutanenitrile (150 mg, 0.56 mmol, yield 59%) in the form of a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.41 (m, 5H), 6.04 (s, 1H), 5.28 (s, 2H), 3.85 (d, J= 5.6 Hz, 1H), 2.42-2.37 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

[00560] Step 5: Preparation of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid

[00561] To a solution of 2-(3-benzyloxyisoxazol-5-yl)-3-methylbutanenitrile (3.40 g, 13.27 mmol, 1.00 eq.) in dioxane (30 ml) was added hydrochloric acid (11.8 M, 120 ml). The mixture was heated to 100°C and stirred at 100°C for 15 hours. LC/MS demonstrated completion of the reaction. The mixture was cooled to 15°C and extracted with ethyl acetate (150 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was further purified by preparative HPLC (column: Daiso 150×25 mm, 5 micron; mobile phase: [water (0.225% TFA)-ACN] to give 2-(3-hydroxyisoxazol-5-yl)-3-methylbutane acid (230 mg, 1.19 mmol, 9% yield) as a yellow solid LC-MS (ESI) wt/charge: 186.1 [M+H ⁺ ].

[00562] Step 6: Preparation of (2S,4R)-4-hydroxy-1-(2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl) )benzyl)pyrrolidine-2-carboxamide

[00563] Into a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoic acid (185 mg, 1.00 mmol, 1.00 eq.) and O-(4-azabenzotriazol-1-yl)-N ,N,N',N'-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol, 1.50 eq.) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (645 mg, 5.0 mmol, 5.00 eq.). The mixture was stirred at 15°C for half an hour, then (2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (353 mg, 1.0 mmol, 1.00 eq., salt hydrochloride). The resulting mixture was stirred at 15°C for an additional 14.5 hours. The mixture was poured into brine (50 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm, 10 microns; mobile phase: [water (0.225%FA)-ACN] to give (2S,4R)-4-hydroxy-1-[2-( 3-hydroxyisoxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (220 mg, 0.45 mmol, 46% yield ) as an off-white solid LC-MS (ESI) mass/charge: 485.1 [M+H ⁺ ].

[00564] Compound 111. (2S,4R)-1-((S)-2-tert-Butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy )phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-R-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide

[00565] Step 1: Preparation of 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene-1-oxide

[00566] Stir a mixture of 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (2 g, 6.23 mmol) and trifluoroacetic acid (20 ml) in dichloromethane (20 ml) at 0°C for 5 minutes followed by the addition of aqueous hydrogen peroxide (30%, 862 mg, 7.47 mmol). After stirring at 0°C for an additional 30 minutes, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 3 hours. TLC demonstrated the formation of the required product. Solid sodium bisulfite (392 mg, 3.11 mmol) was carefully added to the dark solution, followed by the addition of water (3 ml). The resulting mixture was stirred at room temperature for 15 minutes. Volatiles were removed under reduced pressure, the residue was partitioned between dichloromethane (150 ml) and water (80 ml), the organic phase was washed with aqueous sodium bicarbonate (1 N, 50 ml) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 0 to 4% ethyl acetate in dichloromethane) to give 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b ]thiophene-1-oxide (620 mg, 30% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ): 8 3.93 (s, 3H), 7.13-7.16 (m, 1H), 7.19-7.23 (m, 2H), 7.49 -7.50 (m, 1H), 7.56-7.58 (m, 1H), 7.79-7.82 (m, 2H).

[00567] Step 2: Preparation of 2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide

[00568] To a stirred solution of 4-(tetrahydro-2H-pyran-2-yloxy)phenol (303 mg, 1.56 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added sodium hydride (60% in mineral oil) in portions , 113 mg, 2.83 mmol) at 0°C. After stirring for 10 minutes at 0°C, 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene-1-oxide (500 mg, 1.42 mmol) was added and the resulting mixture was allowed to warm to room temperature. temperature and was stirred at room temperature for 2 hours. TLC demonstrated the formation of the required product. The reaction mixture was carefully quenched with water (25 ml) at 0°C and extracted with ethyl acetate (30 ml x 3). The combined organic layer was washed with water (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 0 to 4% ethyl acetate in dichloromethane) to give 2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide (500 mg , yield 75%) as a yellow oil. LC/MS: (ES ⁺ ): mass/charge 467.10 [M+H ⁺ ]; ^1H NMR (400 MHz, CDCl ₃ ): δ 1.59-1.70 (m, 3H), 1.82-1.86 (m, 2H), 1.93-2.04 (m, 1H) , 3.57-3.62 (m, 1H), 3.85-3.91 (m, 4H), 5.29-5.31 (m, 1H), 6.90-6.99 (m, 5H), 7.02-7.07 (m, 3H), 7.50 (s, 1H), 7.72-7.75 (m, 2H).

[00569] Step 3: Preparation of 4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol

[00570] Into a stirred solution of 2-(4-fluorophenyl)-6-methoxy-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenoxy)benzo[b]thiophene-1-oxide (500 mg, 1.0 mmol) and sodium iodide (804 mg, 5.36 mmol) in acetonitrile (5 ml), chlorotrimethylsilane (349 mg, 3.22 mmol) was added dropwise at room temperature, the resulting mixture was stirred at room temperature for 30 minutes. TLC demonstrated the formation of the required product. The reaction mixture was partitioned between aqueous sodium sulfite (1N, 60 ml) and ethyl acetate (150 ml). The organic layer was collected, washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was purified by flash chromatography on silica gel (eluting from 0 to 4% ethyl acetate in dichloromethane) to give 4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol (350 mg, 89% yield) as a white solid. LC/MS: (ES ⁺ ): mass/charge 366.90 [M+H ⁺ ]; ^1H NMR (400 MHz, CDCl ₃ ): δ 3.87 (s, 3H), 4.55 (s, 1H), 6.70-6.73 (m, 2H), 6.82-6.89 (m, 3H), 7.02-7.06 (m, 2H), 7.25-7.29 (m, 2H), 7.69-7.72 (m, 2H).

[00571] Step 4: Preparation of tert-butyl-2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy) ethoxy)ethoxy)acetate

[00572] Stir a mixture of 4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenol (350 mg, 1.00 mmol), tert-butyl-2-(2-(2 -(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (418 mg, 1.00 mmol) and potassium carbonate (414 mg, 3.00 mmol) in acetonitrile (10 ml) at reflux overnight. TLC demonstrated the formation of the required product. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (120 ml) and water (50 ml). The organic layer was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluting with 0 to 5% ethyl acetate in dichloromethane) to give tert-butyl-2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate (500 mg, yield 85%) as a dark oil. LC/MS: (ES ⁺ ): mass/charge 635.10 [M+Na ⁺ ]; ^1H NMR (400 MHz, CDCl ₃ ): δ 1.46 (s, 9H), 3.66-3.73 (m, 8H), 3.81-3.83 (m, 2H), 3.87 (s, 3H), 4.01 (m, 2H), 4.04-4.07 (m, 2H), 6.78-6.82 (m, 2H), 6.85-6.89 (m , 3H), 7.02-7.06 (m, 2H), 7.25-7.27 (m, 2H), 7.68-7.72 (m, 2H).

[00573] Step 5: Preparation of 2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophene-3-loxy)phenoxy)ethoxy)ethoxy)ethoxy) acetic acid

[00574] Stir a mixture of tert-butyl-2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy) ethoxy)acetate (440 mg, 0.72 mmol) and lithium chloride (610 mg, 14.38 mmol) in dry 1-methylpyrrolidin-2-one (4 ml) at 220°C for 3 hours. LC/MS demonstrated the formation of the desired product. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC to give 2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy) phenoxy)ethoxy)ethoxy)ethoxy)acetic acid (200 mg, 51% yield) as a brown oil. LC/MS: (ES ⁺ ): mass/charge 543.20 [M+H ⁺ ].

[00575] Step 6: Preparation of (2S,4R)-1-((S)-2-tert-butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophene-3- yloxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl )pyrrolidine-2-carboxamide

[00576] Into a stirred solution of 2-(2-(2-(2-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)ethoxy)ethoxy)ethoxy) salt acetic acid (130 mg, 0.24 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-( 4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide with hydrochloric acid (200 mg, crude) and N-ethyl-N-isopropylpropan-2-amine (124 mg, 0.96 mmol ) in anhydrous N,N-dimethylformamide (2 ml) was added HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (230 mg, 0.60 mmol ) at 0°C, the resulting mixture was heated to room temperature and it was stirred at room temperature for 30 minutes. TLC demonstrated the formation of the required product. The reaction mixture was partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC to give (2S,4R)-1-((S)-2-tert -butyl-14-(4-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yloxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4 -Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (25 mg, 11% yield) as a white solid. LC/MS: (ES ⁺ ): mass/charge 969.30 [M+H ⁺ ]; ¹ H NMR (400 MHz, CD ₃ OD): δ 1.03 (s, 9H), 1.49 (d, J=6.8 Hz, 3H), 1.92-1.99 (m, 1H) , 2.18-2.23 (m, 1H), 2.48, 2.49 (two separate, 3H), 3.70-3.75 (m, 9H), 3.81-3.86 (m , 3H), 4.03-4.09 (m, 4H), 4.43 (br, 1H), 4.55-4.59 (m, 1H), 4.68 (br, 1H), 4, 97-5.02 (m, 1H), 6.78-6.81 (m, 1H), 6.85-6.87 (m, 4H), 7.07-7.12 (m, 2H), 7.18-7.20 (m, 2H), 7.38-7.45 (m, 4H), 7.12-7.76 (m, 2H), 8.88 and 8.89 (two separate, 1H).

[00577] Compound 112. (2S,4R)-1-((S)-2-(2-(3-(3-(4-(2-(4-Fluorophenyl)-6-hydroxybenzo[b]thiophene- 3-yloxy)phenoxy)propoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine -2-carboxamide

[00578] Compound 112 was prepared using the same method as described for compound 111. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.03, 1.04 (two separate, 9H), 1.48-1 .58 (m, 3H), 1.87-2.03 (m, 5H), 2.19-2.24 (m, 1H), 2.47, 2.49 (two separate, 3H), 3, 57-3.65 (m, 6H), 3.76-4.02 (m, 6H), 4.45 (br, 1H), 4.55-4.71 (m, 2H), 4.97- 5.02 (m, 1H), 6.79-6.87 (m, 5H), 7.08-7.20 (m, 4H), 7.40-7.46 (m, 4H), 7. 72-7.76 (m, 2H), 8.87, 8.89 (two separate, 1H). LC/MS: (ES ⁺ ): mass/charge 953.30 [M+H ⁺ ].

[00579] Compound 113. (2S,4R)-1-((S)-2-(2-(2-(3-(4-(2-(4-Fluorophenyl)-6-hydroxybenzo[b]thiophene- 3-yloxy)phenoxy)propoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine -2-carboxamide

[00580] Compound 113 was prepared using the same method as described for compound 111. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.02 (s, 9H), 1.46-1.57 (m, 3H), 1.96-2.05 (m, 3H), 2.17-2.23 (m, 1H), 2.47 (s, 3H), 3.66-3.76 (m, 7H) , 3.83-3.86 (m, 1H), 3.99 4.08 (m, 4H), 4.44 (br, 1H), 4.55 4.59 (m, 1H), 4.68 -41.69 (m, 1H), 4.97-4.99 (m, 1H), 6.78-6.80 (m, 1H), 6.84, 6.86 (two separate, 4H), 7.07-7.11 (m, 2H), 7.18-7.20 (m, 2H), 7.38-7.44 (m, 4H), 7.64-7.76 (m, 3H ), 8.88 and 8.89 (two separate, 1H). LC/MS: (ES ⁺ ): mass/charge 939.30 [M+H ⁺ ].

[00581] Compound 140. (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-Bromophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Step 1. Preparation of 3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol

[00583] A solution of 3-bromo-2-(4-bromophenyl)-6-methoxy-1-benzothiophene (3.2 g, 7.99 mmol, 1.00 eq.) in dichloromethane (50 ml). Boron tribromide (1 M in dichloromethane) (50 mL, 5.00 eq.) was then added dropwise with stirring at room temperature. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water. The resulting solution was extracted with dichloromethane (100 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. This provided 3.0 g (crude) of 3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol as a brown solid. LC/-MS (ES ⁺ ): mass/charge 383.86/385.86 [M+H ⁺ ].

[00584] Step 2: Preparation of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)benzo[b]thiophene

[00585] A solution of 3-bromo-2-(4-bromophenyl)-1-benzothiophen-6-ol (3.0 g, 7.85 mmol, 1.00 eq.), sodium hydride (471.2 mg, 11.78 mmol, 1.50 eq.) in N,N-dimethylformamide (20 ml). The resulting solution was stirred for 10 minutes at room temperature. (Bromomethyl)benzene (1.5 g, 8.64 mmol, 1.1 eq.) was then added dropwise at room temperature. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water (150 ml). The solids were filtered and the crude product was purified by recrystallization from ethyl acetate. This provided 3.5 g (96%) of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)benzo[b]thiophene as a white solid. LC-MS (ES ⁺ ): mass/charge 473.91/475.91 [M+H ⁺ ].

[00586] Step 3: Preparation of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzothiophene-1-one

[00587] A solution of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1-benzothiophene (2.5 g, 5.27 mmol, 1.0 eq.) in trifluoroacetic acid (10 ml) and dichloromethane (10 ml). Hydrogen peroxide (0.5 mL, 1.20 eq., 33% aq) was then added dropwise at room temperature. The resulting solution was stirred for 5 hours at room temperature. The resulting solution was extracted with dichloromethane (100 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate. This provided 2.2 g (85%) of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-1-benzothiophen-1-one as a yellow solid. LC-MS (ES ⁺ ): mass/charge 489.91/491.91 [M+H ⁺ ].

[00588] Step 4: Preparation of 6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]-benzothiophen-1-one

[00589] A solution of 6-(benzyloxy)-3-bromo-2-(4-bromophenyl)-benzothiophen-1-one (1.2 g, 2.45 mmol, 1.00 eq.), hydride was placed in a round bottom flask sodium (147.0 mg, 6.12 mmol, 1.50 eq.) in N,N-dimethylformamide (20 ml). The resulting solution was stirred for 10 minutes at room temperature. 4-(oxan-2-yloxy)phenol (570.0 mg, 2.93 mmol, 1.20 eq.) was then added. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water. The resulting solution was extracted with ethyl acetate (100 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. This provided 1.5 g (crude) of 6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]benzothiophen-1-one as a yellow oil. LC/MS (ES ⁺ ): mass/charge 604.95/606.95 [M+H ⁺ ].

[00590] Step 5: Preparation of 4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenol

[00591] In a solution of 6-(benzyloxy)-2-(4-bromophenyl)-3-[4-(oxan-2-yloxy)phenoxy]benzothiophen-1-one (1.5 g, 2.49 mmol, 1 .00 eq.) in acetonitrile (20 ml), trimethylchlorosilane (540 mg, 4.97 mmol, 2.00 eq.) and sodium iodide (1.1 g, 3.00 eq.) were added. The resulting solution was stirred for 5 minutes at room temperature. The reaction mixture was then quenched by adding saturated sodium thiosulfate solution. The resulting solution was extracted with ethyl acetate (20 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. The residue was treated with a silica gel column, eluted with ethyl acetate/petroleum ether (v:v=1:2). This provided 800.0 mg (64%) of 4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenol as a yellow solid. ^1H NMR (400 MHz, CD ₃ OD): δ 7.62 (d,J=6.4 Hz, 2H), 7.35 (m, 9H), 6.95 (m, 1H), 6.80 (m, 2H), 6.70 (m, 2H), 5.15 (d, J=14.2 Hz, 2H); LC-MS (ES ⁺ ): mass/charge 504.95 [M+H ⁺ ].

[00592] Step 6: Preparation of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate

[00593] Place 2-(benzyloxy)ethan-1-ol (10.0 g, 65.71 mmol, 1.00 eq), tert-butyl-2-bromoacetate (19.2 g) into a 1000 mL round bottom flask , 98.43 mmol, 1.50 eq.), dichloromethane (150 ml), 37% sodium hydroxide solution (150 ml) and tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00 eq.). The resulting solution was stirred for 4 hours at room temperature in a water/ice bath. The resulting solution was extracted with dichloromethane (100 ml x 3) and the organic layers were combined and concentrated in vacuo. The residue was treated with a silica gel column and eluted with ethyl acetate/petroleum ether (1/15). This provided 15.0 g (86%) tert-butyl 2-[2-(benzyloxy)ethoxy]acetate as a yellow oil.

[00594] Step 7: Preparation of tert-butyl 2-(2-hydroxyethoxy) acetate

[00595] Palladium on carbon (15, 0 g, 92.02 mmol, 10.00 eq.). The solution was degassed and stirred under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. This provided 9.9 g (72%) of tert-butyl 2-(2-hydroxyethoxy)acetate as a light yellow solid.

[00596] Step 8: Preparation of tert-butyl 2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)acetate

[00597] To a solution of tert-butyl-2-(2-hydroxyethoxy)acetate (4.5 g, 25.54 mmol, 1.00 eq) in dichloromethane (50 mL) was added triethylamine (5.2 g, 51, 39 mmol, 2.01 eq.), 4-methylbenzene-1-sulfonyl chloride (5.8 g, 30.42 mmol, 1.20 eq.) and a catalytic amount of 4-dimethylaminopyridine. The resulting solution was stirred for 8 hours at room temperature. The reaction mixture was then quenched by adding water (100 ml). The resulting solution was extracted with dichloromethane (30 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline (20 ml × 1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). This provided 6.1 g (72%) tert-butyl 2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)acetate as a colorless oil. LC/MS (ES ⁺ ): mass/charge 275.06 [M+H ⁺ -Bu ^t ].

[00598] Step 9: Preparation of tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine -1-carboxylate

[00599] A solution of 4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenol ( 6.4 g, 12.71 mmol, 1.00 eq) in methylbenzene (120 ml). To this solution was added tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.9 g, 25.62 mmol, 2.00 eq.), triphenylphosphine (5.0 g, 19.06 mmol, 1.50 eq.) and diethyl azodicarboxylate (3.3 g, 18.95 mmol, 1.50 eq.). The resulting solution was stirred for 4 hours at 110°C in an oil bath. The reaction mixture was then quenched by adding water/ice (100 ml). The resulting solution was extracted with ethyl acetate (80 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline (50 ml × 1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with a C18 reverse phase column and eluted with methanol/water (3:5). The collected fractions were combined and concentrated in vacuo. This provided 4.0 g (44%) tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy )ethyl]piperazine-1-carboxylate as a yellow solid. LC/MS (ES ⁺ ): 716.95/718.95 [M+H ⁺ ].

[00600] Step 10: Preparation of 1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine hydrochloride

[00601] Into a solution of tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine- 1-carboxylate (4.0 g, 5.59 mmol, 1.00 eq.) in methanol (30 ml) was added hydrogen chloride in dioxane (4 N, 5 ml). The resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated in vacuo. This provided 3.3 g (91%) of 1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine hydrochloride as a yellow solid.

[00602] Step 11: Preparation of tert-butyl-2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-benzylkoxy-1-benzothiophen-3-yl]oxy]phenoxy )ethyl]piperazin-1-yl]ethoxy)acetate

[00603] Into a solution of 1-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine hydrochloride (5.6 g, 8.59 mmol, 1.00 eq.) in N,N-dimethylformamide (80 ml) was added potassium carbonate (2.4 g, 17.36 mmol, 2.00 eq.), tert-butyl-2- (2-[(4-methylbenzene)sulfonyl]oxyethoxy)acetate (3.7 g, 11.20 mmol, 1.30 eq.) and sodium iodide (430.0 mg, 4.30 mmol, 0.50 eq. ). The resulting mixture was stirred for 12 hours at 80°C in an oil bath. The reaction mixture was then quenched by adding water/ice (50 mL x 1). The resulting solution was extracted with ethyl acetate (50 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline solution (30 ml × 1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with a silica gel column, eluted with ethyl acetate/petroleum ether (2:1) to give 5.3 g (90%) tert-butyl-2-(2-[4-[2-(4-[[2 -(4-bromophenyl)-6-benzyloxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetate as a yellow solid. LC-MS (ES ⁺ ): mass/charge 773.20/775.20 [M+H ⁺ ].

[00604] Step 12: Preparation of 2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine -1-yl]ethoxy)acetic acid

[00605] Into a stirred solution of tert-butyl-2-(2-[4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy] phenoxy)ethyl]piperazin-1-yl]ethoxy)acetate (5.1 g, 6.59 mmol, 1.00 eq.) in dichloromethane (30 ml) was added dropwise boron tribromide in dichloromethane (1 N, 30, 0 ml) at 78°C. The resulting solution was stirred for 2 hours at -78°C. The reaction mixture was then quenched by adding water (50 ml). The resulting mixture was concentrated in vacuo. The residue was treated using a silica gel column and eluted with a solution of acetonitrile in water (40%). The collected fractions were combined and concentrated in vacuo. This provided 3.7 g (89%) 2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy )ethyl]piperazin-1-yl]ethoxy)acetic acid as a crude yellow solid. LC-MS (ES ⁺ ): mass/charge 626.90/628.90 [M+H ⁺ ]. This solid was further purified using preparative reverse phase HPLC.

[00606] Step 13: Preparation of (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy -1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[00607] Into a solution of 2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1 -yl]ethoxy)acetic acid

(500.0 mg, 0.80 mmol) in N,N-dimethyl form amide (10 ml) was added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4- Hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (445.0 mg, 1.03 mmol, 1.20 eq.), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (353.0 mg, 0.80 mmol, 1.00 eq.) and ethyldiisopropylamine (0.5 ml) at 0°C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water (100 ml). The resulting solution was extracted with ethyl acetate (100 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline solution (20 ml x 2). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: column: Gemini-NX C18 AXAI Packed, 21.2 x 150 mm, 5 µm; mobile phase: water (10 mmol/L ammonium bicarbonate) and acetonitrile (retention of 54.0% acetonitrile in 16 min); detector: UV 220 nm. This provided 207.1 mg (25%) of (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-bromophenyl) -6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4- methyl 1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.81 (s, 1H), 7.63-7.61 (d, J=8.4 Hz, 2H), 7.48-7.46 (d , J=8.4 Hz, 2H), 7.44-7.41 (m, 2H), 7.39-7.36 (m, 2H), 7.19-7.18 (m, 2H), 6.83-6.76 (m, 5H), 4.68 (s, 1H), 4.53-4.50 (m, 3H), 4.31 4.30 (m, 1H), 4.04 -3.98 (m, 4H), 3.97-3.94 (m, 2H), 3.69-3.67 (m, 2H), 2.74-2.65 (m, 12H), 2 .67 (s, 3H), 2.36-2.22 (m, 1H), 2.12-2.01 (m, 1H), 1.00 (m, 9H). LC-MS (ES ⁺ ): mass/charge 1041.25/1043.25 [MH ⁺ ].

[00608] Compound 118. (2S,4R)-1-((S)-2-(2-(2-(4-(2-(4-((2-(4-Fluorophenyl)-6-hydroxybenzo[ b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide

[00609] Compound 118 was prepared using the same method as described for compound 140. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.02, 1.05 (two separate, 9H), 2.07-2 ,12 (m, 1H), 2.21-2.27 (m, 1H), 2.47, 2.48 (two separate, 3H), 2.94-3.22 (m, 12H), 3, 80-3.88 (m, 4H), 4.07-4.18 (m, 4H), 4.34-4.38 (m, 1H), 4.50-4.55 (m, 3H), 4.70 (br, 1H), 6.78-6.86 (m, 5H), 7.07-7.12 (m, 2H), 7.17-7.18 (m, 1H), 7. 21 (d, J=2.0 Hz, 1H), 7.39-7.45 (m, 4H), 1.12-1.16 (m, 2H), 8.87, 8.88 (two separate , 1H). LC/MS: (ES ⁺ ): mass/charge 979.30 [M+H ⁺ ].

[00610] Compound 151. (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-Chlorophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[00611] Compound 151 was prepared using the same method as described for compound 140. ¹ H NMR (300 MHz, CD ₃ OD): δ 8.818 (s, 1H), 7.69-7.66 (m, 2H) , 7.50-7.30 (m, 6H), 7.18-7.14 (m, 2H), 6.83-6.75 (m, 5H), 4.79 (s, 1H), 4 .67-4.48 (m, 4H), 4.31-4.26 (m, 1H), 4.08-3.98 (m, 4H), 3.93-3.80 (m, 2H) , 3.79-3.75 (m, 2H), 2.90-2.61 (m, 11H), 2.43 (s, 3H), 2.19-2.11 (m, 1H), 2 ,10-2.06 (m, 1H), 1.01 (s, 9H); LC-MS (ES ⁺ ): mass/charge 995.30/997.30 [M+H ⁺ ].

[00612] Compound 153. (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2-(4-Bromophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4 -methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[00613] Compound 153 was prepared using the same method as described for compound 140. Briefly, in a solution of 2-(2-[4-[2-(4-[[2-(4-bromophenyl)-6-hydroxy- 1-Benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetic acid (50.0 mg, 0.08 mmol, step 12 for compound 140) in N,N-dimethylformamide (10 ml ) added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (47.0 mg, 0.10 mmol, 1.20 eq.), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (43 .0 mg, 0.10 mmol, 1.20 eq.) and N,N-diisopropylethylamine (41.0 mg, 0.32 mmol, 4.00 eq.). The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water (10 ml). The resulting solution was extracted with ethyl acetate (15 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline solution (10 ml × 1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by preparative HPLC to give 26.0 mg (31%) (2S,4R)-1-[(2S)-2-[2-(2-[4-[2-(4-[[2 -(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazin-1-yl]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[ (1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid. ^1H NMR (400 MHz, CD ₃ OD): δ 8.90-8.80 (s, 1H), 7.64-7.61 (m, 2H), 7.49-7.46 (m 2H) , 7.43-7.36 (m, 4H), 7.19-7.17 (m, 2H), 6.86-6.83 (m, 4H), 6.79-6.76 (m, 1H), 4.99-4.97 (m, 1H), 4.67 (s, 1H), 4.60-4.52 (m, 1H), 4.40 (m, 1H), 4.12 4.05 (m, 4H), 3.90-3.75 (m, 4H), 3.10-2.85 (m, 12H), 2.46-2.45 (2s, 3H), 2, 25-2.15 (m, 1H), 2.00-1.95 (m, 1H), 1.55 and 1.50 (2d, 3H), 1.01 (s, 9H); LC-MS (ES ⁺ ): mass/charge 1055.45/1057.45 [M+H ⁺ ].

[00614] Compound 121. (2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4-[[2-(4-Fluorophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenoxy)ethyl]-1H-pyrazol-3-yl]phenyl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[00615] A solution of 2-(4-[1-[2-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy) was placed in a 25 mL round bottom flask )ethyl]-1H-pyrazol-3-yl]phenyl)acetic acid (40.0 mg, 0.07 mmol, 1.00 eq., prepared according to Scheme 9A) in N,N-dimethylformamide (5.0 ml) and added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-K-[[4-(4-methyl-1,3-thiazol-5 -yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (39.0 mg, 0.08 mmol, 1.20 eq.). This was followed by the addition of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (37.0 mg, 0.08 mmol, 1.20 eq.) N-ethyl-N-isopropylpropan-2-amine (0.3 ml ) at 10°C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (20 ml x 3) and the organic layers were combined. The resulting mixture was washed with saline solution (10 mlx1). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo, then purified using preparative HPLC under the following conditions: column: X Bridge C18, 19 × 250 mm, 5 μm; mobile phase A: water / 110 mmol/l ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 20 ml/min.; gradient: from 10% B to 80%) B in 12 minutes; detection at 254 nm. This provided 15.4 mg (23%) of (2S,4R)-1-[(2S)-2-[2-(4-[1-[2-(4-[[2-(4-fluorophenyl) -6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]-1H-pyrazol-3-yl]phenyl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4- (4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.01 (s, 1H), 7.71-7.68 (m, 5H), 7.48-7.42 (m, 4H), 7. 40-7.36 (m, 2H), 7.34-7.10 (m, 4H), 6.78-6.76 (m, 5H), 6.58-6.58 (m, 1H), 4.64 (s, 1H), 4.62-4.60 (m, 5H), 4.38 4.30 (m, 3H), 3.87-3.80 (m, 1H), 3.77 -3.70 (m, 1H), 3.65-3.63 (m, 2H), 2.47 (s, 3H), 2.19-2.06 (m, 1H), 2.06-1 .98 (m, 1H), 0.99 (s, 9H); LC-MS (ES ⁺ ): mass/charge 993.05 [MH ⁺ ].

[00616] Compound 142. (2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-Fluorophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4 -methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[00617] Step 1: Preparation of 1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one

[00618] A solution of potassium hydroxide (15.6 g, 278.03 mmol, 10.00 eq), 3-methoxybenzene-1-thiol was placed in a 500 mL round bottom flask that was purged with nitrogen and maintained under an inert atmosphere of nitrogen. (35.6 g, 253.92 mmol, 1.00 eq.) in water (100 ml), ethanol (250 ml). This was followed by the dropwise addition of a solution of 2-bromo-1-(4-fluorophenyl)ethan-1-one (50.0 g, 230.38 mmol, 1.00 eq.) in ethyl acetate (80 ml) with stirring at 0 °C for 30 minutes. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. Solids were filtered off. The mixture was dried over anhydrous sodium sulfate. The residue was treated with a silica gel column, eluted with ethyl acetate/petroleum ether (v:v=1:10). This provided 133 g (80%) of 1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one as a yellow oil. LC/MS (ESI) mass/charge: 276.95 [M+1] ⁺ .

[00619] Step 2: Preparation of 2-(4-fluorophenyl)-6-methoxy-1-benzothiophene

[00620] A solution of 1-(4-fluorophenyl)-2-[(3-methoxyphenyl)sulfanyl]ethan-1-one (111.7 g, 404.23 mmol, 1.00 eq.) was placed in a 500 mL round bottom flask. ) in PPA (950 g). The resulting solution was stirred overnight at 130°C. The mixture was then cooled, poured into ice/water and adjusted to pH 7 with sodium carbonate. Solids were collected by filtration. The solid was dried in an oven under reduced pressure. This provided 37.6 g (36%) of 2-(4-fluorophenyl)-6-methoxy-1-benzothiophene as a brown solid. ¹ H NMR (300 MHz, DMSO) δ 7.77 (m, 4H), 7.56 (s, 1H), 7.33 (t, J=3.0 Hz, 2H), 7.02 (d, J=2.4 Hz, 1H), 3.83 (s, 3H).

[00621] Step 3: Preparation of 3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene

[00622] A solution of 2-(4-fluorophenyl)-6-methoxy-1-benzothiophene (17.0 g, 65.81 mmol, 1.00 eq), N-bromoacetamide (9, 1 g, 65.96 mmol, 1.01 eq.) in dichloromethane (420 ml). The resulting solution was stirred for 2 hours at room temperature. The resulting solution was extracted with ethyl acetate (500 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. The residue was treated on a silica gel column using ethyl acetate/petroleum ether (v:v=1:100). This provided 42.2 g (95%) of 3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene as a gray solid. LC/MS (ESI) mass/charge: 336.85 [M+1] ⁺ .

[00623] Step 4: Preparation of 3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol

[00624] A solution of 3-bromo-2-(4-fluorophenyl)-6-methoxy-1-benzothiophene (5.1 g, 15.12 mmol, 1.00 eq) in dichloromethane was placed in a 250 mL round bottom flask. 15 ml, 3.00 eq.). Tribromoborane (2M in dichloromethane, 20 ml) was added dropwise to the resulting mixture at room temperature. The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was then quenched by adding water. The resulting solution was extracted with dichloromethane (100 ml x 2) and the organic layers were combined. The resulting mixture was washed with saline solution. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. This provided 4.8 g (98%) of 3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol as a white solid.

[00625] Step 5: Preparation of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene

[00626] A solution of 3-bromo-2-(4-fluorophenyl)-1-benzothiophen-6-ol (4.8 g, 14. 85 mmol, 1.00 eq.), sodium hydride (890.0 mg, 37.08 mmol, 1.50 eq.) in N,N-dimethylformamide (100 ml). The resulting solution was stirred for 10 minutes at room temperature. (Bromomethyl)benzene (3.8 g, 22.22 mmol, 1.50 eq.) was then added dropwise with stirring for 2 hours at room temperature. The reaction mixture was then quenched by adding water. Solids were collected by filtration. The crude product was purified by recrystallization from ethyl acetate. This provided 5.6 g (91%) of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.77 (m, 3H), 7.45 (m, 6H), 7.17 (m, 3H), 5.25 (s, 2H).

[00627] Step 6: Preparation of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)benzothiophen-1-one

[00628] A solution of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)-1-benzothiophene (20.0 g, 48.39 mmol, 1.00 eq.) was placed in a 1000 mL round bottom flask. trifluoroacetic acid (200 ml), dichloromethane (200 ml). H ₂ O ₂ (30%, 11.3 ml, 3.00 eq.) was then added dropwise at 0°C. The resulting solution was stirred for 3 hours at room temperature. The reaction mixture was then quenched by adding sodium sulfite. The resulting solution was extracted with dichloromethane (500 ml x 2) and the organic layers were combined and dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate to provide 15.5 g (75%) of 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)benzothiophen-1-one as a yellow solid. LC/MS (ESI) mass/charge: 428.90 [M+1] ⁺ .

[00629] Step 7: Preparation of 6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)benzothiophen-1-one

[00630] Place 4-bromophenol (725.9 mg, 4.20 mmol, 1.00 eq), 6-(benzyloxy)-3-bromo-2-(4-fluorophenyl)benzothiophene- into a 100 mL round bottom flask. 1-one (1.8 g, 4.19 mmol, 1.00 eq), potassium carbonate (1.7 g, 12.30 mmol, 3.00 eq), N,N-dimethylformamide (15 ml) . The resulting solution was first stirred for 3 hours at 70°C in an oil bath, and then stirred for 10 minutes at room temperature. The reaction mixture was quenched with water (50 ml), extracted with ethyl acetate (50 ml x 2), washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with a silica gel column, eluted with ethyl acetate/petroleum ether (v:v=1:8). This provided 1.7 g (78%) of 6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)benzothiophen-1-one as a yellow solid. LC/MS (ESI) mass/charge: 520.75 [M+1] ⁺ .

[00631] Step 8: Preparation of tert-butyl-4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3 ,6-tetrahydropyridine-1-carboxylate

[00632] Place 6-(benzyloxy)-3-(4-bromophenoxy)-2-(4-fluorophenyl)-1-benzothiophene (50.0 mg, 0.10 mmol, 1.00 eq) into a 25 mL round bottom flask .), tert-butyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (61.2 mg, 0.20 mmol, 2 .00 eq.), potassium carbonate (41.0 mg, 0.30 mmol, 3.00 eq.), ethylene glycol dimethyl ether (2 ml), water (0.5 ml), tetrakis(triphenylphosphine) palladium (22, 9 mg, 0.02 mmol, 0.05 eq.). The resulting solution was stirred for 2 hours at 100°C in an oil bath. The mixture was concentrated in vacuo. The residue was treated with a silica gel column, eluted with ethyl acetate/petroleum ether (v:v=1:5). This provided 40.0 mg (67%) tert-butyl-4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1 ,2,3,6-tetrahydropyridine-1-carboxylate as a yellow oil. LC/MS (ESI) mass/charge: 608.15 [M+1] ⁺ .

[00633] Step 9: Preparation of 4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3,6-tetrahydropyridine

[00634] Place tert-butyl-4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1 into a 25 mL round bottom flask. 2,3,6-tetrahydropyridine-1-carboxylate (250.0 mg, 0.41 mmol, 1.00 eq.) and hydrogen chloride/dioxane (5 ml). The resulting solution was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo. This provided 230.0 mg (crude) of 4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3 ,6-tetrahydropyridine as a yellow oil. LC/MS (ESI) mass/charge: 508.05 [M+1] ⁺ .

[00635] Step 10a. Preparation of tert-butyl-[2-(2-hydroxyethoxy)ethoxy]acetate

[00636] To a cooled and stirred solution of diethylene glycol (3 eq.) in anhydrous N,N-dimethylformamide [amount of dihydric alcohol (g) x 5 ml] add sodium hydride (60%, 1.2 eq.) in portions at 0°C in a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour, then re-cooled to 0° C. and tert-butyl-2-bromoacetate (1 eq.) was added in portions. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with water (amount of dihydric alcohol × 10 ml) while cooling with ice water and extracted with methylene dichloride. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 1 to 6% methanol in methylene dichloride) to give the desired product as a colorless oil (46% yield). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.03 (s, 2H), 3.62-3.76 (m, 8H), 2.46 (br, 1H), 1.48 (s, 9H ).

[00637] Step 10b. Preparation of tert-butyl-2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1, 2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetate

[00638] 4-(4-[[6-(Benzyloxy)-2-(4-fluorophenyl)-1-benzothiophen-3-yl]oxy]phenyl)-1,2,3 was placed in a 50 mL round bottom flask. 6-tetrahydropyridine (230.0 mg, 0.45 mmol, 1.00 eq.), tert-butyl-2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]acetate ( 169.3 g, 452.13 mmol, 1.00 eq.), potassium carbonate (187.4 g, 1.36 mol, 3.00 eq.), N,N-dimethylformamide (5 ml). The resulting solution was stirred for 3 hours at 70°C in an oil bath. The mixture was diluted with water (15 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was treated with a silica gel column, eluted with dichloromethane/methanol (v:v=10:1). This provided 200.0 mg (62%) tert-butyl-2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophene-3 -yl]oxy]phenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetate as a yellow oil. LC/MS (ESI) mass/charge: 710.15 [M+1] ⁺ .

[00639] Step 11: Preparation of tert-butyl-2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl )piperidin-1-yl]ethoxy]ethoxy)acetate

[00640] Place tert-butyl-2-(2-[2-[4-(4-[[6-(benzyloxy)-2-(4-fluorophenyl)-1-benzothiophene-3-) into a 50 mL round bottom flask. yl]oxy]phenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethoxy]ethoxy)acetate (200.0 mg, 0.28 mmol, 1.00 eq.), methanol (5 ml), palladium on carbon (150.0 mg). Then hydrogen was introduced into it. The resulting solution was stirred for 3 hours at room temperature. Solids were filtered off. The resulting mixture was concentrated in vacuo. This provided 150.0 mg (86%) tert-butyl-2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl ]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetate as a yellow oil. LC/MS (ESI) mass/charge: 622.15 [M+1] ⁺ .

[00641] Step 12: Preparation of 2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidine-1 -yl]ethoxy]ethoxy)acetic acid

[00642] Place tert-butyl-2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl] into a 20 mL round bottom flask oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetate (150.0 mg, 0.24 mmol, 1.00 eq.), dichloromethane (1 ml), trifluoroacetic acid (1 ml). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo. This provided 120.0 mg (88%) of 2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl )piperidin-1-yl]ethoxy]ethoxy)acetic acid as a yellow oil. LC/MS (ESI) mass/charge: 566.25 [M+1] ⁺ .

[00643] Step 13: Preparation of (2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy -1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-( 4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (compound 142)

[00644] A solution of 2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl) was placed in a 50 mL round bottom flask )piperidin-1-yl]ethoxy]ethoxy)acetic acid (100.0 mg, 0.18 mmol, 1.00 eq.), (2S,4R)-1-[(2S)-2-amino-3, 3-dimethylbutanoyl]-4-hydroxy N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (78.5 mg, 0.18 mmol, 1.00 eq.), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (94.0 mg, 1.20 eq.), N,N-diisopropylethylamine (68.5 mg, 0 .53 mmol, 3.00 eq.) in N,N-dimethylformamide (1 ml). The resulting solution was stirred for 10 minutes at 0°C. The reaction mixture was then quenched by adding water. The mixture was extracted with ethyl acetate (20 ml x 2) and the organic layers were combined. The solution was washed with saline and dried over anhydrous sodium sulfate. Solids were filtered off. The resulting solution was concentrated in vacuo. The crude product was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 5 µm, 19 × 150 mm; mobile phase: water with 0.05% trifluoroacetic acid and acetonitrile/methanol=1/1; detector: UV 254 nm. This provided 38.0 mg (22%) of (2S,4R)-1-[(2S)-2-[2-(2-[2-[4-(4-[[2-(4-fluorophenyl) -6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1- [4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid. LC/MS (ESI) mass/charge: 992.40 [M+1] ⁺ ; ¹ H-NMR (400 MHz, CD ₃ OD) δ 8.87 (s, 1H), 7.72 (m, 3H), 7.40 (m, 4H), 7.15 (m, 6H), 6 .92 (m, 1H), 6.79 (m, 1H), 4.97 (m, 1H), 4.72 (m, 1H), 4.55 (m, 1H), 4.30 (m, 1H), 4.09 (m, 2H), 3.89 (m, 2H), 3.74 (m, 7H), 3.45 (m, 3H), 3.18 (m, 2H), 2, 89 (m, 1H), 2.45 (s, 3H), 2.22 (m, 1H), 2.11 (m, 2H), 1.95 (m, 3H), 1.45 (m, 3H ), 1.05 (s, 9H).

[00645] Compound 147. (2S,4R)-N-[(1S)-1-(4-Cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[2-[4- (4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4 -hydroxypyrrolidine-2-carboxamide

[00646] Step 1: Preparation of tert-butyl-N-[(2S)-1-[(2S,4R)-2-{[(1S)-1-(4-cyanophenyl)ethyl]carbamoyl}-4-hydroxypyrrolidine -1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[00647] In a solution containing (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.75 g, 5.10 mmol) and (S)-4-(1-aminoethyl)benzonitrile hydrochloride (933.0 mg, 5.10 mmol) in DMF (10.00 ml), TBTU (2.45 g) was added at room temperature , 7.64 mmol) and DIPEA (2.70 ml, 15.6 mmol). The mixture was stirred for 2 hours and then quenched with water and extracted with EtOAc. The mixture was washed with water (3x), brine (2x), filtered through a Biotage Universal phase separator and then concentrated in vacuo. The crude material was purified by silica gel chromatography using a Teledyne Combiflash ISCO system eluting with MeOH/DCM (0:100 to 7:93) to give tert-butyl-((S)-1-((2S,4R) -2-(((S)-1-(4-cyanophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (2.02 g , 4.27 mmol, 83.8%). LC/MS (ESI) mass/charge: 473.21 [M+1] ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J=4.7 Hz, 1H), 7.64 (dd, J=3.5, 8.2 Hz, 2H), 7, 42 (dd, J=3.5, 8.2 Hz, 2H), 5.20 (d, J=8.6 Hz, 1H), 5.05 (dt, J=3.5, 7.0 Hz , 1H), 4.79 (dt, J=3.1, 7.8 Hz, 1H), 4.50 (br. s., 1H), 4.12-4.23 (m, 2H), 3 .55 (d, J=11.3 Hz, 1H), 2.52-2.62 (m, 1H), 2.03-2.12 (m, 1H), 1.68 (br. s., 1H), 1.39-1.47 (m, 12H), 1.05 (d, J=3.5 Hz, 9H).

[00648] Step 2: Preparation of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-N-[(1S)-1-(4-cyanophenyl)ethyl]-4- Hydroxypyrrolidine-2-carboxamide hydrochloride

[00649] A solution of tert-butyl-((S)-1-((2S,4R)-2-(((S)-1-(4-cyanophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl) was stirred )-3,3-dimethyl-1-oxobutan-2-yl)carbamate (2.03 g, 4.29 mmol) in a solution of hydrogen chloride (4 M) in dioxane (5.93 ml, 171 mmol) was stirred at room temperature within 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a white solid. The material was diluted with toluene and concentrated several times and then placed under high vacuum for 30 minutes to give an off-white solid as (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl) -N-((S)-1-(4-cyanophenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (1.60 g, 3.91 mmol, 91.4%). LC/MS (ESI) mass/charge: 411.24 [M+1] ⁺ ; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=5.9 Hz, 1H), 8.04 (br. s., 3H), 7.54 (d, J=8, 6 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.93-5.04 (m, 2H), 4.56 (br. s., 1H), 4.46 (d, J=4.3 Hz, 1H), 4.09 (d, J=11.7 Hz, 1H), 3.59 (d, J=11.0 Hz, 1H), 2.24 (dd ,J=7.6, 13.1 Hz, 1H), 1.93-2.04 (m, 1H), 1.53 (d, J=7.0 Hz, 3H), 1.29 (s, 9H).

[00650] Step 3: Preparation of (2S,4R)-N-(1S)-1-(4-cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[2-[4- (4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4 -hydroxypyrrolidine-2-carboxamide (147)

[00651] A solution of 2-(2-[2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl) was placed in a 50 mL round bottom flask )piperidin-1-yl]ethoxy]ethoxy)acetic acid (100.0 mg, 0.18 mmol, 1.00 eq.), (2S,4R)-1-[(2S)-2-amino-3, 3-dimethylbutanoyl]-N-[(1S)-1-(4-cyanophenyl)ethyl]-4-hydroxypyrrolidine-2-carboxamide hydrochloride (66.0 mg, 0.18 mmol, 1.00 eq.) in N, N-dimethylformamide (5 ml). Then (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (94.0 mg, 1.20 eq.), N,N-diisopropylethylamine (68.0 mg, 0.53 mmol, 3.00 eq.) .) at 0°C. The reaction mixture was stirred for 4 hours and then quenched by adding water. The resulting solution was extracted with ethyl acetate (20 ml x 2) and the organic layers were combined. The solution was washed with saline. The mixture was dried over anhydrous sodium sulfate. Solids were filtered off. The filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19 x 150 mm; mobile phase: water with 0.05% trifluoroacetic acid and acetonitrile/methanol = 1/1; detector: UV 254 nm. This provided 35.2 mg (22%) of (2S,4R)-N-[(1S)-1-(4-cyanophenyl)ethyl]-1-[(2S)-2-[2-(2-[ 2-[4-(4-[[2-(4-fluorophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl)piperidin-1-yl]ethoxy]ethoxy)acetamido]-3,3 -dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxamide as a white solid. LC/MS (ESI) mass/charge: 920.35 [M+1] ⁺ ; ¹ H-NMR (400 MHz, CD ₃ OD) δ 7.77 (m, 4H), 7.45 (m, 2H), 7.20 (m, 4H), 7.09 (m, 2H), 6 .92 (m, 2H), 6.79 (m, 1H), 4.93 (m, 1H), 4.72 (m, 1H), 4.55 (m, 1H), 4.30 (m, 1H), 4.09 (m, 2H), 3.89 (m, 2H), 3.74 (m, 7H), 3.45 (m, 3H), 3.18 (m, 2H), 2, 89 (m, 1H), 2.22 (m, 1H), 2.12 (m, 2H), 1.90 (m, 3H), 1.45 (m, 3H), 1.02 (s, 9H ).

[00652] Compound 158. (2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4-[[2-(4-Bromophenyl)-6-hydroxy- 1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[00653] Step 1: Preparation of 1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene

[00654] A solution of 4-(benzyloxy)phenol (5 g, 24.97 mmol, 1.00 eq.) in tetrahydrofuran (200 mL), 37% NaOH (200 mL) and 1-bromo was placed in a 1000 mL round bottom flask. -2-(2-bromoethoxy)ethane (57.5 g, 247.94 mmol, 10.00 eq.). The resulting solution was stirred overnight at 70°C in an oil bath. The reaction mixture was cooled. The resulting solution was extracted with dichloromethane and the organic layers were combined. The solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified using a silica gel column (ethyl acetate/petroleum ether) to give 1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene (6.67 g, 76%) as a white solid.

[00655] Step 2: Preparation of tert-butyl 4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate

[00656] A solution of 1-(benzyloxy)-4-[2-(2-bromoethoxy)ethoxy]benzene (2 g, 5.69 mmol, 1.00 eq) in acetonitrile (100 mL) was placed in a 250 mL round bottom flask ), tert-butylpiperazine-1-carboxylate (1.79 g, 9.61 mmol, 1.20 eq), potassium carbonate (3.31 g, 23.95 mmol, 3.00 eq) and KI (0 .0664 g, 0.05 eq.). The resulting mixture was stirred for 16 hours at 80°C in an oil bath and then filtered and concentrated in vacuo. The residue was treated with a silica gel column, eluted with dichloromethane/methanol (10:1) to give tert-butyl 4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate ( 2.48 g, 95%) as a yellow oil. LC/MS (ESI) mass/charge: 456.26 [M+1] ⁺ .

[00657] Step 3: Preparation of tert-butyl 4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate

[00658] In a solution of tert-butyl 4-(2-[2-[4-(benzyloxy)phenoxy]ethoxy]ethyl)piperazine-1-carboxylate (2.48 g, 5.43 mmol, 1.00 eq. ) Pd/C (10%, 1.0 g) was added to 50 mL MeOH under nitrogen atmosphere in a 100 mL round bottom flask. The flask was degassed and purged with hydrogen. The reaction mixture was hydrogenated at 40°C for 16 hours under a hydrogen atmosphere using a hydrogen cylinder, then filtered through a pad of celite and concentrated under reduced pressure. The residue was treated with a silica gel column, eluted with dichloromethane/methanol (10:1) to give tert-butyl 4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate (1.6 g, 80%) as an off-white solid. LC/MS (ESI) mass/charge: 366.22 [M+1] ⁺ .

[00659] Step 4: Preparation of tert-butyl-4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-oxobenzothiophen-3-yl]oxy]phenoxy) ethoxy]ethyl]piperazine-1-carboxylate

[00660] A solution of tert-butyl 4-[2-[2-(4-hydroxyphenoxy)ethoxy]ethyl]piperazine-1-carboxylate (500 mg, 1.36 mmol, 1.00 eq) was placed in a 100 mL round bottom flask .) in N,N-dimethylformamide (30 ml). This was followed by the addition of sodium hydride (56.6 mg, 2.36 mmol, 2.30 eq.) and the mixture was stirred at 0°C for bromophenyl)benzothiophen-1-one (450 mg, 0.92 mmol, 1. 20 eq.). The resulting solution was stirred for 16 hours at room temperature and then diluted with ethyl acetate. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column (dichloromethane/methanol = 10/1 to 8/1) to give tert-butyl-4-[2-[2-(4-[[6-(benzyloxy)-2-(4 -bromophenyl)-1-oxobenzothiophene-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine-1-carboxylate (916 mg, 87%) as a yellow crude oil. LC/MS (ESI) mass/charge: 774.20 [M+1] ⁺ .

[00661] Step 5: Preparation of tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine -1-carboxylate

[00662] Place tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-oxobenzothiophen-3-yl]oxy]phenoxy) into a 100 mL round bottom flask. ethyl]piperazine-1-carboxylate (916 mg, 1.25 mmol, 1.00 eq), NaI (1882.5 mg, 10.00 eq), TMSCl (406.6 mg, 3.74 mmol, 3 .00 eq.) in 40 ml of acetonitrile. The mixture was stirred for 16 hours at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified using a silica gel column (dichloromethane/methanol = (10/1 to 8/1) to give tert-butyl-4-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl )-1-Benzothiophen-3-yl]oxy]phenoxy)ethyl]piperazine-1-carboxylate (147 mg, 16%) as a yellow oil. LC/MS (ESI) wt/charge: 758.20

[00663] Step 6: Preparation of 1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl] piperazine

[00664] A solution of tert-butyl-4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl] was placed in a 50 mL round bottom flask. oxy]phenoxy)ethoxy]ethyl]piperazine-1-carboxylate (147 mg, 0.19 mmol, 1.00 eq.) in dichloromethane (10 ml) and trifluoroacetic acid (3 ml). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated in vacuo. This provided 1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazine; 2,2,2-trifluoroacetaldehyde (920 mg) as a yellow crude oil. LC/MS (ESI) mass/charge: 658.15 [M+1] ⁺ .

[00665] Step 7: Preparation of tert-butyl-2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy ]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetate

[00666] A solution of 1-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy) was placed in a 100 mL round bottom flask. ethoxy]ethyl]piperazine in acetonitrile (20 ml), DIEA (2.0 ml) and tert-butyl-2-bromoacetate (619.1 mg, 3.17 mmol, 3.00 eq.). The resulting solution was stirred for 3 hours at room temperature and then evaporated. The residue was diluted with dichloromethane and washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was treated with a silica gel column and eluted with ethyl acetate/petroleum ether. This provided the production of tert-butyl-2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophen-3-yl]oxy]phenoxy) ethoxy]ethyl]piperazin-1-yl)acetate (280 mg, 39%) as a yellow oil. LC/MS (ESI) mass/charge: 772.22 [M+1] ⁺ .

[00667] Step 8: Preparation of 2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl ]piperazin-1-yl)acetic acid

[00668] A solution of tert-butyl-2-(4-[2-[2-(4-[[6-(benzyloxy)-2-(4-bromophenyl)-1-benzothiophene-3) was placed in a 100 mL round bottom flask -yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetate (266 mg, 0.34 mmol, 1.00 eq.) in dichloromethane (30 ml). This was followed by dropwise addition of BBr ₃ (10 ml) with stirring at -70°C. The resulting solution was stirred for 4 hours at -70°C. The reaction mixture was then quenched by adding water. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to provide 2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy )ethoxy]ethyl]piperazin-1-yl)acetic acid (147 mg, 68%) as a yellow oil. LC/MS (ESI) mass/charge: 626.11 [M+1] ⁺ .

[00669] Step 9: Preparation of (2S,4R)-1-[(2S)-2-[2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy -1-benzothiophen-3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (compound 158)

[00670] A solution of 2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenoxy) was placed in a 50 mL round bottom flask )ethoxy]ethyl]piperazin-1-yl)acetic acid (50 mg, 0.08 mmol, 1.00 eq.) in N,N-dimethylformamide (20 ml). (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5) was added to this solution -yl)phenyl]methyl]pyrrolidine-2-carboxamide (37.3 mg, 0.09 mmol, 1.00 eq.), BOP (35.3 mg, 1.00 eq.) and DIEA (2 ml). The mixture was stirred for 1 hour at 0°C in a water/ice bath. The resulting solution was diluted with ethyl acetate and washed with saline. The solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD, 5 µm, 19 x 150 mm; mobile phase: water (0.1%) formic acid) and acetonitrile (from 32.0%) to 52.0% acetonitrile in 8 minutes); detector: UV 254 nm. This provided the production of (2S,4R)-1-[(28)-2-[2-(4-[2-[2-(4-[[2-(4-bromophenyl)-6-hydroxy-1-benzothiophene -3-yl]oxy]phenoxy)ethoxy]ethyl]piperazin-1-yl)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol- 5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (31.3 mg, 38%) as a white solid. LC/MS (ESI) mass/charge: 1038.30/1040.30 [M+1] ⁺ ; ¹ H-NMR (300 MHz, δ 8.862 (s, 1H), 8.323 (s, 1H), 7.64-7.60 (m, 2H), 7.49-7.37 (m, 5H), 7 ,18-7.15 (m, 2H), 6.83-6.75 (m, 5H), 4.63-4.31 (m, 5H), 4.08-4.05 (m, 2H) , 3.85-3.78 (m, 5H), 3.18-3.07 (m, 7H), 2.71-2.62 (m, 3H), 2.45-2.40 (m, 3H), 2.29-2.03 (m, 2H), 1.28-1.27 (m,

[00671] Compound 164. (2S,4R)-1-((S)-2-(3-(2-(4-(2-(4-((2-(4-Bromophenyl)-6-hydroxybenzo[ b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide

[00672] Step 1: Preparation of tert-butyl 4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate

[00673] In a solution of tert-butyl-4-(2-chloroethyl)piperazine-1-carboxylate (1.00 g, 4.02 mmol, 1.00 eq.), 4-benzyloxyphenol (965 mg, 4.82 mmol , 1.20 eq.) in N,N-dimethylformamide (20 ml) was added cesium carbonate (1.57 g, 4.82 mmol, 1.20 eq.) and potassium iodide (66 mg, 0.4 mmol, 0 .10 eq.) in a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 10 hours. TLC (petroleum ether/ethyl acetate = 3/1) and LC/MS demonstrated that most of the starting material was consumed. Water (100 ml) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with brine (80 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 3/1) to give tert-butyl 4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate (1,4 g, 3.39 mmol, yield 84%) as a colorless oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.29 (m, 5H), 6.95-6.88 (m, 2H), 6.88-6.81 (m, 2H), 5.02 (s, 2H), 4.07 (t, J=5.8 Hz, 2H), 3.51-3.42 (m, 4H), 2.80 (t, J=5.8 Hz , 2H), 2.56

[00674] Step 2: Preparation of tert-butyl 4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate

[00675] To a solution of tert-butyl 4-[2-(4-benzyloxyphenoxy)ethyl]piperazine-1-carboxylate (1.40 g, 3.39 mmol, 1.00 eq.) in methanol (20 mL) was added palladium on carbon (200 mg, purity 10%) in a nitrogen atmosphere. The suspension was degassed in vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 20°C for 4 hours. TLC (petroleum ether/ethyl acetate = 1/1) demonstrated that most of the starting material had been consumed. The reaction mixture was filtered and the filtrate was evaporated and dried in vacuo to give tert-butyl 4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate (1 g, 3.07 mmol, 90% yield, 99% purity, as a light yellow solid ^1H NMR (400 MHz, CDCl ₃ ) 6.74 (s, 4H), 4.04 (t, J=5.6 Hz, 2H), 3.54-3.38 (m, 5H), 2.79 (t, J=5.6 Hz, 2H), 2.53 (s, 4H), 1.46 (s, 9H).

[00676] Step 3: Preparation of tert-butyl-4-(2-(4-((2-(4-bromophenyl)-6-methoxy-1-oxidobenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl )piperazine-1-carboxylate

[00677] A solution of tert-butyl-4-[2-(4-hydroxyphenoxy)ethyl]piperazine-1-carboxylate (234 mg, 0.72 mmol, 1.00 eq.) in N,N-dimethylformamide (5 ml ) NaH (29 mg, 0.72 mmol, 60% mineral oil, 1.00 eq.) was added at 0°C. The mixture was stirred at 20°C for 0.5 hour. Then 3-bromo-2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium (300 mg, 0.72 mmol, 1.00 eq.) was added and the mixture was stirred at 20°C for 1 hours. LC/MS demonstrated completion of the reaction and the required MS could be determined. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy -1-oxidobenzothiophene-1-yl-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate (430 mg, 0.66 mmol, 90% yield) as a yellow solid, which was directly used for the next step without further purification . LC/MS (ESI) mass/charge: 657.5 [M+1] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J=8.4 Hz, 2H), 7.52-7.46 (m, 3H), 7.05-6.89 (m, 4H), 6.81 (d, J=8.4 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.89 (s, 3H), 3.50-3, 42 (m, 4H), 2.81 (t, J=5.6 Hz, 2H), 2.52 (s, 4H), 1.47 (s, 9H).

[00678] Step 4: Preparation of tert-butyl-4-(2-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazine-1 -carboxylate

[00679] Into a solution of tert-butyl-4-[2-[4-[2-(4-bromophenyl)-6-methoxy-1-oxidobenzothiophene-1-ium-3-yl]oxyphenoxy]ethyl]piperazine-1- carboxylate (370 mg, 0.56 mmol, 1.00 eq.) in acetonitrile (6 ml) added sodium iodide (254 mg, 1.69 mmol, 3.00 eq.) and trimethylchlorosilane (123 mg, 1.13 mmol , 2.00 eq.). The mixture was stirred at 20°C for 1 hour. LC/MS demonstrated that the reaction was complete and the required MS was determined. The reaction mixture was quenched with saturated sodium sulfite solution (2 ml), diluted with water (15 ml) and extracted with ethyl acetate (10 ml x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product tert-butyl-4-[2-[4-[2-(4-bromophenyl )-6-methoxybenzothiophen-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate (350 mg, crude), as a yellow oil, which was directly used for the next step without further purification. LC/MS (ESI) mass/charge: 639.0 [M+1] ⁺ .

[00680] Step 5: Preparation of 2-(4-bromophenyl)-3-(4-(2-(piperazin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-6-ol

[00681] Into a solution of tert-butyl 4-[2-[4-[2-(4-bromophenyl)-6-methoxybenzothiophen-3-yl]oxyphenoxy]ethyl]piperazine-1-carboxylate (350 mg, 0.55 mmol, 1.00 eq.) in dichloromethane (6 ml) was added boron tribromide (410 mg, 1.64 mmol, 0.16 ml, 3.00 eq.) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution (5 ml) at 0°C, diluted with water (10 ml) and extracted with dichloromethane (10 ml x 3). The combined organic phase was washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-(4-bromophenyl)-3-[4-(2-piperazin-1-ylethoxy)phenoxy] benzothiophen-6-ol (250 mg, crude) as a yellow solid, which was directly used for the next step without further purification. LC/MS (ESI) mass/charge: 527.0 [M+1] ⁺ ; ^1H NMR (400 MHz, DMSO) δ 7.65-7.56 (m, 4H), 7.31 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.86 (s, 4H), 6.83 (dd,7=2.0, 8.4 Hz, 1H), 5.75 (s, 1H), 3.97 (t, J =5.6 Hz, 2H), 2.78-2.66 (m, 4H), 2.61 (t, J=5.6 Hz, 2H), 2.40 (s, 4H), 2.45 -2.34 (m, 1H).

[00682] Step 6: Preparation of (2S,4R)-1-(2-(3-(2,2-dimethoxyethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00683] Into a solution of (2S,4R)-4-hydroxy-1-[2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methylthiazol-5-yl) phenyl]methyl]pyrrolidine-2-carboxamide (220 mg, 0.45 mmol, 1.00 eq.) and 2-bromo-1,1-dimethoxyethane (153 mg, 0.91 mmol, 0.91 mmol, 2. 00 eq.). The mixture was stirred at 100°C for 3 hours. The mixture was poured into saline (50 ml) and then extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (2S,4R)-1-[2-[3-(2,2-dimethoxyethoxy)isoxazole-5 -yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (220 mg, crude) as a yellow oil, which directly used for the next step without further purification. mass/charge: 573.2 [M+1] ⁺ .

[00684] Step 7: Preparation of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-(4-(4 -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00685] Into a solution of (2S,4R)-1-[2-[3-(2,2-dimethoxyethoxy)isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N[-[[4-( 4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 0.35 mmol, 1.00 eq.) in dioxane (2 ml) added hydrochloric acid (2.0 M, 2 ml) . The mixture was stirred at 50°C for 3 hours. The mixture was diluted with saline (30 ml), adjusted to pH 7.0-8.0 with solid sodium carbonate, and then extracted with ethyl acetate (30 ml x 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (2S,4R)-4-hydroxy-1-[3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl ]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (160 mg, crude) as a yellow oil, which was directly used for the next step without further purification. LC/MS (ESI) mass/charge: 527.1 [M+1] ⁺ .

[00686] Step 8: Preparation of (2S,4R)-1-(2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophene -3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide

[00687] Into a solution of (2S,4R)-4-hydroxy-1-[3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl]-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (160 mg, 0.30 mmol, 1.00 eq.) and 2-(4-bromophenyl)-3-[4-(2-piperazine-1 -ylethoxy)phenoxy]benzothiophen-6-ol (184 mg, 0.30 mmol, 1.00 eq., hydrobromide salt) in methanol (5 ml) was added acetic acid (5 mg, 0.06 mmol, 0.20 eq. .). The mixture was stirred at 20°C for 1 hour. Sodium cyanoborohydride (38 mg, 0.60 mmol, 2.00 eq.) was then added. The resulting mixture was stirred at 20°C for an additional 14 hours. The resulting solution was poured into saturated sodium bicarbonate solution (50 ml) and then extracted with ethyl acetate (50 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm, 10 μm; mobile phase: [water (0.05% HCl)-ACN]; V%: 35% to 55%, 7.8 min.) to give (2S,4R)-1-(2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl) oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2- carboxamide (85 mg, 0.08 mmol, 27% yield) as an off-white solid. LC/MS (ESI) mass/charge: 1037.1 [M+1] ⁺ .

[00688] Step 9. Preparation of (2S,4R)-1-((S)-2-(3-(2-(4-(2-(4-((2-(4-bromophenyl)-6-hydroxybenzo [b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 -yl)benzyl)pyrrolidine-2-carboxamide (compound 164)

[00689] (2S,4R)-1-[2-[3-[2-[4-[2-[4-[2-(4-bromophenyl)-6-hydroxybenzothiophen-3-yl]oxyphenoxy]ethyl was separated ]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide ( 85 mg, 0.08 mmol, 1.00 eq.) by SFC (column: OD, 250 mm × 50 mm, 10 μm); mobile phase: [0.1%NH ₃ H ₂ O EtOH]; In%: from 60% to 60%, each run for 3.3 minutes, total 70 minutes) to obtain (2S,4R)-1-[(2R)-2-[3-[2-[4- [2-[4-[2-(4-bromophenyl)-6-hydroxybenzothiophen-3-yl]oxyphenoxy]ethyl]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy -N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (19 mg, 0.018 mmol, 56% yield, 99% purity) and (2S,4R)-1-[ (2S)-2-[3-[2-[4-[2-[4-[2-(4-bromophenyl)-6-hydroxybenzothiophen-3-yl]oxyphenoxy]ethyl]piperazin-1-yl]ethoxy] isoxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (50 mg, 0.46 mmol, yield 93%, purity 96%) as a yellow solid. LC/MS (ESI) mass/charge: 1037.3 [M+1] ⁺ ; ¹ H-NMR for compound 164 (400 MHz, CD ₃ OD) δ 8.89 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.51-7.48 (m , 6H), 7.22-7.19 (m, 2H), 6.92-6.79 (m, 5H), 6.05 (s, 1H), 4.60-4.42 (m, 6H ), 3.90-3.68 (m, 5H), 3.20-2.74 (m, 12H), 2.49 (s, 3H), 2.48-2.45 (m, 1H), 2.38-2.35 (m, 1H), 2.10-2.08 (m, 1H), 1.05 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 7.2 Hz, 3H).

[00690] Compound 232. 3-[5-[4-[[1-[5-[2-(4-Fluorophenyl)-6-hydroxybenzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl ]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione

[00691] Step 1: Preparation of 5-benzyloxy-2-bromo-pyridine

[00692] To a solution of 6-bromopyridin-3-ol (2 g, 11.49 mmol, 1 eq.) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.18 g, 22.99 mmol, 2 eq.) and benzyl bromide (2.16 g, 12.64 mmol, 1.5 ml, 1.1 eq.). The mixture was stirred at 20°C for 2 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1). The compound 5-benzyloxy-2-bromopyridine (2.6 g, 9.84 mmol, 86% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ 8.14 (d, J=3.2 Hz, 1H), 7.46-7.31 (m, 6H), 7.16 (dd, J= 3.2 8.8 Hz, 1H), 5.10 (s, 2H).

[00693] Step 2: Preparation of 5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

[00694] In a solution containing 5-benzyloxy-2-bromopyridine (2.4 g, 9.09 mmol, 1 eq.), 4-(dimethoxymethyl)piperidine (2.67 g, 13.63 mmol, 1.5 eq., HCl) in toluene (20 ml), add sodium tert-butoxide (2.62 g, 27.26 mmol, 3 eq.), XPhos (866 mg, 1.82 mmol, 0.2 eq.) and palladium acetate (306 mg, 1.36 mmol, 0.15 eq.) under nitrogen. The reaction mixture was stirred at 90°C for 16 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1) indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was filtered and the filtrate was concentrated. Water (50 ml) was poured into the mixture and it was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with dichloromethane and methanol (10/1, 50 ml x 2). The compound 5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (2.95 g, 8.61 mmol, 95% yield) was confirmed by ¹ H NMR as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ -d) δ: 7.98 (d, J=2.8 Hz, 1H), 7.49-7.29 (m, 5H), 7.18 (dd, J =3.2, 9.2 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.02 (s, 2H), 4.06 (d, J=6.8 Hz , 1H), 3.67 (s, 6H), 2.79-2.66 (m, 2H), 1.95-1.64 (m, 5H), 1.45-1.33 (m, 2H ).

[00695] Step 3: Preparation of 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol

[00696] To a solution of 5-benzyloxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (3 g, 8.76 mmol, 1 eq.) in methanol (15 ml) was added catalyst (300 mg) as palladium (10%) on activated carbon. The mixture was stirred at 20°C for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1). The desired compound 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol (1.54 g, 6.10 mmol, 70% yield) was obtained as a light yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ -d) δ 7.83 (d, J=2.8 Hz, 1H), 7.11 (dd, J=3.2, 9.2 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 4.12-4.00 (m, 3H), 3.37 (s, 6H), 2.72 (dt, J=2.0, 12.4 Hz, 2H), 1.91-1.71 (m, 3H), 1.47-1.30 (m, 2H).

[00697] Step 4: Preparation of 5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxidobenzothiophene-1-yl-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

[00698] To a solution of 6-[4-(dimethoxymethyl)-1-piperidyl]pyridin-3-ol (176 mg, 0.70 mmol, 1 eq.) in N,N-dimethylformamide (8 ml) was added sodium hydride ( 34 mg, 0.84 mmol, 60% in mineral oil, 1.2 eq.) at 0°C. The mixture was stirred at 0°C for 0.5 hour, then 6-benzyloxy-3-bromo-2-(4-fluorophenyl)-1-oxidobenzothiophene-1-ium (300 mg, 0.70 mmol, 1 eq.). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding saturated ammonium chloride solution (10 ml) at 20°C, and then it was diluted with 10 ml water and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20/1 to 3/1). Required compound 5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxido-benzothiophene-1-yl-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (350 mg , 0.58 mmol, 83% yield) was obtained as a light yellow solid.

[00699] Step 5: Preparation of 5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine

[00700] Into a solution of 5-[6-benzyloxy-2-(4-fluorophenyl)-1-oxidobenzothiophene-1-yl-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (350 mg, 0.58 mmol, 1 eq.) in acetonitrile (4 ml), trimethylchlorosilane (190 mg, 1.75 mmol, 3 eq.) and sodium iodide (262 mg, 1.75 mmol, 3 eq.) were added. The mixture was stirred at 20°C for 1 hour and quenched with water. The reaction mixture was extracted with ethyl acetate (20 ml x 2). The combined organic layers were first washed with anhydrous sodium sulfite (40 ml), then washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was transferred to the next step without further purification. Required compound 5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (320 mg, 0.55 mmol, 94% yield ) was obtained as a light yellow oil. LC/MS (ESI) mass/charge: 585.1 [M+1] ⁺ .

[00701] Step 6: Preparation of 1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4-carbaldehyde

[00702] Into a solution of 5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (320 mg, 0.55 mmol, 1 eq.) in tetrahydrofuran (11 ml), sulfuric acid (2 M, 11 ml, 40 eq.) was added. The reaction mixture was stirred at 70°C for 0.5 hour. LC-MS demonstrated that the starting material was completely consumed and one major peak with the required MS was detected. The reaction mixture was quenched by adding saturated sodium bicarbonate solution, adjusting the pH to 7-8 and it was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was transferred to the next step without further purification. The desired compound 1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4-carbaldehyde (270 mg, 0.5 mmol, 92% yield) was obtained in the form of a light yellow oil. LC/MS (ESI) mass/charge: 539.1 [M+1] ⁺ .

[00703] Step 7: Preparation of 3-[5-[4-[[1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl ]methyl]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione

[00704] A solution of 3-(1-oxo-5-piperazin-1-ylisoindolin-2-yl)piperidin-2,6-dione (176 mg, 0.48 mmol, 1 eq., HCl salt) in dichloromethane ( 2 ml) and methyl alcohol (2 ml), sodium acetate (158 mg, 1.93 mmol, 4 eq.) was added. The mixture was stirred at 20°C for 0.5 hours. Then 1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]piperidine-4- carbaldehyde (260 mg, 0.48 mmol, 1 eq.). The mixture was stirred at 20°C for 0.5 hour followed by the addition of sodium cyanoborohydride (60 mg, 0.97 mmol, 2 eq.). The reaction mixture was stirred at 20°C for 2 hours. LC-MS demonstrated that the starting material was completely consumed and one major peak with the required MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1). The required compound is 3-[5-[4-[[1-[5-[6-Benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazine- 1-yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione (300 mg, 0.32 mmol, 65% yield, 89% purity) was obtained as a white solid. LC/MS (ESI) mass/charge: 851.1 [M+1] ⁺ .

[00705] Step 8: Preparation of 3-[5-[4-[[1-[5-[2-(4-fluorophenyl)-6-hydroxybenzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl] methyl]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione (compound 232)

[00706] Into a solution of 3-[5-[4-[[1-[5-[6-benzyloxy-2-(4-fluorophenyl)benzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl ]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione (300 mg, 0.31 mmol, 1 eq.) in tetrahydrofuran (10 ml), catalyst (30 mg) was added as palladium (10%) on activated carbon. The reaction mixture was stirred at 20°C for 1 hour under a hydrogen atmosphere (15 psi). Ethyl alcohol (5 ml) was added to the mixture, and the reaction mixture was stirred at 20° C. under a hydrogen atmosphere (15 psi) for 18 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm, 10 μm; mobile phase: [water (0.225%) formic acid)-ACN]; In%: from 18% to 38%, 10 min.). Required compound 3-[5-[4-[[1-[5-[2-(4-fluorophenyl)-6-hydroxybenzothiophen-3-yl]oxy-2-pyridyl]-4-piperidyl]methyl]piperazine-1 -yl]-1-oxoisoindolin-2-yl]piperidin-2,6-dione (126.0 mg, 0.15 mmol, 49% yield, 98% purity, formate) was obtained as a white solid. LC/MS (ESI) mass/charge: 761.3 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d) δ 10.94 (s, 1H), 8.14 (s, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.73- 7.67 (m, 2H), 7.51 (d, J=8.4 Hz, 1H), 7.32-7.19 (m, 4H), 7.11 (dd, J=2.8, 9.2 Hz, 1H), 7.08-7.01 (m,2H), 6.84 (dd, J=2.4, 8.8 Hz, 1H), 6.74 (d, J=9 ,6 Hz, 1H), 5.04 (dd, J=5.2, 13.2 Hz, 1H), 4.37-4.28 (m, 1H), 4.23-4.15 (m, 1H), 4.14-4.06 (m, 2H), 3.29-3.21 (m, 7H), 2.96-2.84 (m, 1H), 2.76-2.68 ( m, 2H), 2.62-2.53 (m, 2H), 2.42-2.29 (m, 1H), 2.22-2.15 (m, 2H), 2.01-1, 90 (m, 1H), 1.80-1.68 (m, 3H), 1.16-1.00 (m, 2H).

EXAMPLES

[00707] All synthesized compounds were characterized by both ¹ H-NMR and LC/MS, and their purity was analyzed by LC/MS at 214 and 254 nm with UV detection as described below. The purity of each compound in Tables 1-5 was greater than 90%. The observed molecular weight from the LC/MS data in Table 1, Table 2 and Table 3 is given as [M+H] ⁺ . Synthetic methods used to obtain individual compounds are also listed in Tables 1-3.

[00708] All NMR experiments were recorded on either a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR or on a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR. All deuterated solvents contained, as a rule, from 0.03% to 0.05% v/v. tetramethylsilane, which was used as a sample to obtain a standard signal (set to δ 0.00 for both ¹ H and ¹³ C).

[00709] LC-MS analyzes were performed on a SHIMADZU LC-MS device consisting of a UFLC 20-AD system and an FCMS 2020 MS detector. The column used was Shim-pack XR-ODS, 2.2 µm, 3.0 × 50 mm. A linear gradient was applied starting from 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in acetonitrile) over 2.2 min. with a total analysis time of 3.6 min. The column temperature was 40°C and the flow rate was 1.0 mL/min. The diode array detector provided scanning at 200-400 nm. The mass spectrometer was equipped with an electrospray (ES) ion source operated in positive or negative ion mode. The mass spectrometer provided scanning of mass/charge values in the range of 90-900, and the scanning time was 0.6 s.

[00710] Chimeric molecules were assessed for target binding in T47D cells using a commercial ERE-luciferase reporter gene assay kit. 10%) FBS was included in the analysis and the estrogen level was measured to be 10 pM. Target binding was expressed as _IC50 for estrogen-induced signal suppression, and the results are listed in Tables 1-3.

[00711] Compounds prepared herein were also assayed for ERα disruption in MCF7 and T47D cells. Figure 2 shows the result of disruption caused by the use of the selected compound and demonstrates the mechanism of disruption in the cereblon-mediated E3 ligase complex pathway.

[00712] ERE-luciferase assay for compounds in Tables 1-3

[00713] T47D-KBluc cells (ATCC #CRL_2865, T47D human breast cancer cells stably transfected with an estrogen responsive element/promoter/luciferase reporter gene construct) were seeded in 96-well white opaque plates in RPMI growth medium supplemented with 10% fetal bovine serum, and ensured their adhesion overnight in an incubator at 37°C with high humidity. The next day, cells were treated with PROTAC using a 12-point concentration curve (maximum final concentration was 300 nM, followed by 3-fold lower concentrations, with the lowest concentration in the assay being 2 pM). Each PROTAC was tested independently in two experiments in 96-well plates. After 24 hours, the medium was removed and lysis buffer was added to the wells. After lysis, Bright-Glo™ luciferase assay substrate (Promega, Madison, WI) was added and luciferase activity was measured using a Cytation 3 plate reader (TioTek™, Winooski, VT). Each compound was assayed in duplicate and activity was calculated as IC50 using GraphPad Prism software (San Diego, CA).

[00714] Estrogen receptor alpha (ERα) disruption assay in MCF-7 cells using Western blot method for Table 4

[00715] Exemplary novel ERα disruptors were evaluated for their ERα disruption activity in MCF-7 cells by Western blotting. The assay was performed in the presence of 10% fetal bovine serum (FBS) or high percentage human or mouse serum. Western blot protocols that provide comparable results are described below.

[00716] MCF7 cells were grown in DMEM/F12 with 10% fetal bovine serum and seeded at a density of 24,000 cells per 100 μl well in 96-well clear tissue culture plates. The next day, cells were treated with PROTAC using a 7-point concentration curve, with 100 nM being the maximum concentration, and serial dilutions were made to obtain other concentrations (30 nM, 10 nM, 3 nM, 1 nM, and 0.3 nM). At all concentrations, 0.01% DMSO is the final well concentration. The next day, the contents of the plates were aspirated and washed with 50 μl of cold PBS. Cells were lysed with 50 μl/well cell lysis buffer at 4°C (cat. no. 9803; Cell Signaling Technology, Danvers, MA) (20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na ₂ EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mM sodium vanadate, 1 μg/ml leupeptin). Lysates were cleared at 16,000 × g for 10 min, and 2 μg of protein was subjected to SDS-PAGE analysis and subsequent immunoblotting according to standard protocols. Antibodies used were anti-ERα (Cell Signaling Technologies, cat. no. 8644) and tubulin (Sigma, cat. no. T9026; St. Louis, MO). Detection reagents were ECL Clarity Western Blot Substrates (Bio-Rad Cat# 170-5060; Hercules, CA).

[00717] Alternatively, MCF7 cells were grown in DMEM/F12 with 10%) fetal bovine serum and seeded at a density of 24,000 cells per 500 μl well in 24-well clear tissue culture plates. The next day, cells were treated with PROTAC using a 5-point concentration curve (100 nM, 33 nM, 11 nM, 3.7 nM, and 1.2 nM) in the presence of 0.01% DMSO. After 72 hours, the contents of the wells were aspirated and washed with 500 μl PBS. Cells were lysed with 100 μl/well cell lysis buffer at 4°C (cat. no. 9803; Cell Signaling Technology, Danvers, MA) (20 mM Tris-HCL (pH 7.5), 150 mM NaCl, 1 mM Na ₂ EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mM sodium vanadate, 1 μg/ml leupeptin). Lysates were cleared at 16,000 × g for 10 min, and 2 μg of protein was subjected to SDS-PAGE analysis and subsequent immunoblotting according to standard protocols. Antibodies used were anti-ERα (Cell Signaling Technologies, cat. no. 8644) and tubulin (Sigma, cat. no. T9026; St. Louis, MO). Detection reagents were ECL Clarity Western Blot Substrates (Bio-Rad Cat# 170-5060; Hercules, CA).

[00718] Estrogen receptor alpha (ERα) disruption assay in T47D cells using Western blotting technique

[00719] The same protocol as described above for MCF7 cells was used, except that T47D cells were used instead of MCF7 cells.

[00720] Estrogen receptor alpha (ERα) disruption assay using the In-Cell Western™ assay for Table 5.

[00721] ERα disruption by the claimed compounds was determined in MCF7 cells using an In-Cell Western™ assay. Briefly, MCF7 cells were seeded in 96-well plates (2000 cells per well in 100 μl medium) and incubated at 37°C in a 5% CO ₂ atmosphere in a humidified incubator overnight. One hundred (100) µl of medium containing the test compound (at 2x concentration) was added to the appropriate wells to provide 11 serially decreasing concentrations (maximum final concentration of 1 µM, then 3 times less for the next 10 concentrations); vehicle control (DMSO) was also added for each compound. For each experiment, all compounds were assayed on plates in duplicate. The cells were then incubated for 3 or 5 days in the above medium. The assay was completed by removing the medium, washing once with ice-cold PBS, and adding 50 μL paraformaldehyde (PFA: 4% in PBS). After 15 min in PFA at room temperature, cells were permeabilized in Tris-phosphate buffered saline with Tween (0.1%) (TBST) supplemented with Triton X-100 (0.5%) for 15 min. Cells were then blocked in BSA (TBST with BSA, 3%) for one hour. Primary antibodies were added to detect ERα (rabbit monoclonal antibody, 1:1000, Cell Signaling Technology, catalog no. 8644) and tubulin (mouse monoclonal antibody, 1:5000, Sigma catalog no. T6074) in TBST with BSA (3%). Cells were incubated overnight at 4°C. Cells were then washed twice with TBST at room temperature and then incubated with fluorescently labeled anti-rabbit and anti-mouse Ig secondary antibodies (IRDye®; LI-COR; Lincoln, NE) in LI-COR blocking buffer (cat. no. 927-50000 ) for one hour at room temperature. After 3 washes with TBST, the buffer was removed and the plates were read on an Odyssey® Infrared Imaging System (LI-COR®; Lincoln, NE) at 700 nm and 800 nm. Using commercial software (ImageStudio™; LI-COR, Lincoln, NE), the staining intensity for ERα and tubulin in each well was quantified and exported for analysis. For each data point, the intensity for ERα was normalized relative to the intensity for tubulin, and for each compound, all normalized intensity values were normalized relative to the vehicle control. DC ₅₀ and D _max values were determined after 4-parameter IC ₅₀ curve fitting using the ACAS dose-response curve module (McNeil & Co Inc.).

[00722] The following PROTACs demonstrated target protein degradation when tested under the conditions described above.

Specific Embodiments of the Present Invention

[00723] As described above, in any aspect or embodiment described herein, the present invention provides bifunctional PROTAC compounds containing at least one of a benzothiophene derivative, an ER binding moiety, or combinations thereof; a linker and at least one of a cereblon binding ligand, a VHL binding ligand, an IAP binding fragment, an MDM2 binding fragment, or a combination thereof. The present invention covers the following specific embodiments. These further embodiments may include all of the features listed in the previous embodiment, as indicated. If applicable, the following embodiments may also include features listed in any of the previous embodiments, inclusive or alternatively (for example, the eighth embodiment may include features listed in the first embodiment as listed and/or features of any of the second through seventh embodiments implementation).

[00724] An aspect of the present invention provides a bifunctional compound having the chemical structure:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

Where

PTM is characterized by a structure selected from the group consisting of PTM-I and PTM-II:

ULM is a small molecule E3 ubiquitin ligase binding fragment that binds to or targets E3 ubiquitin ligase, selected from the group consisting of Eippel-Lindau protein (VLM), cereblon (CLM), double-minute mouse homolog 2 (MLM) and IAP (ILM);

L represents a bond or chemical linker moiety connecting ULM and PTM;

X _PTM is O or C=O;

each of X _PTM1 and X _PTM2 is independently selected from N or CH;

R _PTM1 is independently selected from OH, O(CO)R _PTM , lower O-alkyl, where R _PTM represents an alkyl or aryl group in an ester;

R _PTM2 and R _PTM4 are independently selected from H, OH, halogen, CN, CF3, 802-alkyl, lower O-alkyl;

R _PTM3 and R _PTM5 are independently selected from H, halogen; And

PTM-I contains at least one _PTM2 R and at least one _PTM3 R at each of the respective rings.

[00725] In any aspect or embodiment described herein, lower O-alkyl is an alkyl chain having 1 to 3 carbon atoms.

[00726] In any aspect or embodiment described herein, VLM has the chemical structure represented by:

Where

each of X ¹ , X ² is independently selected from the group consisting of bond, O, NR ^Y3 , CR ^Y3 R ^Y4 , C=O, C=S, SO and SO ₂ ;

each of R ^Y3 , R ^Y4 is independently selected from the group consisting of H, straight or branched C _1-6 alkyl, optionally substituted with 1 or more halogen atoms, optionally substituted C _1-6 alkoxy (e.g., optionally substituted with 0-3 R groups ^P );

R ^P represents 0, 1, 2 or 3 groups, each independently selected from the group consisting of H, halogen, -OH, C _1-3 alkyl, C=O;

W ³ is selected from the group consisting of optionally substituted -TN(R ^1a R ^1b )X ³ , optionally substituted -TN(R ^1a R ^1b ), -TN(R ^1a R ^1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted T-biheteroaryl, optionally substituted -T-heterocycle, optionally substituted T-biheterocycle, optionally substituted -NR ¹ -T-aryl, optionally substituted -NR ¹ -T-heteroaryl or optionally substituted -NR ¹ - T-heteroaryl;

X ³ represents C=O, R ¹ , R ^1a , R ^1b ;

each of R ¹ , R ^1a , R ^1b is independently selected from the group consisting of an H, straight or branched C ₁ -C ₆ alkyl group, optionally substituted with 1 or more halogen atoms or -OH groups, R ^Y3 C=O, R ^Y3 C=S, R ^Y3 SO, R ^Y3 SO ₂ , N(R ^Y3 R ^Y4 )C=O, N(R ^Y3 R ^Y4 )C=S, N(R ^Y3 R ^Y4 )SO and N(R ^Y3 R ^Y4 )SO ₂ ;

T is selected from the group consisting of an optionally substituted alkyl, the -(CH ₂ ) _n - group, wherein each of the methylene groups is optionally substituted with one or two substituents selected from the group consisting of halogen, methyl, linear or branched C ₁ -C ₆ an alkyl group optionally substituted with 1 or more halogen atoms or -OH groups, or an optionally substituted amino acid side chain; And

n is 0-6,

W ⁴ represents

each of R ^14a , R ^14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl;

and wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[00727] In any aspect or embodiment described herein, VLM has the chemical structure represented by:

Where

W ³ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, or

R ₉ and R ₁₀ independently represent hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R ₉ , R ₁₀ and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R ₁₁ is selected from the group consisting of optionally substituted heterocyclic group, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R ₁₂ is selected from the group consisting of H or optionally substituted alkyl;

R ₁₃ is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

each of R _14a , R _14b is independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl;

W ⁵ is selected from the group consisting of phenyl or 5-10 membered heteroaryl,

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , NR _14a R _14b , OR _14a , CONR _14a R _14b , NR _14a COR _14b , SO ₂ NR _14a R _14b , NR _14a SO ₂ R _14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted or optionally substituted cycloheteroalkyl;

R ₁₆ is independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy or optionally substituted haloalkoxy;

o equals 0, 1, 2, 3 or 4;

R ₁₈ is independently selected from the group consisting of H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; And

p is 0, 1, 2, 3 or 4, and where the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety binding at least one PTM or ULM', or both of them, to ULM.

[00728] In any aspect or embodiment described herein, the VLM provides a chemical structure selected from the group consisting of:

Where

R ₁ is H, ethyl, isopropyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

R _14a represents H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

R ₁₅ is selected from the group consisting of H, halogen, CN, OH, NO ₂ , optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl;

X represents C, CH ₂ or C=O;

R ₃ is absent or is an optionally substituted 5- or 6-membered heteroaryl; And

wherein the dotted line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to the ULM.

[00729] In any aspect or embodiment described herein, VLM provides a group in accordance with the chemical structure:

Where

R ^1' in ULM-g is an optionally substituted C ₁ -C ₆ alkyl group, optionally substituted -(CH ₂ ) _n OH, optionally substituted -(CH ₂ ) _n SH, optionally substituted (CH ₂ ) _n -O-( a C ₁ -C ₆ )alkyl group, an optionally substituted (CH ₂ ) _n -WCOCW-(C ₀ -C ₆ )alkyl group containing a WCOCW epoxy moiety, where each W independently represents an H or a C ₁ -C ₃ alkyl group, optionally substituted -(CH ₂ ) _n COOH, optionally substituted -(CH ₂ ) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ ) _n C(O)-NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n OC(O)-NR ₁ R ₂ , -(CH ₂ O) _n H, optionally substituted -(CH ₂ ) _n OC(O)-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ ) _n C(O)-O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n COOH, optionally substituted -(OSH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted -(OCH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ O) _n C(O)-NR ₁ R ₂ , -(CH ₂ CH ₂ O) _n H, optionally substituted -(CH ₂ CH ₂ O) _n COOH , optionally substituted -(OSH ₂ CH ₂ ) _n O-(C ₁ -C ₆ alkyl), optionally substituted -(CH ₂ CH ₂ O) _n C(O)-(C ₁ -C ₆ alkyl), optionally substituted - (OCH ₂ CH ₂ ) _n NHC(O)-R ₁ , optionally substituted -(CH ₂ CH ₂ O) _n C(O)-NR ₁ R ₂ , optionally substituted -SO ₂ R _S , optionally substituted with S(O) _RS , NO ₂ , CN or halogen (F, Cl, Br, I, preferably F or Cl);

each of R ₁ and R ₂ in ULM-g independently represents an H or a C ₁ -C ₆ alkyl group, which may be optionally substituted by one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

_RS in ULM-g represents a C ₁ -C ₆ alkyl group, optionally substituted by an aryl, heteroaryl or heterocyclic group or a -(CH ₂ ) _m NR ₁ R ₂ group;

each of X and X' in ULM-g independently represents C=O, C=S, -S(O), S(O) ₂ (preferably both X and X' represent C=O);

R ^2' in ULM-g represents an optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w alkyl group, an optionally substituted -(CH ₂ ) _n -(C= O) _u (NR ₁ ) _v (SO ₂ ) _w NR _1N R _2N , optionally substituted -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -( CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optional substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ NR ₂ N, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R ₁ N , optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -NR ¹ -(CH ₂ ) _n -(C=O) _v NR ₁ (SO ₂ ) _w -heterocycle, optionally substituted -X ^R2' -alkyl group ; an optionally substituted -X ^R2' -aryl group; an optionally substituted -X ^R2' -heteroaryl group; an optionally substituted -X ^R2' -heterocyclic group; optionally substituted;

R ^3' in ULM-g is optionally substituted alkyl, optionally substituted -(CH ₂ ) _n -(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -(CH ₂ ) _n -C( O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ NR ₂ N, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O )R ₁ N, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -C(O)NR ₁ R ₂ , optionally substituted -(CH ₂ ) _n -C( O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -NR ₁ C(O)R _1N , optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl, optionally substituted -NR ¹ -(CH ₂ ) _n -C(O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle, optionally substituted -O-(CH ₂ ) _n -(CH ₃ ) _u (NR ₁ ) _v (SO ₂ ) _w -alkyl, optionally substituted -O-(CH ₂ ) _n - (C=O) _u (NR ₁ ) _v (SO ₂ ) _w -NR _1N R _2N , optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ )w- NR ₁ C(O)R _1N , optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -aryl, optionally substituted -O-(CH ₂ ) _n - (C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heteroaryl or optionally substituted -O-(CH ₂ ) _n -(C=O) _u (NR ₁ ) _v (SO ₂ ) _w -heterocycle; -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -( V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -(V) _n' -(CH ₂ ) _n -(V) _n' -heterocyclic group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -alkyl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -aryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C= O) _m' -(V) _n' -heteroaryl group, optionally substituted -(CH ₂ ) _n -N(R _1' )(C=O) _m' -(V) _n' -heterocyclic group, optionally substituted -X ^R3' is an alkyl group; an optionally substituted -X ^R3' -aryl group; an optionally substituted -X ^R3' -heteroaryl group; an optionally substituted -X ^R3' heterocyclic group; optionally substituted;

each of R _1N and R _2N in ULM-g independently represents H, C ₁ -C ₆ alkyl, which is optionally substituted with one or two hydroxyl groups and no more than three halogen-containing groups, or optionally substituted -(CH ₂ ) _n -aryl , -(CH ₂ ) _n -heteroaryl or -(CH ₂ ) _n -heterocyclic group;

V in ULM-g is O, S or NR ₁ ;

R ₁ in ULM-g is the same as above;

each of R ₁ and R _1' in ULM-g independently represents an H or a C ₁ -C ₃ alkyl group;

each of X ^R2' and X ^R3' in ULM-g is independently optionally substituted -(CH ₂ ) _n -, -(CH ₂ ) _n -CH(X _v )=CH(X _v )- (cis or trans) , -(CH ₂ ) _n -CH≡CH-,. (CH ₂ CH ₂ O) _n - or C ₃ -C ₆ cycloalkyl group, where X _v represents H, halogen or a C ₁ -C ₃ alkyl group, which is optionally substituted;

each m in ULM-g is independently equal to 0, 1, 2, 3, 4, 5, 6;

each m' in ULM-g is independently 0 or 1;

each n in ULM-g is independently equal to 0, 1, 2, 3, 4, 5, 6;

each n' in ULM-g is independently 0 or 1;

each u in ULM-g is independently 0 or 1;

each v in ULM-g is independently 0 or 1;

each w in ULM-g is independently 0 or 1; And

any one or more of R ^1' , R ^2' , R ^3' , X and X' in ULM-g are optionally modified to be covalently linked to a PTM group via a linker group if the PTM is not ULM', or if the PTM is ULM', then any one or more of R ^1' , R ^2' , R ^3' , X and X' in each of ULM and ULM' are optionally modified to be covalently linked to each other directly or via a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[00730] In any aspect or embodiment described herein, the ULM is a cereblon E3 ligase complex (CLM) binding moiety selected from the group consisting of thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives.

[00731] In any aspect or embodiment described herein, CLM has the chemical structure represented by:

Where

W is selected from the group consisting of CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

each X is independently selected from the group consisting of O, S and H ₂ ;

Y is selected from the group consisting of CH ₂ , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

Z is selected from the group consisting of O, S and H ₂ ;

G and G' are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH ₂ -heterobutyl, optionally substituted with R', and benzyl, optionally substituted with R ';

Q ₁ , Q ₂ , Q ₃ and Q ₄ represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

A is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl and F;

R provides -CONR'R", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R", -CR'R"-, -CR'NR'R" -, (-CR'O) _n 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, -CF ₃ , -CN, -NR'SO ₂ NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N- CN)R", -NR'C(=C-NO ₂ )NR'R", -SO ₂ NR'COR", -NO ₂ , -CO ₂ R', -C(C=N-OR')R ", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF ₅ and -OCF ₃ ;

R' and R" are independently selected from the group consisting of a bond, H, alkyl (linear, branched, optionally substituted), cycloalkyl, aryl, heteroaryl, heterocyclic group, -C(=O)R, heterocyclyl, each of which is optionally substituted ;

is a bond that may or may not provide a stereospecific configuration ((R) or (S)); And

_Rn provides a functional group or atom,

where n is an integer from 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), and where

if n is 1, then R _n is modified to covalently bind to the linker group (L), and

if n is 2, 3 or 4, then one R _n is modified to covalently bind to a linker group (L), and any other R _n is optionally modified to covalently bind to a PTM, a CLM, a second CLM having the same chemical a structure such as CLM, CLM', a second linker, or any plurality or combination thereof.

[00732] In any aspect or embodiment described herein, CLM has the chemical structure represented by:

Where

W in formulas (h) - (ab) is independently selected from CH ₂ , CHR, C=O, SO ₂ , NH and N-alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , Q ₅ in formulas (h) - (ab) independently represent a C carbon atom substituted by a group independently selected from R', N or N-oxide;

R ¹ in formulas (h) - (ab) is selected from H, CN, C1-C3-alkyl;

R ² in formulas (h) - (ab) is selected from the group consisting of H, CN, C1-C3 alkyl, CHF ₂ , CF ₃ , CHO;

R ³ in formulas (h) - (ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R ⁴ in formulas (h) - (ab) is selected from H, alkyl, substituted alkyl;

R ⁵ in formulas (h) - (ab) represents H or lower alkyl;

X in formulas (h) - (ab) represents C, CH or N;

R' in formulas (h) - (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

R in formulas (h) - (ab) represents H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;

in formulas (h) - (ab) represents a single or double bond; And

CLM is covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[00733] In any aspect or embodiment described herein, the MLM contains a chemical moiety selected from the group consisting of substituted imidazolines, substituted spiroindolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazolo imidazoline, substituted pyrrolopyrrolidinones and substituted isoquinolinones.

[00734] In any aspect or embodiment described herein, the ILM provides the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or non-natural mimetics thereof.

[00735] In any aspect or embodiment described herein, the ILM provides a tetrapeptide fragment of AVPI or a derivative thereof.

[00736] In any aspect or embodiment described herein, the linker (L) provides a chemical unit represented by the formula:

Where

(A ^L ) _q represents a group that is linked to at least a ULM moiety, a PTM moiety, or a combination thereof;

q is an integer that is greater than or equal to 1;

each A ^L is independently selected from the group consisting of a link, CR ^L1 R ^L2 , O, S, SO, SO ₂ , NR ^L3 , SO ₂ NR ^L3 , SONR ^L3 , CONR ^L3 , NR ^L3 CONR ^L4 , NR ^L3 SO ₂ NR ^L4 , CO, CR ^L1 =CR ^L2 , C≡С, SiR ^L1 R ^L2 , P(O)R ^L1 , P(O)OR ^L1 , NR ^L3 C(=NCN)NR ^L4 , NR ^L3 C(=NCN) , NR ^L3 C(=CNO ₂ )NRL4, C _3-11 cycloalkyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , Opheterocyclyl, optionally substituted with 0-6 groups ^RL1 and/or ^RL2 , aryl, optional substituted with 0-6 groups R ^L1 and/or R ^L2 , heteroaryl, optionally substituted with 0-6 groups R ^L1 and/or R ^L2 , where each of R ^L1 or R ^L2 is independently optionally linked to other groups to form a cycloalkyl and/or heterocyclyl fragment optionally substituted with 0-4 R ^L5 groups; And

R ^L1 , R ^L2 , R ^L3 , R ^L4 and R ^L5 are each independently H, halogen, C _1-8 alkyl, OC _1-8 alkyl, SC _1-8 alkyl, NHC _1-8 alkyl, N(C _1-8 alkyl) ₂ , C _3-11 cycloalkyl, aryl, heteroaryl, C _3-11 heterocyclyl, OC _1-8 cycloalkyl, SC _1-8 cycloalkyl, NHC _1-8 cycloalkyl, N(C _1-8 cycloalkyl) ₂ , N(C _1-8 cycloalkyl)(C _1-8 alkyl), OH, NH ₂ , SH, SO ₂ C _1-8 alkyl, P(O)(OS _1-8 alkyl)(C _1-8 alkyl) , P(O)(OS _1-8 alkyl) ₂ , CC-C _1-8 alkyl, CCH, CH=CH(C _1-8 alkyl), C(C _1-8 alkyl)=CH(C _1-8 alkyl), C(C _1-8 alkyl)=C(C _1-8 alkyl) ₂ , Si(OH) ₃ , Si(C _1-8 alkyl) ₃ , Si(OH)(C _1-8 alkyl) ₂ , COC _1-8 alkyl, CO ₂ H, halogen, CN, CF ₃ , CHF ₂ , CH ₂ F, NO ₂ , SF ₅ , SO ₂ NHC _1-8 alkyl, SO ₂ N(C _1-8 alkyl) ₂ , SONHC _1-8 alkyl, SON(C _1-8 alkyl)2, CONHC _1-8 alkyl, CON(C _1-8 alkyl)2, N(C _1-8 alkyl)CONH(C _1-8 alkyl), N(C _1-8 alkyl)CONH(C _1-8 alkyl) ₂ , NHCONH(C _1-8 alkyl), NHCON(C _1-8 alkyl) ₂ , NHCONH ₂ , N(C _1-8 alkyl)SO ₂ NH(C _1-8 alkyl), N(C _1-8 alkyl)SO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH(C _1-8 alkyl), NHSO ₂ N(C _1-8 alkyl) ₂ , NHSO ₂ NH ₂ .

[00737] In any aspect or embodiment described herein, the linker (L) includes a group represented by a general structure selected from the group consisting of:

-N(R)-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -OCH ₂ - ,

-O-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -OCH ₂ -,

-O-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -O-;

-N(R)-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -O-;

-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -O-;

-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -OCH ₂ -;

where each m, n, o, p, q and r, independently equals 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 provided that if the number is zero then there is no N-O or O-O bond, R is selected from the group consisting of H, methyl and ethyl, and X is selected from the group consisting of H and F ;

\

where each n m in the linker can independently be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[00738] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

where each m and n are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[00739] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

where each of m, n, o, p, q or r is independently equal to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[00740] In any aspect or embodiment described herein, L is selected from:

[00741] In any aspect or embodiment described herein, the linker (L) is a polyethyleneoxy group, optionally substituted with aryl or phenyl, containing from 1 to 10 ethylene glycol units.

[00742] In any aspect or embodiment described herein, the linker (L) provides the following chemical structure:

Where

W ^L1 and W ^L2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, wherein each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (linear , branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups, taken together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms ;

each Y ^L1 independently represents a bond, C1-C6alkyl (straight, branched, optionally substituted), and optionally one or more C atoms are replaced by O; or C1-C6alkoxy (linear, branched, optionally substituted);

n is 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[00743] In any aspect or embodiment described herein, the linker (L) provides the following chemical structure:

Where

W ^L1 and W ^L2 are each independently aryl, heteroaryl, cyclic group, heterocyclic group, C _1-6 alkyl, bicyclic group, biaryl, biheteroaryl or biheterocyclic group, each optionally substituted with ^RQ , each RQ independently represents H, halogen, OH, CN, CF ₃ , hydroxyl, nitro, C≡CH, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkyl (linear, branched, optionally substituted), C ₁ -C ₆ alkoxy (linear, branched, optionally substituted), OC _1-3 alkyl (optionally substituted with 1 or more -F), OH, NH ₂ , NR ^Y1 R ^Y2 , CN, or 2 R ^Q groups taken together with an atom , to which they are attached, form a 4-8-membered ring system containing 0-4 heteroatoms;

Each Y ^L1 independently represents a bond, NRY ^L1 , O, S, NR ^YL2 , CR ^YL1 R ^YL2 , C=O, C=S, SO, _SO2 , _C1 - _C6 alkyl (linear, branched, optionally substituted) , and optionally one or more C atoms are replaced by O; C ₁ -C ₆ alkoxy (linear, branched, optionally substituted);

Q ^L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally containing a bridged bond, optionally substituted with 0-6 R ^Q , each RQ independently representing H, C _1-6 alkyl (linear, branched , optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or 2 R ^Q groups, taken together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms);

each of R ^YL1 , R ^YL2 independently represents H, OH, C _1-6 alkyl (linear, branched, optionally substituted with 1 or more halogen atoms, C _1-6 alkoxyl), or R ¹ , R ² together with an atom, k to which they are attached form a 3-8-membered ring system containing 0-2 heteroatoms);

n is 0-10; And

the dotted line indicates the point of attachment to the PTM or ULM fragments.

[00744] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[00745] In any aspect or embodiment described herein, the compound comprises multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[00746] In any aspect or embodiment described herein, the compound is selected from compounds in Tables 1, 2, 3, 4, or 5 (eg, selected from compounds 1-245).

[00747] In a further aspect of the present invention, there is provided a composition comprising an effective amount of a bifunctional compound of the present invention and a pharmaceutically acceptable carrier.

[00748] In any aspect or embodiment described herein, the composition further comprises at least one of an additional bioactive agent or other bifunctional compound of the present invention.

[00749] In any aspect or embodiment described herein, the additional biologically active agent is an anticancer agent.

[00750] In another aspect of the present invention, there is provided a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of the present invention for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or alleviating at least one symptom of a disease or disorder.

[00751] In any aspect or embodiment described herein, the disease or disorder is associated with estrogen receptor accumulation and aggregation.

[00752] In any aspect or embodiment described herein, the disease or disorder is a cancer associated with estrogen receptor accumulation and aggregation.

[00753] In any aspect or embodiment described herein, the disease or disorder is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof.

[00754] In any aspect or embodiment described herein, the disease or disorder is breast cancer.

[00755] In some embodiments, the description provides the following illustrative ER-targeting PROTAC molecules (compounds 1-245 of Table 1, Table 2, Table 3, Table 4, and Table 5), including salts, prodrugs, polymorphs, analogues, derivatives and deuterated forms. In any aspect or embodiment described herein, a compound of the present invention is selected from Tables 1, 2, 3, 4, and 5. For example, the compound may be selected from compounds 1-245 in any aspect or embodiment described herein. document.

[00756] A novel bifunctional molecule comprising a moiety that recruits the ER and a moiety that recruits the cereblon E3 ligase complex, derived from PROTAC technology, is described. The bifunctional molecules of the present invention actively disrupt the ER. PROTAC-mediated protein degradation provides a promising strategy for targeting pathological proteins that are “undruggable” from traditional approaches.

[00757] The contents of all references, patents, pending patent applications and published patents cited throughout this application are therefore expressly incorporated herein by reference.

[00758] Those skilled in the art will recognize many equivalents to the specific embodiments of the present invention described herein or will be able to determine the same using only standard experimentation. Such equivalents are intended to be covered by the following claims. It is understood that the detailed examples and embodiments described herein are provided by way of example for illustrative purposes only and are not intended to limit the present invention in any way. With this in mind, various modifications or changes will be apparent to those skilled in the art and are included within the spirit and scope of this application and are contemplated within the scope of the appended claims. For example, relative amounts of ingredients may be varied to optimize desired effects, additional ingredients may be added, and/or similar ingredients may be substituted for one or more of the ingredients described. Additional advantageous features and functions associated with the systems, methods and methods of the present invention will be apparent from the accompanying claims. Moreover, many equivalents to the specific embodiments of the present invention described herein will be apparent to those skilled in the art, or will be able to determine the same using only standard experimentation. Such equivalents are intended to be covered by the following claims.

Claims (62)

1. A compound having a chemical structure CLM-L-PTM, where PTM is PTM-I or PTM-II: CLM represents the chemical structure L represents a chemical linker moiety including a chemical structural unit represented by the formula -(A ^L ) _q -, where (A ^L ) _q represents a group that is connected to CLM and PTM; X _PTM is O; X _PTM1 and X _PTM2 are each independently N or CH; R _PTM1 is OH or OC _1-3 -alkyl; R _PTM2 and R _PTM4 are independently selected from H, OH, halogen, CF ₃ and OC _1-3 alkyl; R _PTM3 and R _PTM5 represent H; W represents CH ₂ or C=O; each X represents an O; Z represents O; G represents H; Q ₁ , Q ₂ , Q ₃ and Q ₄ are N or CH; A represents H or linear and branched C _1-6 alkyl; where n represents 1, R is -OR', -NR'R" or -CR'R"-, wherein R is covalently linked to a chemical linker moiety; R' and R” are independently selected from the bond, H, C _1-6 alkyl; is a bond that may or may not provide a stereospecific configuration; q is an integer from 3 to 15; each A ^L is independently selected from the bond, CR ^L1 R ^L2 , O, NR ^L3 , CONR ^L3 , CO and C _3-8 heterocyclyl; And each of R ^L1 , R ^L2 and R ^L3 independently represents H, halogen and C _1-8 alkyl, wherein each heterocyclyl contains one or two heteroatoms, each heteroatom is independently selected from nitrogen. 2. The compound according to claim 1, where PTM has the chemical structure 3. A compound according to claim 1 or 2, where CLM has the chemical structure represented by: 4. Connection according to any one of paragraphs. 1-3, where each ^AL is independently selected from CR ^L1 R ^L2 , O, NR ^L3 , CO and C _3-8 heterocyclyl. 5. Connection according to any one of paragraphs. 1-3, wherein the chemical linker moiety (L) is selected from: -O-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -O-; -NH-(CH ₂ ) _m -O(CH ₂ ) _n -O(CH ₂ ) _o -O(CH ₂ ) _p -O(CH ₂ ) _q -O(CH ₂ ) _r -O-; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , where each of the m, n, o, p, q and r of the chemical linker moiety (L) is independently 0, 1, 2, 3 or 4, provided that when the number is zero there is no NO or OO bond, and when In this case, the number of units of the chemical linker fragment -(A ^L ) _q - does not exceed 15. 6. The connection according to claim 1, where the connection is selected from: 7. Use of a compound according to one of paragraphs. 1-6 for the treatment of estrogen receptor-associated breast cancer. 8. Use according to claim 7, wherein breast cancer is associated with accumulation and aggregation of the estrogen receptor.