Compounds and methods for targeted degradation of RAF (rapidly aggressive fibrosarcoma) polypeptide

Abstract

The present disclosure relates to bifunctional compounds that find utility as modulators of RAF (such as Rapidly Accelerated Fibrosarcoma, c-RAF, A-RAF, and / or B-RAF; target proteins). In particular, the present disclosure is directed to bifunctional compounds containing at one end a mouse double-minute homolog 2 (MDM2) ligand that is bound to von Hippel-Lindau, cereblon, apoptosis inhibitor protein, or the respective E3 ubiquitin ligase, and at the other end a moiety that binds the target protein RAF, such that the target protein is positioned in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein. The present disclosure exhibits a wide range of pharmacological activities related to target protein degradation / inhibition. Diseases or disorders resulting from the aggregation or accumulation of target proteins, or constitutive activation of target proteins, are treated or prevented using the compounds and compositions of the present disclosure.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to U.S. Provisional Application No. 62 / 438,803, filed December 23, 2016, and U.S. Provisional Application No. 62 / 582,698, filed November 7, 2017, both of which are incorporated by reference in their entireties. Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed August 5, 2016; U.S. Patent Application No. 15 / 206,497, filed July 11, 2016; U.S. Patent Application No. 15 / 209,648, filed July 13, 2016; U.S. Patent Application No. 62 / 406,888, filed October 11, 2016; U.S. Patent Application No. 14 / 686,640, filed April 14, 2015 and published as U.S. Patent Application Publication No. 2015 / 0291562; U.S. Patent Application No. 14 / 792,414, filed July 6, published as U.S. Patent Application Publication No. 2016 / 0058872, U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322, and U.S. Patent Application No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639, are hereby incorporated by reference in their entireties. Additionally, all references cited herein are hereby incorporated by reference in their entireties. STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with government support under Grant No. NIH R35CA197589 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0002] Provided herein are bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use, which are useful as regulators of target ubiquitination, particularly with respect to Rapidly Accelerated Fibrosarcoma (RAF) proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds of the present disclosure. [Background technology]

[0003] Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. Targeting protein-protein interactions using small molecule compounds is notoriously difficult because of the large protein contact surfaces and the shallow groove-like or flat interfaces involved. E3 ubiquitin ligases (of which several hundred are known in humans) confer substrate specificity to ubiquitination. They are therefore more attractive therapeutic targets than generic proteasome inhibitors due to their specificity for specific protein substrates. The development of ligands for E3 ligases has proven difficult, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds targeting E3 ligases have been reported, but the field is still largely unexplored. For example, since the discovery of nutrin, the first small molecule E3 ligase inhibitor of mouse double minute 2 homolog (MDM2), additional compounds targeting MDM2 (i.e., human double minute 2 (HDM2)) E3 ligase have been reported. (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0004] The tumor suppressor gene p53 plays an important role in arresting cell proliferation and apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 has been proposed as one of the important pathways for tumor cell survival (AJ Levine, et al. Nature (2000), 408, 307-310). Mutations of p53 have been found in approximately 50% of cancer patients (M. Hollstein, et al. Science (1991), 233, 49-53), while patients with wild-type p53 have been found to downregulate p53 by MDM2 through protein-protein interaction between p53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109). In normal cells without oncogenic stress signals, MDM2 maintains p53 at low concentrations. In response to DNA damage or cellular stress, p53 levels increase, and MDM2 levels also increase due to a feedback loop from the p53 / MDM2 autoregulatory system. In other words, p53 regulates MDM2 at the transcriptional level, and MDM2 regulates p53 at the activity level (AJ Levine, et al. Genes Dev. (1993) 7, 1126-1132).

[0005] The downregulation of p53 by MDM2 can be explained by several mechanisms. First, MDM2 binds to the N-terminal domain of p53 and inhibits the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). Second, MDM2 shuttles p53 back and forth from the nucleus to the cytoplasm, promoting proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 has intrinsic E3 ligase activity and binds ubiquitin to p53, leading to its degradation through the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Since MDM2 functions as an E3 ligase, recruiting MDM2 to disease-causing proteins and exploiting its ubiquitination and degradation activities is a very interesting approach for drug development.

[0006] One of the attractive therapeutic potential E3 ligases is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate recognition subunit of the E3 ligase complex VCB, which further consists of elongin B and C, Cul2 and Rbx1. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), which is a transcription factor that upregulates genes such as VEGF, a vascular endothelial growth factor, and erythropoietin, an erythroid-derived cytokine, in response to low oxygen levels. The first small molecule ligand for the substrate recognition subunit of the E3 ligase, von Hippel-Lindau (VHL), was generated and its crystal structure was obtained, and it was confirmed that this compound mimics the binding mode of the transcription factor HIF-1α, which is the main substrate of VHL.

[0007] Cereblon is a protein that in humans is encoded by the CRBN gene. Orthologues of CRBN are highly conserved from plants to humans, underscoring its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through mechanisms that are not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 is then It is conclusively concluded that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage binding protein.

[0008] Inhibitor of Apoptosis Proteins (IAPs) are a family of proteins involved in the suppression of apoptosis, i.e., cell death. The human IAP family includes eight members, and many other organisms contain IAP homologs. IAPs contain E3 ligase-specific and baculoviral IAP repeat (BIR) domains that recognize substrates and promote their ubiquitination. IAPs promote ubiquitination and can directly bind and inhibit caspases. Caspases are proteases that execute apoptosis (e.g., caspase-3, caspase-7, and caspase-9). Thus, through binding of caspases, IAPs inhibit cell death. However, proapoptotic stimuli result in the release of the mitochondrial proteins DIABLO (also known as second mitrochondria-derived activator of caspases, or SMAC) and HTRA2 (also known as Omi). The binding of DIABLO to HTRA2 is thought to inhibit IAP activity.

[0009] SMAC interacts with essentially all known IAPs, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin. The first four amino acids of mature SMAC (AVPI) bind to a portion of IAPs that is thought to be essential for inhibiting the anti-apoptotic effects of IAPs.

[0010] Bifunctional compounds such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (herein incorporated by reference) function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, the patent publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds.

[0011] There is a continuing need in the art for effective treatment of diseases associated with overexpression or aggregation of RAF (Rapidly Accelerated Fibrosarcoma) or hyperactivation of RAF (such as constitutively active RAF). For example, current BRaf inhibitors (such as vemurafenib and dabrafenib) only target V600 mutant BRaf. Thus, there is a need for diseases or disorders with different BRaf mutations (such as melanoma, lung cancer, pancreatic cancer, and / or colorectal cancer) that are insensitive to currently marketed drugs. Furthermore, resistance mutations may emerge in response to BRaf / MEK inhibitor therapy. For example, p61 splice variants may emerge in melanoma patients treated with BRaf / MEK inhibitor therapy, leaving these patients without clinical options. Currently marketed drugs also lead to and cause paradoxical activation of wild-type BRaf, resulting in clinical complications. Furthermore, a family of low-activity class III BRaf mutants that signal through heterodimerization with BRaf constitutes 40% of BRaf mutations in non-small cell lung cancer (NSCLC), is found sporadically across other cancers, and cannot be targeted by any currently approved or clinical-stage BRaf inhibitors.

[0012] Thus, non-specific effects and the inability to target and regulate RAF remain obstacles to the development of effective therapies. Thus, small molecule therapeutics that effectively target RAF (e.g., effectively inhibit and / or degrade mutant forms of BRaf while preserving wild-type BRaf) and exploit or enhance the substrate specificity of VHL, cereblon, MDM2, and IAPs would be highly useful. Summary of the Invention

[0013] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of use thereof. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they may have a broad range of pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein species or family. Additionally, the present specification provides methods of using an effective amount of a compound described herein for the treatment or amelioration of disease conditions such as cancer (e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma), cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD (mole, electrocardiogram abnormality, ocular hypertelorism, pulmonary valve stenosis, genital abnormalities, growth retardation, hearing loss) syndrome.

[0014] Thus, in one aspect, the disclosure provides bifunctional or PROTAC compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase, or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand, or "PTM" group), thereby placing the target protein / polypeptide in proximity to a ubiquitin ligase for degradation (and inhibition) of the protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double miniute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of a bifunctional compound can be shown as follows:

[0015] [ka]

[0016] The locations of each of the PTM and ULM moieties (e.g., VLM, CLM, MLM, or ILM), as well as the number thereof, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and location of each functional moiety can be varied as desired.

[0017] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this example, the structure of the bifunctional compound can be shown as follows:

[0018] [ka]

[0019] where PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group that connects the PTM and ULM, and ULM is an IAP E3 ubiquitin ligase binding moiety, or a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM) or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM).

[0020] For example, the structure of a bifunctional compound can be shown as follows:

[0021] [ka]

[0022] wherein PTM is a protein / polypeptide targeting moiety, "L" is a linker (e.g., a bond or a chemical linker group) that links the PTM to at least one of a VLM, a CLM, an MLM, an ILM, or a combination thereof, VLM is a von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds VHL E3 ligase, CLM is a ceroblon E3 ubiquitin ligase binding moiety that binds cereblon, MLM is an MDM2 E3 ubiquitin ligase binding moiety, and ILM is an IAP binding moiety that binds an IAP.

[0023] In certain preferred embodiments, the ILM is a tetrapeptide fragment of AVPI. Thus, 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 of the AVPI tetrapeptide fragment are linked to each other through amide bonds (i.e., -C(O)NH- or -NHC(O)-).

[0024] In certain embodiments, the compounds described herein comprise an independently selected ULM, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0025] In certain embodiments, the ILM comprises a chemical moiety, such as, for example, a chemical moiety described herein.

[0026] In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Additionally, other contemplated VLMs are described in U.S. Patent Application Publication No. 2014 / 03022523, as discussed above, which is incorporated herein in its entirety.

[0027] In certain embodiments, the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other anticipated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562. No. 60 / 639,933, filed on Oct. 23, 2007, which application is incorporated herein in its entirety.

[0028] In certain embodiments, the MLM can be nutrine or a derivative thereof. Additionally, other anticipated MLMs are listed in U.S. Patent Application No. 15 / 206,497, filed July 11, 2016, as discussed above, which is incorporated herein in its entirety. In certain additional embodiments, the MLM of the bifunctional compound includes chemical moieties such as substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.

[0029] In additional embodiments, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as either cis or trans configurations.

[0030] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a connector having a linear number of non-hydrogen atoms ranging from 1 to 20. The connector "L" can contain functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. The linker can include substitution with halogens such as Cl, F, Br, and I. Fluorine substitution can include single or multiple fluorines.

[0031] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides.

[0032] In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, where the piperidine-2,6-dione may be substituted at the 3-position, and the 3-position substitution may be a bicyclic hetero-aromatic compound with a bond as a CN bond or a CC bond. Examples of CLMs include, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their derivatives.

[0033] In an additional aspect, the disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof and a pharma- ceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal, such as a human, and treat or ameliorate a disease state or condition modulated via the degraded protein. In certain embodiments, the therapeutic composition described herein can be used to cause degradation of a target protein for the treatment or amelioration of a disease, e.g., cancer. In yet another aspect, the disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising an ILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and a MLM, preferably linked through a linker moiety as otherwise described herein, wherein the VLM / ILM / CLM / MLM is linked to the PTM through a linker to target a protein bound to the PTM for degradation. Similarly, the PTM can be linked to the VLM or CLM or MLM or ILM through a linker to target a protein or polypeptide for degradation. Degradation of a target protein occurs when the target protein is placed in close proximity to an E3 ubiquitin ligase, resulting in degradation of the target protein / inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment of a disease state or condition by reducing the levels of that protein in the patient's cells. It is regulated by target proteins.

[0034] In yet another aspect, the present specification provides a method of treating or ameliorating a disease, disorder, or a symptom thereof in a subject or patient, e.g., an animal, e.g., a human, the method comprising administering to a subject in need thereof a composition comprising an effective, e.g., a therapeutically effective amount, of a compound as described herein, or a salt form thereof, and a pharma- ceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder, or a symptom thereof, in the subject.

[0035] In another aspect, the present description provides methods for identifying the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0036] The general fields of the specification are presented for illustrative purposes only and are not intended to limit the scope of the disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be apparent to those skilled in the art in view of the claims, detailed description, and examples. For example, the various aspects and embodiments of the present disclosure can be used in many combinations, all of which are expressly contemplated by this specification. These additional aspects and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to describe the background of the disclosure and, in certain cases, to provide additional details regarding the implementation are incorporated by reference.

[0037] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure. [Brief description of the drawings]

[0038]

Figure 1A

Figure 1B

Figure 2

Figure 3

[0039] The following is a detailed description provided to assist those skilled in the art in implementing the present disclosure. Those skilled in the art may make modifications and changes to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned in this specification are expressly incorporated by reference in their entirety.

[0040] E3 ubiquitin ligase proteins (e.g., inhibitor of apoptosis proteins (IAPs), Described herein are compositions and methods relating to the surprising and unexpected discovery that an E3 ubiquitin ligase protein ubiquitinates a target protein when the E3 ubiquitin ligase protein and the target protein are brought into close proximity by a bifunctional or chimeric construct that binds to the target protein (von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon E3 ubiquitin ligase, or mouse double minute 2 homolog E3 ubiquitin ligase (MDM2). Accordingly, the present disclosure provides compounds and compositions that include an E3 ubiquitin ligase binding moiety (ULM) linked to a protein target binding moiety (PTM), which results in ubiquitination of a selected target protein, leading to degradation of the target protein by the proteasome (see FIG. 1). The present disclosure also provides libraries of compositions and uses thereof.

[0041] In certain embodiments, the disclosure provides compounds that include a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2000 Daltons, 1000 Daltons, 500 Daltons, or 200 Daltons), that can bind to a ubiquitin ligase, such as IAP, VHL, MDM2, or cereblon. The compound also includes a moiety that can bind to a target protein in such a way as to place the target protein in proximity to a ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. In addition to the above, small molecule means that the molecule is non-peptidyl, i.e., often not considered a peptide, e.g., containing fewer than 4, 3, or 2 amino acids. According to the present specification, a PTM, ULM, or PROTAC molecule may be a small molecule.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0043] Where a range of values ​​is provided, it is to be understood that each intervening value between the upper and lower limit of that range and any other stated range, to one-tenth of the unit of the lower limit, or intervening value in that stated range, is encompassed within the invention unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided). The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, which are also encompassed within the disclosure, as are any specifically excluded limits in the stated ranges. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0044] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in the context of its use in describing this disclosure.

[0045] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0046] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined. That is, in some instances the elements are present conjunctively and in other instances they are present non-conjunctively. Multiple elements listed with "and / or" should be interpreted in the same manner. that is, "one or more" of the elements are so conjoined. Other elements other than those specifically identified by the "and / or" clause may optionally be present, whether or not related to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can, in one embodiment, refer only to A (optionally including elements other than B), in another embodiment, refer only to B (optionally including elements other than A), in yet another embodiment, refer to both A and B (optionally including other elements), and so forth.

[0047] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one of a number or list of elements, but also including a plurality, and optionally including additional items not listed. Only terms that clearly suggest the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by an exclusive term, such as, for example, "either," "one of," "only one of," or "exactly one of."

[0048] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean inclusive but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Guidelines, Section 2111.03.

[0049] As used herein, in the specification and claims, the phrase "at least one" in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of all elements specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. Furthermore, this definition allows for optional elements to be present other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether or not related to those specifically identified elements. Thus, as a 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") can refer in one embodiment to at least one A, optionally including multiple A, and no B (optionally including elements other than B). In another embodiment, it refers to at least one B, optionally including multiple B, and no A (optionally including elements other than A). In yet another embodiment, it can refer to at least one A, optionally including multiple As, and at least one B, optionally including multiple Bs (optionally including other elements).

[0050] Naturally, in the specific methods described in this specification that include a plurality of steps or operations, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are recited, unless the context otherwise indicates.

[0051] The terms "co-administration" and "co-administering" or "combination therapy" refer to both co-administration (administering two or more therapeutic agents simultaneously) and administering the therapeutic agents at different times while they are present in the patient's body to some extent, preferably with effective amounts present simultaneously (administering one or more therapeutic agents at a time different from the time of administration of an additional therapeutic agent). In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly including anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or treatment including anti-cancer activity.

[0052] As used herein, unless the context otherwise indicates, the term "compound" refers to any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and, where appropriate, stereoisomers including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives including, where appropriate in the context, their prodrugs and / or deuterated forms. A deuterated small molecule is expected to be a small molecule in which one or more of the hydrogen atoms contained in the drug molecule are replaced with deuterium.

[0053] Within its use in context, the term compound generally refers to a single compound, but may include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or mixtures enriched in specific enantiomers. In context, the term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in the description of the compounds, many substituents and variables associated therewith, among others, are described. It is understood by those skilled in the art that the molecules described herein are stable compounds, as outlined below. Where bonds are shown, both double and single bonds are depicted or understood within the context of the compounds shown and known rules regarding valency interactions.

[0054] 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 degradation. For example, IAP E3 ubiquitin ligase proteins, either in conjunction with E2 ubiquitin conjugating enzymes or alone, attach ubiquitin to lysines on target proteins, and then target the specific protein substrate for degradation by the proteasome. Thus, either in complex with E2 ubiquitin conjugating enzymes or alone, E3 ubiquitin ligases are involved in the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, a third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. A monoubiquitinated protein is not targeted for proteasomal degradation, but may instead change its cellular location or function, for example through binding to other proteins that have domains to which ubiquitin can be attached. To further complicate matters, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to generate polyubiquitin that is recognized by the proteasome.

[0055] The terms "patient" or "subject" are used throughout this specification to refer to a subject who is receiving the compositions of the present disclosure. The term patient is used to describe an animal, preferably a human or domestic animal, to which treatment, including preventive treatment, is provided. With respect to treatment of an infection, condition or pathology specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals, such as dogs or cats, or livestock, such as horses, cows, sheep, etc. In general, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied from the context in which the term is used.

[0056] The term "effective," when used within the context of its intended use, is used to describe an amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms that are otherwise described or used in this application. Compounds and Compositions In one aspect, provided herein are compounds comprising an E3 ubiquitin ligase binding moiety (ULM), which is an IAP E3 ubiquitin ligase binding moiety (ILM), a cereblon E3 ubiquitin ligase binding moiety (CLM), a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), and / or a mouse double minute 2 homologue (MDM2) E3 ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, the ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure: (A) PTM-L-ULM In the formula, L is a bond or a 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 the moieties in the compounds exemplified herein are provided for illustrative purposes only. As will be understood by those skilled in the art, the compounds described herein can be synthesized with any desired number of each functional moiety and / or relative positions of each functional moiety.

[0057] The terms ULM, ILM, VLM, MLM and CLM are used in their inclusive sense unless otherwise indicated by context. For example, the term ULM encompasses all ULMs, including those that bind IAPs (i.e. ILM), MDM2 (i.e. MLM), cereblon (i.e. CLM), and VHL (i.e. VLM). Additionally, the term ILM encompasses all possible IAP E3 ubiquitin ligase binding moieties, the term MLM encompasses all possible MDM2 E3 ubiquitin ligase binding moieties, the term VLM encompasses all possible VHL binding moieties, and the term CLM encompasses all possible cereblon binding moieties.

[0058] In another aspect, the disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compounds include an ILM or VLM or CLM or MLM linked directly or indirectly, e.g., covalently, to a moiety that binds to a target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the ILM / VLM / CLM / MLM and the PTM are linked or joined via a chemical linker (L). The ILM binds to an IAP E3 ubiquitin ligase, the VLM binds to VHL, the CLM binds to cereblon E3 ubiquitin ligase, and the MLM binds to MDM2 E3 ubiquitin ligase, and the PTM recognizes the target protein and places the target protein and the ubiquitin ligase protein in close proximity, thereby promoting degradation of the target protein through interaction of each moiety with its target. Exemplary bifunctional compounds can be depicted as follows: (B) PTM-ILM (C) PTM-CLM (D) PTM-VLM (E) PTM-MLM In certain embodiments, the bifunctional compound further comprises a chemical linker (L). For example, the bifunctional compound can be depicted as follows: (F) PTM-L-ILM (G) PTM-L-CLM (H) PTM-L-VLM (I) PTM-L-MLM where PTM is a protein / polypeptide targeting moiety, L is a chemical linker, ILM is an IAP E3 ubiquitin ligase binding moiety, CLM is a cereblon E3 ubiquitin ligase binding moiety, VLM is a VHL binding moiety, and MLM is an MDM2 E3 ubiquitin ligase binding moiety.

[0059] In certain embodiments, a ULM (e.g., an ILM, a CLM, a VLM, or a MLM) has an IC of less than about 200 μM. 50 and exhibits activity against or binds to E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, MDM2 E3 ubiquitin ligase). IC 50 can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay.

[0060] In certain additional embodiments, the bifunctional compounds described herein have an IC 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. 50 The activity of

[0061] In certain embodiments, the compounds described herein include multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that specifically bind multiple / different E3 ubiquitin ligases, such as VHL, IAP, cereblon, and / or MDM2), or a combination thereof. In any of the aspects or embodiments described herein, the PTMs and ULMs (e.g., ILM, VLM, CLM, and / or MLM) can be linked directly or via one or more chemical linkers, or a combination thereof. In additional embodiments, when a compound has multiple ULMs, the ULMs can be directed to the same E3 ubiquitin ligase, or each ULM can specifically bind to a different E3 ubiquitin ligase. In yet further embodiments, when a compound has multiple PTMs, the PTMs can bind to the same target protein, or each PTM can specifically bind to a different target protein.

[0062] In certain embodiments, when a compound comprises multiple ULMs, the ULMs are the same. In additional embodiments, a compound comprises multiple ULMs (e.g., ULM, ULM', etc.), at least one PTM linked to the ULMs directly, or via a chemical linker (L), or both. In certain additional embodiments, a compound comprising multiple ULMs further comprises multiple PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0063] In certain embodiments, the compound may comprise multiple ULMs and / or multiple ULMs'. In further embodiments, the compound comprises at least two different ULMs, multiple ULMs, and / or a compound comprising multiple ULM's further comprises at least one PTM linked to a ULM or ULM', either directly or via a chemical linker, or both. In any of the embodiments described herein, a compound comprising at least two different ILMs can further comprise multiple PTMs. In still further embodiments, the PTMs are the same or, optionally, different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target. In still further embodiments, the PTM itself is a ULM (or ULM'), such as, for example, an ILM, a VLM, a CLM, an MLM, an ILM', a VLM', a CLM', and / or an MLM'.

[0064] In additional embodiments, the present disclosure provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharma- ceutically acceptable salt forms, such as acid salt forms and base salt forms. Example ILM AVPI tetrapeptide fragment In any of the compounds described herein, the ILM can comprise an alanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment, or a non-natural mimetic thereof. In certain embodiments, the ILM is selected from the group consisting of chemical structures represented by the following formulas (I), (II), (III), (IV) and (V):

[0065] [ka]

[0066] During the ceremony, R in formulas (I), (II), (III), (IV), and (V) 1 is selected from H or alkyl; R in formulas (I), (II), (III), (IV), and (V) 2 is selected from H or alkyl; R in formulas (I), (II), (III), (IV), and (V) 3 is selected from H, alkyl, cycloalkyl, and heterocycloalkyl; R for formulas (I), (II), (III), (IV), and (V) 5 and R 6 is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably R for formulas (I), (II), (III), (IV), and (V). 5 and R 6 together form a pyrrolidine or piperidine ring, which is optionally further fused to one or two cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, each of which can then be further fused to another cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R for formulas (I), (II), (III), (IV), and (V) 3 and R 5 can be taken together to form a 5-8 membered ring, which is optionally further fused to 1-2 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R for formulas (I), (II), (III), (IV), and (V) 7 is cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl , aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally further substituted with 1 to 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 4is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, which are optionally further substituted with 1 to 3 substituents as described above.

[0067] As noted above, P1, P2, P3, and P4 of formula (II) correlate with A, V, P, and I, respectively, of an AVPI tetrapeptide fragment or a non-natural mimetic thereof. Similarly, each of formulas (I) and (III)-(V) has moieties that correlate with A, V, P, and I of an AVPI tetrapeptide fragment or a non-natural mimetic thereof.

[0068] In any of the compounds described herein, the ILM can have the structure of a derivative of the IAP antagonist described in International Patent Application Publication No. WO 2008 / 014236, Formula (VI), or a non-naturally occurring mimetic thereof, or a pharma- ceutically acceptable salt or hydrate thereof:

[0069] [ka]

[0070] During the ceremony, R in formula (VI) 1 , H, C 1 -C 4 -Alkyl, C 1 -C 4 -Alkenyl, C 1 -C 4 -alkynyl, or C 3 -C 1O -cycloalkyl, which are unsubstituted or substituted; R in formula (VI) 2 , H, C 1 -C 4 -Alkyl, C 1 -C 4 -Alkenyl, C 1 -C 4 -alkynyl, or C 3 -C1O -cycloalkyl, which are unsubstituted or substituted; R in formula (VI) 3 -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 H, -OH, F, Cl, -CH 3、 -CF 3、 -CH 2 Cl, -CH 2 F or -CH 2 is independently selected from OH, R in formula (VI) 4 is 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, wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; R in formula (VI) 5 , H, C 1-10 -Alkyl, aryl, phenyl, C 3-7 -Cycloalkyl, -(CH 2 ) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -Alkyl-aryl, -(CH 2) 0-6 -C 3-7 -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 is independently selected from or R 5 is selected from the residues of an amino acid, the alkyl, cycloalkyl, phenyl, and aryl substituents being unsubstituted or substituted; Z in formula (VI) 1 is -N(R 10 )-C(O)-C 1-10 -Alkyl, -N(R 1O )-C(O)-(CH 2 ) 0-6 -C 3-7 -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)-OC 1-10 -Alkyl, -C(O)-O-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -C(O)-O-(CH 2 ) 0-6 -phenyl, -C(O)-O-(CH 2 ) 1-6-het, -OC(O)-C 1-10 -Alkyl, -OC(O)-(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, -OC(O)-(CH 2 ) 0-6 -phenyl, -OC(O)-(CH 2 ) 1-6 -het is independently selected from alkyl, cycloalkyl, and phenyl, which are unsubstituted or substituted; het in formula (VI) is independently selected from a 5-7 membered heterocyclic ring containing 1-4 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, said heterocyclic ring or fused ring system being unsubstituted or substituted on carbon or nitrogen atoms; R in formula (VI) 10 -H, -CH 3、 -CF 3 , -CH 2 OH, or -CH 2 Cl, R in formula (VI) 11 and R 12 , H, C 1-4 -Alkyl, C 3-7 -Cycloalkyl, -(CH 2 ) 1-6 -C 3-7 -Cycloalkyl, (CH 2 ) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R 11 and R 12 forms het with nitrogen, and U in formula (VI) is independently as shown in formula (VII) below:

[0071] [ka]

[0072] During the ceremony, Each n in formula (VII) is independently selected from 0 to 5; X in formula (VII) is selected from the group consisting of -CH and N; R in formula (VII) a and R b is an O atom, a S atom, a N atom, or a C atom 0-8 -alkyl, wherein one or more of the carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, where each alkyl is independently unsubstituted or substituted; R in formula (VII) d is Re-Q-(R f ) p (R g ) q、 and Ar 1 -D-Ar 2 is selected from the group R in formula (VII) c is selected from the group of H, or any R c and R d together form a cycloalkyl or het, R c and R d cycloalkyl or het In the case of formation, R 5 is attached to the formed ring at a C atom or a N atom, and p and q in formula (VII) are independently selected from 0 or 1; R in formula (VII) e is C 1-8 - selected from the group of alkyl and alkylidene, each Re being either unsubstituted or substituted; Q is N, O, S, S(O) and S(O) 2 is selected from the group Ar of formula (VII) 1 and Ar 2 is independently selected from the group of substituted or unsubstituted aryl and het; R in formula (VII) f and R g -H, -C 1-10 -Alkyl, C 1-10-Alkylaryl, -OH, -OC 1-10 -Alkyl, -(CH 2 ) 0-6 -C 3-7 -cycloalkyl, -O-(CH 2 ) 0-6 -aryl, phenyl, aryl, phenyl-phenyl Nil, -(CH 2 ) 1-6 -het, -O-(CH 2 ) 1-6 -het, -OR 13 , -C(0)-R 13 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -SR 13 , -S(O)-R 13 , -S(O) 2 -R 13 , -S(O) 2 -NR 13 R 14 , -NR 13 -S(O) 2 -R 14 , -SC 1-10 -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, -OC 1-4 -alkyl or any R g and R f together form a ring selected from het or aryl; D in formula (VII) is -CO-, -C(O)-C 1-7 -Alkylene or arylene, -CF 2 -, -O-, -S(O) r where r is 0 to 2 1,3-dioxalane, or C 1-7-alkyl-OH, where the alkyl, alkylene or arylene is unsubstituted or has one or more halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -Alkyl, or -CF 3 or each D is replaced by N(R h ), Rh is H, unsubstituted or substituted C 1-7 -Alkyl, aryl, unsubstituted or substituted -O-(C 1-7 -cycloalkyl), -C(O)-C 1-10 -Alkyl, -C(O)-C 0-10 -Alkyl-aryl, -COC 01-10 -Alkyl, -COC 0-10 -Alkyl-Aryl, -SO 2 -C 1-10 -Alkyl, or -SO 2 -(C 0-10 -alkylaryl), R in formula (VII) 6 , R 7 , R 8 and R 9 -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 optionally together form a ring system, R in formula (VII) 13 and R 14 , 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, each alkyl, cycloalkyl, and aryl is unsubstituted or substituted. : or any R 13 and R 14 forms het with the nitrogen atom, In the formula (VII), R 13 and R 14 The alkyl substituents of are unsubstituted or substituted, and when substituted, are 1-10 -Alkyl, halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -Alkyl, and -CF 3 and R 13 and R 14 The substituted phenyl or aryl of 1-4 -Alkyl, C 1-4 -Alkoxy, nitro, -CN, -OC(O)-C 1-4 -Alkyl, and -C(O)-OC 1-4 -substituted by one or more substituents selected from aryl.

[0073] 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 certain embodiments, the second ILM is a derivative of formula (VI) or a non-natural mimetic thereof. In certain embodiments, the at least one additional independently selected linker group comprises two additional independently selected linker groups that chemically couple the ILM and the second ILM. In certain embodiments, the at least one additional linker group to the ILM of formula (VI) or a non-natural mimetic thereof is 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, can be linked as shown below:

[0074] [ka]

[0075] In certain embodiments, the ILM, the at least one additional independently selected linker group L, and the second ILM have a structure selected from the group consisting of:

[0076] [ka]

[0077] [ka]

[0078] These are derivatives of the IAP antagonists described in WO 2008 / 014236.

[0079] In any of the compounds described herein, the ILM may be represented by formula (VIII) (which is Ndubaku, C., et al. Antagonism of c-IAP and XIAP proteins are required for efficient Induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4(7) (2009) or a non-natural mimetic thereof,

[0080] [ka]

[0081] wherein each of A1 and A2 in formula (VIII) is independently selected from optionally substituted monocyclic, fused ring, aryl and heteroaryl; R in formula (VIII) is selected from H or Me.

[0082] In certain embodiments, the linker group L is attached to A1 of formula (VIII). In other embodiments, the linker group L is attached to A2 of formula (VIII).

[0083] In certain embodiments, the ILM is selected from the group consisting of:

[0084] [ka]

[0085] In any of the compounds described herein, the ILM can have the structure of the following formula (IX) (derived from the species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010)), or a non-natural mimetic thereof:

[0086] [ka]

[0087] In the formula, R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, most preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, and R 2 is selected from -OPh or H.

[0088] In any of the compounds described herein, the ILM may be represented by the following formula (X): candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010), or a non-natural mimetic thereof,

[0089] [ka]

[0090] During the ceremony, R in formula (X) 1 -H, -CH 2 OH, - CH 2 CH 2 OH, - CH 2 NH 2 , - CH 2 CH 2 NH 2 is selected from X in formula (X) is S or CH 2 is selected from R in formula (X) 2 is selected from:

[0091] [ka]

[0092] R in formula (X) 3 and R 4 is independently selected from H or Me. In any of the compounds described herein, the ILM can have the structure of the following formula (XI) (derived from the species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010)), or a non-natural mimetic thereof:

[0093] [ka]

[0094] In the formula (XI), R 1 is selected from H or Me, and R in formula (XI) 2 is H or

[0095] [ka]

[0096] is selected from. In any of the compounds described herein, the ILM can have the structure of the following formula (XII) (derived from species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010)), or a non-natural mimetic thereof:

[0097] [ka]

[0098] During the ceremony, R in formula (XII) 1 is selected from:

[0099] [ka]

[0100] R in formula (XII) 2 is selected from the following:

[0101] [ka]

[0102] In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0103] [ka]

[0104] [ka]

[0105] In any of the compounds described herein, the ILM is an IAP ligand as summarized in formula (XIII), (Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010) ) or a non-natural mimetic thereof,

[0106] [ka]

[0107] During the ceremony, Z in formula (XIII) is absent or O; R in formula (XIII) 1 is as follows:

[0108] [ka]

[0109] is selected from

[0110] [ka]

[0111] R 10is selected from H, alkyl, or aryl; X is selected from CH2 and O; and

[0112] [ka]

[0113] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM can have the structure of formula (XIV) (based on the IAP ligands summarized in Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010)), or a non-natural mimetic thereof;

[0114] [ka]

[0115] During the ceremony, Z in formula (XIV) is absent or O; R in formula (XIV) 3 and R 4 is independently selected from H or Me; R in formula (XIV) 1 is selected from:

[0116] [ka]

[0117] [ka]

[0118] R 10 is selected from H, alkyl, or aryl;

[0119] [ka]

[0120] X is CH 2 and O;

[0121] [ka]

[0122] of

[0123] [ka]

[0124] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM is selected from the group consisting of:

[0125] [ka]

[0126] It is a derivative of the ligand disclosed in US Patent Publication No. 2008 / 0269140 and US Pat. No. 7,244,851.

[0127] In any of the compounds described herein, the ILM can have the structure of formula (XV), which is a derivative of the IAP ligands described in WO 2008 / 128171, or a non-natural mimetic thereof:

[0128] [ka]

[0129] During the ceremony, Z in formula (XV) is absent or O; R in formula (XV) 1is selected from:

[0130] [ka]

[0131] [ka]

[0132] R 10 is selected from H, alkyl, or aryl;

[0133] [ka]

[0134] X is CH 2 and O;

[0135] [ka]

[0136] of

[0137] [ka]

[0138] is a nitrogen-containing heteroaryl, and R in formula (XV) 2 is selected from H, alkyl or acyl.

[0139] In certain embodiments, the ILM has the structure:

[0140] [ka]

[0141] In any of the compounds described herein, the ILM can have the structure of formula (XVI) (based on the IAP ligands described in WO 2006 / 069063), or a non-natural mimetic thereof:

[0142] [ka]

[0143] During the ceremony, R in formula (XVI) 2 is selected from alkyl, cycloalkyl and heterocycloalkyl, more preferably isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably cyclohexyl; Formula (XVI)

[0144] [ka]

[0145] is a 5- or 6-membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl, most preferably thiazole; and In formula (XVI), Ar is aryl or heteroaryl.

[0146] In any of the compounds described herein, the ILM can have the structure of formula (XVII) (based on 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 a non-natural mimetic thereof,

[0147] [ka]

[0148] During the ceremony, R in formula (XVII) 1 is a halogen (e.g., fluorine), cyano,

[0149] [ka]

[0150] is selected from the group X in formula (XVII) is O or CH 2 is selected from the group:

[0151] In any of the compounds described herein, the ILM may be represented by formula (XVIII) (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 a non-natural mimetic thereof;

[0152] [ka]

[0153] wherein R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (at variable substitution positions).

[0154] In any of the compounds described herein, the ILM can have the structure of formula (XIX) (based on 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 a non-natural mimetic thereof,

[0155] [ka]

[0156] During the ceremony

[0157] [ka]

[0158] is a 6-membered nitrogen heteroaryl. In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0159] [ka]

[0160] In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0161] [ka]

[0162] In any of the compounds described herein, the ILM can have the structure of formula (XX) (based on the IAP ligands described in WO 2007 / 101347), or a non-natural mimetic thereof:

[0163] [ka]

[0164] Formula X in (XX) is CH 2 , O, NH or S.

[0165] In any of the compounds described herein, the ILM can have the structure of formula (XX) (based on the IAP ligands described in U.S. Pat. Nos. 7,345,081 and 7,419,975), or a non-natural mimetic thereof:

[0166] [ka]

[0167] During the ceremony, R in formula (XXI) 2 is selected from the following:

[0168] [ka]

[0169] R in formula (XXI) 5 is selected from the following:

[0170] [ka]

[0171] W in formula (XXI) is selected from CH or N;

[0172] [ka]

[0173] R 6 is independently a monocyclic or bicyclic fused aryl or heteroaryl. In certain embodiments, the ILM of the compound is selected from the group consisting of:

[0174] [ka]

[0175] In certain embodiments, the ILM of the compound is selected from the group consisting of:

[0176] [ka]

[0177] [ka]

[0178] These are described in WO 2009 / 060292, U.S. Pat. No. 7,517,906, WO 2008 / 134679, WO 2007 / 130626 and WO 2008 / 128121.

[0179] In any of the compounds described herein, the ILM may be represented by formula (XXII) or formula (XXIII) (see International Patent Application Publication No. 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity). ivity. J. Med. Chem. 58(3), 1556-62 (2015)), or a non-natural mimetic thereof, and / or the ILM is a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof;

[0180] [ka]

[0181] During the ceremony, R of formula (XXII) or formula (XXIII) 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXII) or formula (XXIII) 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; or alternatively R of formula (XXII) or formula (XXIII) 1 and R 2 is independently an optionally substituted thioalkyl, and the substituent attached to the S atom of the thioalkyl 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 and During the ceremony, v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 R 23 R 20 and R 22 , OH, NR 24 R 25 OR 26 are independently selected from -CH 2 CHR 21 COR 2 R 21 is NR 24 R 25 is selected from the group -CH 2 R 23 R 23 is selected from optionally substituted aryl, or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 2 O) m CH 3 or a polyamine chain such as spermine or spermidine, OR 26 R 26 is selected from optionally substituted alkyl, the optional substituents being OH, halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXII) or formula (XXIII) 3 and R 4 is 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, wherein the substituents are alkyl, halogen, or OH; R of formula (XXII) or formula (XXIII) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, and X is selected from a bond or a chemical linker group, and / or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof.

[0182] In certain embodiments, X is a bond or is selected from the group consisting of:

[0183] [ka]

[0184] where "*" is the attachment point of a PTM, L or ULM, e.g., an ILM. In any of the compounds described herein, the ILM may be represented by formula (XXIV) or formula (XXVI) (see International Patent Application Publication 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 non-natural mimetic thereof, and a chemical linker to the linker group L as shown below, and / or the ILM is a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof,

[0185] [ka]

[0186] During the ceremony, R of formula (XXIV), formula (XXV) or formula (XXVI) 1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXIV), formula (XXV) or formula (XXVI) 2 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 of formula (XXIV), formula (XXV) or formula (XXVI) 1 and R 2 is independently selected from optionally substituted thioalkyl, where the substituent attached to the S atom of the thioalkyl 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 and During the ceremony, v is an integer from 1 to 3 , -(CH 2 ) v COR 20 and -CH 2 R 23 R 20 and R 22 , OH, NR 24 R 25 OR 26 are independently selected from -CH 2 CHR 21 COR 2 R 21 is NR 24 R 25 is selected from -CH 2 R 23 R 23 is selected from optionally substituted aryl, or optionally substituted heterocyclyl, the optional substituents including alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 2 O) m CH 3 or a polyamine chain such as spermine or spermidine, OR 26 R 26 is selected from optionally substituted alkyl, the optional substituents being OH, halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXIV), formula (XXV) or formula (XXVI) 3 and R 4 is independently 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, wherein the substituents are alkyl, halogen, or OH; R of formula (XXIV), formula (XXV) or formula (XXVI) 5 , R 6 , R 7 and R 8 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0187] In certain embodiments, the ILM is according to formula (XXII)-(XXVI): R 7 and R 8 is selected from H or Me; R 5 and R 6 is selected from the group comprising:

[0188] [ka]

[0189] R 3 and R 4 is selected from the group including:

[0190] [ka]

[0191] In any of the compounds described herein, the ILM can have the structure of formula (XXVII) or formula (XXVII) (derived from the IAP ligands described in International Patent Application Publication No. WO 2014 / 055461, and Kim, K.S., Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014)), or a non-natural mimetic thereof, and / or the ILM can also be a pharma- ceutically acceptable salt, tautomer, or the like thereof. or stereoisomers,

[0192] [ka]

[0193] During the ceremony, R 35 is 1 to 2 substituents selected from alkyl, halogen, alkoxy, cyano, and haloalkoxy; R of formula (XXVII) and formula (XXVIII) 1 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 of formula (XXVII) and formula (XXVIII) 2is 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 of formula (XXVII) and formula (XXVIII) 1 and R 2 is an optionally substituted thioalkyl-CR 60 R 61 S.R. 70 wherein R 60 and R 61 teeth , H or methyl; 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 is selected from During the ceremony, v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 CHR 21 COR 22 R 20 and R 22 , OH, NR 24 R 25 OR 26 are independently selected from -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH 2 R 23 R 23is selected from optionally substituted aryl, or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 CH 2 (OCH 2 CH 2 ) m CH 3 or a polyamine chain such as spermine or spermidine -[CH 2 CH 2 (CH 2 )δNH]ΨCH 2 CH 2 (CH 2 )ωNH 2 from Selected, In the formula, δ=0 to 2, Ψ=1 to 3, and ω=0 to 2. OR 26 R 26 is an optionally substituted alkyl, the optional substituents being OH, halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXVII) and formula (XXVIII) 3 and R 4 is 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, wherein the substituents are alkyl, halogen, or OH; R of formula (XXVII) and formula (XXVIII) 5 , R6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R of formula (XXVII) and formula (XXVIII) 31 is selected from optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably selected from the group consisting of:

[0194] [ka]

[0195] X in formulae (XXVII) and (XXVIII) is -(CR 81 R 82 ) m -, optionally substituted heteroaryl or heterocyclyl,

[0196] [ka]

[0197] is selected from Z in formula (XXVII) is selected from C=O, -O-, -NR, -CONH-, -NHCO- or may be absent; -(CR 81 R 82 ) m -R 81 and R 82 are independently selected from hydrogen, halogen, alkyl or cycloalkyl, or R 81 and R 82 can together form a carbocyclic ring,

[0198] [ka]

[0199] R 10 and R 11is independently selected from hydrogen, halogen or alkyl;

[0200] [ka]

[0201] R 12 , R 13 , R 14 , R 15 and R 16 is hydrogen, halogen, or optionally substituted alkyl, or OR 17 are independently selected from R 17 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 21 R 22 ) m - and

[0202] [ka]

[0203] m and n are independently 0, 1, 2, 3, or 4;

[0204] [ka]

[0205] o and p are independently 0, 1, 2 or 3;

[0206] [ka]

[0207] q and t are independently 0, 1, 2, 3, or 4;

[0208] [ka]

[0209] where r is 0 or 1. In any of the compounds described herein, the ILM can have the structure of formula (XXIX), formula (XXX), formula (XXXI) or formula (XXXII) (derived from the IAP ligands described in International Patent Application Publication No. WO 2014 / 055461, and Kim, K.S., Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014)), or a non-natural mimetic thereof, and a chemical linker to the linker group L as shown below:

[0210] [ka]

[0211] [ka]

[0212] During the ceremony, R of formula (XXIX) to formula (XXXII) 2 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted selected from heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; or alternatively, R of formula (XXVII) and formula (XXVIII) 1 and R 2 is H, optionally substituted thioalkyl-CR 60 R 61 S.R. 70 wherein R 60 and R 6 1 is selected from H or methyl; R 70is 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 and During the ceremony, v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 CHR 21 COR 22 R 20 and R 22 O H, N.R. 24 R 25 OR 26 are independently selected from -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH 2 R 23 R 23 is selected from optionally substituted aryl, or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 CH 2 (OCH 2 CH 2 ) m CH 3or -[CH 2 CH 2 (CH 2 )δNH] Ψ CH 2 CH 2 (CH 2 ) ω r NH 2 is selected from During the ceremony δ =0~2, Ψ =1~3, ω = 0 to 2, OR 26 R 26 is an optionally substituted alkyl, the optional substituents being OH, halogen or NH 2 and m is an integer from 1 to 8; R of formula (XXIX) to formula (XXXII) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and R of formula (XXIX) to formula (XXXII) 31 is selected from optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably from the group consisting of

[0213] [ka]

[0214] is selected from. In certain embodiments, the ILM of the compound is

[0215] [ka]

[0216] It is. In any of the compounds described herein, the ILM can have the structure of formula (XXXIII), which is a derivative of the IAP ligands described in WO 2014 / 074658 and WO 2013 / 071035, or a non-natural mimetic thereof;

[0217] [ka]

[0218] Formula Inside, R in formula (XXXIII) 2 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXXIII) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R in formula (XXXIII) 32 is (C 1 -C 4 Alkylene)-R 33 wherein R 33 is selected from hydrogen, aryl, heteroaryl, or cycloalkyl, optionally further substituted; X in formula (XXXIII) is selected from the following:

[0219] [ka]

[0220] Z and Z′ in formula (XXXIII) are independently selected from:

[0221] [ka]

[0222] During the ceremony, each

[0223] [ka]

[0224] represents the point of attachment to the compound, and Z and Z' are both

[0225] [ka]

[0226] It cannot be. Y in formula (XXXIII) is selected from:

[0227] [ka]

[0228] In the formula (XXXIII), Z and Z' are the same, and Z is

[0229] [ka]

[0230] where each

[0231] [ka]

[0232] represents a point of attachment to the compound, and X is selected from:

[0233] [ka]

[0234] Y in formula (XXXIII) is independently selected from the following:

[0235] [ka]

[0236] [ka]

[0237] During the ceremony,

[0238] [ka]

[0239] represents the point of attachment to the -C=O moiety of the compound,

[0240] [ka]

[0241] represents the point of attachment to the -NH moiety of the compound,

[0242] [ka]

[0243] represents the first attachment point to Z,

[0244] [ka]

[0245] represents the second attachment point to Z, m is an integer from 0 to 3; n is an integer from 1 to 3, p is an integer from 0 to 4; A is -C(O)R 3 and R 3 is -C(O)R 3 , OH, NHCN, NHSO2 R 10 , N.H.O.R. 11 or N( R 12 )(R 13 ), NHSO 2 R 10 and NHOR 11 R 10 and F 11 is hydrogen, optionally substituted -C 1 -C 4 independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocycloalkyl; N(R 12 )(R 13 )R 12 and R 13 is hydrogen, -C 1 -C 4 Alkyl, -(C 1 -C 4 )alkylene)-NH-(C 1 -C 4 alkyl), and -(C 1 -C 4 Alki Ren)-O-(C 1 -C 4 hydroxyalkyl), or R 12 and R 13 together with the nitrogen atom to which they are commonly bonded form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O and S, said saturated heterocycle optionally substituted with methyl.

[0246] In any of the compounds described herein, the ILM can have the structure of formula (XXXIV) or formula (XXXV) (derived from the IAP ligands described in WO 2014 / 047024), or a non-natural mimetic thereof, and / or the ILM is a pharma- ceutically acceptable salt, tautomer or stereoisomer thereof;

[0247] [ka]

[0248] During the ceremony, In the formula (XXXIV) or (XXXV), X is absent or -(CR 10 R 11 ) m -, optionally substituted heteroaryl, or optionally substituted heterocyclyl,

[0249] [ka]

[0250] is a group selected from Y and Z in formula (XXXIV) or formula (XXXV) are each independently selected from the group consisting of C=O, -O-, -NR 9 -, -CONH-, -NHCO-, or may be absent; R of formula (XXXIV) or formula (XXXV) 1 and R 2 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl, or R of formula (XXXIV) or formula (XXXV) 1 and R 2 is independently selected from optionally substituted thioalkyl, where the substituent attached to the S atom of the thioalkyl 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 wherein v is an integer from 1 to 3; -(CH 2 ) v COR 20 and -CH 2 CHR 21 COR 22 R20 and R 22 , OH, NR 24 R 25 OR 26 are independently selected from -CH 2 CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH 2 R 23 R 23 is selected from optionally substituted aryl, or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen; NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 20 ) m CH 3 or a polyamine chain, R 26 is an optionally substituted alkyl, the optional substituents being OH, halogen or NH 2 and -(CR 10 R 11 ) m m is an integer from 1 to 8; R of formula (XXXIV) or formula (XXXV) 3 and R 4is 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, wherein the substituents are alkyl, halogen, or OH; R of formula (XXXIV) or formula (XXXV) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 10 R 11 ) m -R 10 and R 11 are independently selected from hydrogen, halogen, or optionally substituted alkyl;

[0251] [ka]

[0252] R 12 and R 13 are independently selected from hydrogen, halogen, or optionally substituted alkyl, or R 12 and R 13 can together form a carbocyclic ring,

[0253] [ka]

[0254] R 14 , R 15 , R 16 , R 17 and R 18 is hydrogen, halogen, optionally substituted alkyl, or OR 19 are independently selected from OR 19 R19 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 10 R 11 ) m m and n are independently 0, 1, 2, 3, or 4; 10 R 11 ) m - o and p are independently 0, 1, 2, or 3; -(CR 10 R 11 ) m q is 0, 1, 2, 3, or 4 and r is 0 or 1; -(CR 10 R 11 ) m -t is 1, 2, or 3.

[0255] In any of the compounds described herein, the ILM can have the structure of formula (XXXVI) (derived from the IAP ligands described in International Patent Application Publication No. WO 2014 / 025759), or a non-natural mimetic thereof, and / or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof;

[0256] [ka]

[0257] During the ceremony, A in formula (XXXVI) is

[0258] [ka]

[0259] where the dotted line represents an optional double bond; X in formula (XXXVI) is -(CR 21 R 22 ) m -,

[0260] [ka]

[0261] is selected from In the formula (XXXVI), Y and Z are each independently -O-, -NR 6 - independently selected from or absent, V in formula (XXXVI) is selected from -N- or -CH-; W in formula (XXXVI) is selected from -CH- or -N-; R in formula (XXXVI) 1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl; R in formula (XXXVI) 3 and R 4 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl; R of formula (XXIV), formula (XXV) or formula (XXVI) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or is preferably methyl;

[0262] [ka]

[0263] R 9 and R 10 are independently selected from hydrogen, halogen, or optionally substituted alkyl, or R 9 and R 10 can form a ring together,

[0264] [ka]

[0265] R 11 , R 12 , R 13 and R 14 is hydrogen, halogen, optionally substituted alkyl or OR 15 are independently selected from OR 15 R 15 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 21 R 22 ) m - and

[0266] [ka]

[0267] m and n are independently selected from 0, 1, 2, 3, or 4;

[0268] [ka]

[0269] o and p are independently selected from 0, 1, 2 or 3;

[0270] [ka]

[0271] q is selected from 0, 1, 2, 3, or 4;

[0272] [ka]

[0273] In the formula, r is selected from 0 or 1. In any of the compounds described herein, the ILM can have the structure of formula (XXXVII) or formula (XXXVIII) (derived from the IAP ligands described in International Patent Application Publication No. WO 2014 / 011712), or a non-natural mimetic thereof, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof;

[0274] [ka]

[0275] [ka]

[0276] During the ceremony, X in the formula (XXXVII) and the formula (XXXVIII) is -(CR 16 R 17 ) m -,

[0277] [ka]

[0278] or absent, Y and Z in formula (XXXVII) and formula (XXXVIII) are each independently -0-, C=0, NR 6 or are absent, R of formula (XXXVII) and formula (XXXVIII) 1 and R 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylaryl, or optionally substituted aryl; R of formula (XXXVII) and formula (XXXVIII) 3 and R 4is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXXVII) and formula (XXXVIII) 5 and R 6 is optionally replaced alkyl, or optionally substituted cycloalkyl; R of formula (XXXVII) and formula (XXXVIII) 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or is preferably methyl;

[0279] [ka]

[0280] R 9 and R 10 are independently selected from hydrogen, optionally substituted alkyl, or R 9 and R 10 may together form a ring,

[0281] [ka]

[0282] R 11 ~R 14 are independently hydrogen, halogen, optionally substituted alkyl, or OR 15 are independently selected from OR 15 R 15 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 16 R 17 ) m -R 16 and R 17are independently selected from hydrogen, halogen, or optionally substituted alkyl; R of formula (XXXVII) and formula (XXXVIII) 50 And R 51 is independently selected from optionally substituted alkyl, or R 50 and R 51 together form a ring, -(CR 16 R 17 ) m - and

[0283] [ka]

[0284] m and n are independently an integer of 0 to 4;

[0285] [ka]

[0286] o and p are independently an integer of 0 to 3;

[0287] [ka]

[0288] q is an integer from 0 to 4, and

[0289] [ka]

[0290] The r is an integer of 0 to 1.

[0291] In one embodiment, R of the ILM of formula (XXXVII) or formula (XXXVIII) 1 and R 2 is t-butyl, and R of the ILM of formula (XXXVII) or formula (XXXVIII)3 and R 4 is tetrahydronaphthalene.

[0292] In any of the compounds described herein, the ILM can have the structure of formula (XXXIX) or formula (XL) (derived from the IAP ligands described in International Patent Application Publication No. WO 2013 / 071039), or a non-natural mimetic thereof;

[0293] [ka]

[0294] During the ceremony, R in formula (XXXIX) and formula (XL) 43 And R 44 is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, which are further optionally substituted; and R in formula (XXXIX) and formula (XL) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; Each X in formulas (XXXIX) and (XL) is independently selected from:

[0295] [ka]

[0296] Each Z in formula (XXXIX) and formula (XL) is

[0297] [ka]

[0298] wherein each

[0299] [ka]

[0300] represents the point of attachment to the compound, and Each Y is selected from:

[0301] [ka]

[0302] [ka]

[0303] During the ceremony,

[0304] [ka]

[0305] represents the point of attachment to the -C=O moiety of the compound,

[0306] [ka]

[0307] represents the point of attachment to the amino moiety of the compound,

[0308] [ka]

[0309] represents the first attachment point to Z,

[0310] [ka]

[0311] represents the second attachment point to Z, and A is -C(O)R 3 ,or

[0312] [ka]

[0313] or any of the foregoing tautomeric forms, wherein: -C(O)R 3 R 3 OH, NHCN, NHSO 2 R 10 , N.H.O.R. 11 or N(R 12 )(R 13 ), NHS0 2 R 10 and NHOR 11 R 10 and R 11 -C 1 -C 4 independently selected from alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which is optionally substituted, and hydrogen; N(R 12 )(R 13 )R 12 and R 13 Each of 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 N(R 12 )(R13 )R 12 and R 13 together with the nitrogen atom to which they are commonly bonded form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O and S, said saturated heterocycle optionally substituted with methyl.

[0314] In any of the compounds described herein, the ILM can have the structure of formula (XLI) (derived from the IAP ligands described in International Patent Application Publication No. WO 2013 / 071039), or a non-natural mimetic thereof:

[0315] [ka]

[0316] During the ceremony, W in formula (XLI) 1 are O, S, and NR A , or C(R 8a )(R 8b ), W in formula (XLI) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or neither S, R in formula (XLI) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 From alkyl-(substituted or unsubstituted heteroaryl) Selected, X 1 But, O, NR A , S, S(O), or S(O) 2 If selected from, X 2 teeth, C(R 2a R 2b ) and or X in formula (XLI) 1 is CR 2c R 2d Selected from X 2 CR 2a R 2b and R 2c and R 2a form a bond together, or X in formula (XLI) 1 and X 2 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; or X in formula (XLI) 1 CH 2 Also selected from X 2 For C=0, C=C(R C ) 2 or C=NR C where each R c are independently H, -CN, -OH, alkoxy, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 2 -C 5 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 -C6 Cycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted C 2 -C 5 Heterocycloalkyl), -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 selected from alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d and C.R. 2a R 2b R 2a , R 2b , R 2c , R 2d is 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 6Alkyl-(substituted or unsubstituted heteroaryl) and -C(=O)R B are independently selected from -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 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 is selected from NR D R E R D and R E is 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), -C1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl are selected independently from m in formula (XLI) is selected from 0, 1 or 2; -U- in formula (XLI) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 NH-, R in formula (XLI) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLI) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 is selected from -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 , and -OR 5 Each R 5 , 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 in formula (XLI) 3 and R 5form a substituted or unsubstituted 5- to 7-membered ring together with the atom to which they are attached, or R in formula (XLI) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLI) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7, -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 Each R 7 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 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 C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 )p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P is independently selected from: -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); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d , H, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 independently selected from heteroalkyl, and substituted or unsubstituted aryl; or R 8a and R 8d is as defined above, and R 8b and R 8c form a bond together, or R 8a and R 8d is as defined above, and R 8b and R 8c together with the atom to which they are attached, represent a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from S, O, and N, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered aryl ring containing 1 to 3 heteroatoms selected from S, O, and N. forming a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing up to 3 heteroatoms; or R 8c and R 8d is as defined above, and R 8a and R 8b together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; or R 8a and R 8b is as defined above, and R 8c and R 8d together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from 1 to 3 R 9 is replaced by, and R 8a , R 8b , R 8c and R 8d Each R 9 are halogens, -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-(CC 4 alkyl), -O(C 1 -C 4 Alkyl)-NH 2 ;-O(C 1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 -C 4 Alkyl)-N-(C 1 -C 4 Alkyl) 2 or two R 9 together with the atom to which they are attached, halogen, -OH, or C 1 -C 3 It forms a methylenedioxy ring or an ethylenedioxy ring which may or may not be substituted with alkyl.

[0317] In any of the compounds described herein, the ILM can have the structure of formula (XLII) (derived from the IAP ligands described in International Patent Application Publication No. WO 2013 / 071039), or a non-natural mimetic thereof:

[0318] [ka]

[0319] During the ceremony, W in formula (XLII) 1 are O, S, and NR A , or C(R 8a )(R 8b ) and W in formula (XLII) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2are not both O or neither S, R in formula (XLII) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl) Selected from X in formula (XLII) 1 NR A If X 2 is C=O or CR 2c R 2d And X 3 is CR 2a R 2b and or X in formula (XLII) 1 is S, S(O) or S(O) 2 If selected from, X 2 is CR 2c R 2d And X 3 is CR 2a R 2b and or X in formula (XLII) 1 If is O, then X 2 is CR 2c R 2d and NR A and X 3 is CR 2a R 2b and or X in formula (XLII) 1 CH 3 If X 2 , O, NRA , S, S(O), or S(O) 2 and X 3 is CR 2a R 2b and X in formula (XLII) 1 CR 2e R 2f and X 2 CR 2c R 2d If R 2e and R 2c together form a bond, and X in formula (VLII) 3 is CR 2a R 2b and or X in formula (XLII) 1 and X 3 Both are CH 2 and X of formula (XLII) 2 is C=0, C=C(R C )2, or C=NR C where each R C is 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 Independently of alkyl-(substituted or unsubstituted heteroaryl) Selected by or X in formula (XLII) 1 and X 2 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; and X 3 CR 2a R 2b and or X in formula (XLII) 2 and X 3 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X in formula (VLII) 1 CR 2e R 2f and NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 selected from alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Heteroalkyl, substituted or unsubstituted C3 -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 are independently selected from -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 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 is selected from NR D R E RD and R E is 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); In formula (XLII), m is selected from 0, 1 or 2; -U- in formula (XLII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 NH-, R in formula (XLII) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLII) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 is selected from -NHR 5 , -N(R 5 )2 , -N + (R 5 ) 3 , and -OR 5 Each R 5 , 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 in formula (XLII) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atom to which they are attached, or R in formula (XLII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 Each R 7 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 10Heterocycloalkyl, 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 C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P -CH(substituted or unsubstituted aryl)(substituted or unsubstituted 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 aryl)-(substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d , H, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C 6 Alkoxy, C 1 -C 6heteroalkyl, and substituted or unsubstituted aryl; or R 8a and R 8d is as defined above, and R 8b and R 8c form a bond together, or R 8a and R 8d is as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O and N; or R 8c and R 8d is as defined above, and R 8a and R 8b together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; or R 8a and R 8b is as defined above, and R 8c and R 8d together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl has 1 to 3 R 9 is replaced by, and R 8a , R 8b , R 8c and R 8dEach R 9 are halogens, -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-(CC 4 alkyl), -O(C 1 -C 4 Alkyl)-NH 2 ;-O(C 1 -C 4 Alkyl)-NH-(C 1 -C 4 alkyl), and -O(C 1 -C 4 Alkyl)-N-(C 1 -C 4 Alkyl) 2 or two R 9 together with the atom to which they are attached, halogen, -OH, or C 1 -C 3 It forms a methylenedioxy ring or an ethylenedioxy ring which may or may not be substituted with alkyl.

[0320] In any of the compounds described herein, the ILM can have the structure of formula (XLIII) (derived from the IAP ligands described in International Patent Application Publication No. WO 2013 / 071039), or a non-natural mimetic thereof:

[0321] [ka]

[0322] During the ceremony, W in formula (XLIII) 1 are O, S, and NR A , or C(R 8a )(R 8b ), W in formula (XLIII) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or neither S, R in formula (XLIII) 1 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), or -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl) is selected from X in formula (XLIII) 1 But NR A , S, S(O), or S(O) 2 When selected from the group consisting of X in formula (XLIII), 2 is CR 2c R 2dand X of formula (XLIII) 3 is CR 2a R 2b and or X in formula (XLIII) 1 When is O, X in formula (XLIII) 2 , O, NR A , S, S(O), or S(O) 2 and X of formula (XLIII) 3 CR 2a R 2b and or X in formula (XLIII) 1 CR 2e R 2f and X in formula (XLIII) 2 CR 2c R 2d If R 2e and R 2c and X in formula (XLIII) form a bond. 3 is CR 2a R 2b and or X in formula (XLIII) 1 and X 2 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; and X in formula (XLIII) 3 CR 2a R 2b and or X in formula (XLIII) 2 and X 3is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; and X in formula (VLII) 1 CR 2e R 2f and NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is 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 6Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R B are independently selected from -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 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 and NR D R E R D and R E is 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 6Alkyl-(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 are selected independently from In formula (XLIII), m is 0, 1 or 2; -U- in formula (XLIII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 NH-, R in formula (XLIII) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 is a fluoroalkyl; R in formula (XLIII) 4 -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 -OR 5 and -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 , and -OR 5 Each R 5 , 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 in formula (XLIII) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atom to which they are attached, or R in formula (XLIII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLIII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 Each R 7 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 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 C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 )p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P is independently selected from: -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); R 7 p is 0, 1, or 2; C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d , 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 is as defined above, and R 8b and R 8c form a bond together, or R 8a and R 8d is as defined above, and R 8b and R 8ctogether with the atoms to which they are attached form a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O and N; or R 8c and R 8d is as defined above, and R 8a and R 8b together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; or R 8a and R 8b is as defined above, and R 8c and R 8d together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N; wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one to three R 9 is replaced by, and R 8a , R 8b , R 8c and R 8d Each R 9 are halogens, -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(C1 -C 4 Alkyl) 2 , -C(=O)OH, -C(=0)NH 2 , -C(=O)C 1 -C 3 Alkyl, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 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 atom to which they are attached, halogen, -OH, or C 1 -C 3 It forms a methylenedioxy ring or an ethylenedioxy ring which may or may not be substituted with alkyl.

[0323] In any of the compounds described herein, the ILM may be represented by formula (XLIV) (derived from the IAP ligands described in International Patent Application Publication No. WO 2013 / 071039): or a non-natural mimetic structure thereof,

[0324] [ka]

[0325] During the ceremony, W in formula (XLIV) 1 are O, S, and NR A , or C(R 8a )(R 8b), W in formula (XLIV) 2 are O, S, and NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or neither S, W in formula (XLIV) 3 are O, S, and NR A , or C(R 8e )(R 8f ), where W 1 , W 2 and W 3 does not contain two adjacent oxygen or sulfur atoms; R in formula (XLIV) 1 , 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) Selected from X in formula (XLIV) 1 When is O, X in formula (XLIV) 2 CR 2c R 2d and N.R. A X of formula (XLIV) is selected from 3 CR 2a R 2b and or X in formula (XLIV) 1 CH 2 When X in formula (XLIV) is 2 , O, NR A , S, S(O), or S(O)2 X of formula (XLIV) is selected from 3 CR 2a R 2b and or X in formula (XLIV) 1 CR 2e R 2f and X in formula (XLIV) 2 CR 2c R 2d If R 2e and R 2c Together they form a bond, and X in formula (XLIV) 3 is CR 2a R 2b and or X in formula (XLIV) 1 and X 3 Both are CH 2 and X in formula (XLII) 2 is C=0, C=C(R C )2, or C=NR C where each R C is 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 in formula (XLIV) 1 and X 2 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; and X in formula (XLIV) 3 CR 2a R 2b and or X in formula (XLIV) 2 and X 3 is independently selected from C and N and is a component of a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl ring, a fused substituted or unsubstituted 5- to 10-membered aryl ring, or a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring; and X in formula (VLIV) 1 CR 2e R 2f and NR A R A , H, C 1 -C 6 Alkyl, -C(=O)C 1 -C 2 selected from alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is 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 are independently selected from -C(=O)R B R B is a substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 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 is selected from NR D R E R D and RE is 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 are selected independently from In formula (XLIV), m is selected from 0, 1 or 2; -U- in formula (XLIV) is -NHC(=O)-, -C(=O)NH-, -NHS(=O) 2 -, -S(=O) 2 NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O) 2 NH-, R in formula (XLIV) 3 is C 1 -C 3 Alkyl, or C 1 -C 3 fluoroalkyl; R in formula (XLIV) 4 -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 -OR 5 is selected from -NHR 5 , -N(R 5) 2 , -N + (R 5 ) 3 , and -OR 5 Each R 5 , 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 in formula (XLIV) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atom to which they are attached, or R in formula (XLIII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring; R in formula (XLIII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O) 2 R 7 , -S(=O) 2 NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O) 2 NHR 7 , -(C 1 -C 3 Alkyl)-NHC(=O)R 7 , -(C 1 -C 3 Alkyl)-C(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 R 7 , -(C 1 -C 3 Alkyl)-S(=O) 2 NHR 7 ;-(C 1 -C 3 Alkyl)-NHC(=O)NHR 7 , -(C 1 -C 3 Alkyl)-NHS(=O) 2 NHR 7 Each R 7 is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Heteroalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 2 -C 10Heterocycloalkyl, 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 C 2 -C 10 Heterocycloalkyl, -C 1 -C 6 Alkyl-(substituted or unsubstituted aryl), -C 1 -C 6 Alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 ) P is independently selected from: -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); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f , H, C 1 -C 6 Alkyl, C 1 -C 6 Fluoroalkyl, C 1 -C6 Alkoxy, C 1 -C 6 independently selected from heteroalkyl, and substituted or unsubstituted aryl; or C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8d , R 8e , and R 8f is as defined above, and R 8b and R 8c form a bond together, or C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8b , R 8d , and R 8f is as defined above, and R 8c and R 8e form a bond together, or C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8d , R 8e , and R 8f is as defined above, and R 8b and R 8ctogether with the atoms to which they are attached form a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N; or C(R 8a )(R 8b ), C(R 8c )(R 8d ), and C(R 8e )(R 8f )R 8a , R 8b , R 8d , and R 8f is as defined above, and R 8c and R 8e together with the atom to which they are attached, are a substituted or unsubstituted fused 5- to 7-membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from S, O, and N, a substituted or unsubstituted fused 5- to 10-membered aryl ring, or a substituted or unsubstituted fused 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms selected from S, O, and N. Forming a reel loop, or C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8c , R 8d , R 8e , and R 8f is as defined above, and R 8a and R 8b together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N, or C(R 8a )(R 8b ) and C(R 8e )(R 8f )R 8a , R8b , R 8e , and R 8f is as defined above, and R 8c and R 8d together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N, or C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c , and R 8d is as defined above, and R 8e and R 8f together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O and N, or wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from 1 to 3 R 9 is replaced by, and R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f Each R 9 are halogens, -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)NH2 , -C(=O)C 1 -C 3 Alkyl, -S(=O) 2 CH 3 , -NH(C 1 -C 4 alkyl)-OH, -NH(C 1 -C 4 Alkyl)-O-(CC 4 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 atom to which they are attached, halogen, -OH, or C 1 -C 3 It forms a methylenedioxy ring or an ethylenedioxy ring which may or may not be substituted with alkyl.

[0326] In any of the compounds described herein, the ILM may be represented by formula (XLV), formula (XLVI) or formula (XLVII) (Vamos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013) or a non-natural mimetic thereof;

[0327] [ka]

[0328] [ka]

[0329] During the ceremony, R in formula (XLV) 2 , R 3 and R 4 is independently selected from H or Me; X in formula (XLV) is independently selected from O or S; and R in formula (XLV) 1 is selected from the following:

[0330] [ka]

[0331] In certain embodiments, the ILM has a structure according to formula (XLVIII):

[0332] [ka]

[0333] In the formula (XLVIII), R 3 , and R 4 is independently selected from H or ME;

[0334] [ka]

[0335] is a 5-membered heterocycle selected from:

[0336] [ka]

[0337] In certain embodiments, the compound of formula (XLVIII)

[0338] [ka]

[0339] teeth,

[0340] [ka]

[0341] It is. In certain embodiments, the ILM has the structure as shown below and is attached to a linker group L as shown.

[0342] [ka]

[0343] In certain embodiments, the ILM has a structure according to formula (XLIX), (L), or (LI):

[0344] [ka]

[0345] [ka]

[0346] During the ceremony, R of formula (XLIX), formula (L) or formula (LI) 3 is independently selected from H or ME,

[0347] [ka]

[0348] is a 5-membered heterocycle selected from

[0349] [ka]

[0350] L in formula (XLIX), formula (L) or formula (LI) is selected from the following:

[0351] [ka]

[0352] In certain embodiments, L in formula (XLIX), formula (L), or formula (LI) is

[0353] [ka]

[0354] It is. In certain embodiments, the ILM has a structure according to formula (LII):

[0355] [ka]

[0356] In certain embodiments, the ILM according to formula (LII) is

[0357] [ka]

[0358] and is chemically attached to a linker group L at the area indicated as

[0359] [ka]

[0360] In any of the compounds described herein, the ILM can have the structure of formula (LIII) or (LIV) (based on the IAP ligands described in Hennessy, EJ, et al., Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4 (2012)), or a non-natural mimetic thereof;

[0361] [ka]

[0362] [ka]

[0363] During the ceremony, R of formula (LIII) and formula (LIV) 1 is selected from:

[0364] [ka]

[0365] R of formula (LIII) and formula (LIV) 2 is selected from H or Me; R of formula (LIII) and formula (LIV) 3 is selected from:

[0366] [ka]

[0367] X is selected from H, halogen, methyl, methoxy, hydroxy, nitro, or trifluoromethyl.

[0368] In any of the compounds described herein, the ILM can have a structure as shown in formula (LV) or formula (LVI) and can be chemically attached to a linker as shown in formula (LV) or formula (LVI), or can have the structure of a non-natural mimetic thereof.

[0369] [ka]

[0370] In any of the compounds described herein, the ILM can have the structure of formula (LVII) (based on 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 non-natural mimetic thereof,

[0371] [ka]

[0372] During the ceremony, R in formula (LVII) 1 is selected from:

[0373] [ka]

[0374] [ka]

[0375] X is selected from H, fluoro, methyl, or methoxy. In certain embodiments, the ILM is represented by the following structure:

[0376] [ka]

[0377] In certain embodiments, the ILM is selected from the group consisting of:

[0378] [ka]

[0379] [ka]

[0380] In any of the compounds described herein, the ILM is selected from the group consisting of the following structures derived from IAP ligands described in Asano, M, et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitors of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18):5725-37 (2013), or non-natural mimetics thereof:

[0381] [ka]

[0382] In certain embodiments, the ILM is selected from the group consisting of:

[0383] [ka]

[0384] In any of the compounds described herein, the ILM can have the structure of formula (LVIII) (derived from the IAP ligand 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 a non-natural mimetic thereof,

[0385] [ka]

[0386] wherein X in formula (LVIII) is one or two substituents independently selected from H, halogen, or cyano.

[0387] In any of the compounds described herein, the ILM can have a structure as shown in formula (LIX) or formula (LX), and ) or can have the structure of a non-natural mimetic thereof,

[0388] [ka]

[0389] wherein X in formulae (LIX) and (LX) is one or two substituents independently selected from H, halogen or cyano, and L in formulae (LIX) and (LX) is a linker group as described herein.

[0390] In any of the compounds described herein, the ILM can have the structure of formula (LXI) (derived from the IAP ligand described in Ardecky, RJ, et al., Design, systemthesis 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 a non-natural mimetic thereof;

[0391] [ka]

[0392] During the ceremony, Formula (LXI)

[0393] [ka]

[0394] is a natural or unnatural amino acid, and R in formula (LXI) 2 is selected from the following:

[0395] [ka]

[0396] In any of the compounds described herein, the ILM can have a structure as shown in formula (LXII) or formula (LLXIII) and can be chemically attached to a linker group L as shown in formula (LXII) or formula (LLXIII), or can have the structure of a non-natural mimetic thereof;

[0397] [ka]

[0398] Formula (LXI)

[0399] [ka]

[0400] is a natural or unnatural amino acid, and L in formula (LXI) is a linker group as described herein.

[0401] In any of the compounds described herein, the ILM is selected from the group consisting of Wang, J, et al., Discovery of novel second mitochondrial-derived activator of caspase mimetics The IAP ligands described in, for example, IAP inhibitors such as selective inhibitors or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2):319-29 (2014), can have a structure selected from the group consisting of the following, or a non-natural mimetic structure thereof:

[0402] [ka]

[0403] In any of the compounds described herein, the ILM has a structure according to formula (LXIX) (based on 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 a non-natural mimetic thereof;

[0404] [ka]

[0405] wherein R of formula LIX is selected from the group consisting of:

[0406] [ka]

[0407] [ka]

[0408] R 1 is selected from H or Me;

[0409] [ka]

[0410] R 2 is selected from alkyl or cycloalkyl;

[0411] [ka]

[0412] X is 1 to 2 substituents independently selected from halogen, hydroxy, methoxy, nitro, and trifluoromethyl;

[0413] [ka]

[0414] Z is O or NH;

[0415] [ka]

[0416] HET is a monocyclic heteroaryl or a fused bicyclic heteroaryl; and In formula (LIX), --- represents an optional double bond.

[0417] In certain embodiments, the ILM of the compound has the chemical structure represented by:

[0418] [ka]

[0419] In certain embodiments, the ILM of the compound has a chemical structure selected from the group consisting of:

[0420] [ka]

[0421] [ka]

[0422] As used herein, the term "independently" is used to indicate that the variable that is independently applied varies independently from application to application.

[0423] The term "alkyl" shall mean, within its context, a straight-chain, branched-chain, or cyclic fully saturated hydrocarbon radical or group of alkyl, preferably C 1 -C 10 , more preferably C 1 -C 6 , or C 1 -C 3Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, among others. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes. These compounds generally contain a side chain (often attached through a polyethylene glycol group) that terminates in an alkyl group that has a halogen substituent (often chlorine or bromine) at its distal end, thereby resulting in a covalent bond between the compound containing the moiety and the protein.

[0424] The term "alkenyl" refers to a straight, branched or cyclic C alkyl group containing at least one C=C bond. 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0425] The term "alkynyl" refers to any straight, branched or cyclic C alkyl group containing at least one C≡C bond. 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0426] The term "alkylene," when used, refers to an optionally substituted --(CH 2 ) n -group where n is typically an integer from 0 to 6. When substituted, the alkylene group may be one or more of a methylene group, a C 1 -C 6It is preferably substituted with an alkyl group (including a cyclopropyl group or a t-butyl group), but may also contain one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, O-(C 1 -C 6 In certain embodiments, the alkylene groups may be substituted with urethane or alkoxy groups (or other groups), which in turn are substituted with polyethylene glycol chains (chains of 1-10, preferably 1-6, often 1-4 ethylene glycol units) to which an alkyl group is substituted (preferably, but not exclusively, on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with one halogen group, preferably a chlorine group. In yet other embodiments, the alkylene (often methylene) groups may be substituted with amino acid side chain groups, such as the side chain groups of natural or unnatural amino acids, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0427] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. 0 The range of carbon atoms including means that the carbon is not present and has been replaced with H. Hence, C 0 -C 6 The carbon atom range includes 1, 2, 3, 4, 5 and 6 carbon atoms, C 0 In the case of , there is an H instead of a carbon.

[0428] The terms "substituted" or "optionally substituted" shall mean, within context, independently one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents, on a moiety in a compound according to the present disclosure, which may include substituents which may themselves be further substituted) at any carbon (or nitrogen) position on a molecule (i.e., when there are multiple substituents, each substituent is independent of the other substituents), and include as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO 2 ), halogen (especially alkyl, preferably 1, 2 or 3 halogens on the methyl group, e.g. trifluoromethyl), alkyl group (preferably C 1 -C 10 , more preferably C 1-6 ), aryl (especially phenyl and substituted phenyl, e.g. benzyl or benzoyl), alkoxy groups (preferably C 1 -C 6 alkyl or aryl, including phenyl and substituted phenyl), thioethers (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) with alkylene ester (the bond is on the alkylene group, not the ester functionality, preferably C 1 -C 6 substituted with alkyl or aryl groups), preferably C 1 -C 6 Alkyl or aryl containing, halogen (preferably F or Cl), amines (including 5- or 6-membered cyclic alkylene amines, C 1 -C 6 Alkylamine or C 1 -C 6 Dialkylamines further include dialkylamines, where the alkyl groups may be substituted with one or two hydroxyl groups, or optionally substituted -N (C 0 -C6 Alkyl)C(O)(OC 1 -C 6 alkyl) groups (which may be optionally substituted with a polyethylene glycol chain to which is further attached an alkyl group containing one halogen, preferably chlorine, substituent); hydrazines; amides, which preferably have one or two C 1 -C 6 Alkyl groups (one or two C 1 -C 6 including carboxamides optionally substituted with alkyl groups), alkanols (preferably C 1 -C 6 alkyl or aryl), or alkanoic acid (preferably C 1 -C 6 Substituents according to the present disclosure include, for example, -SiR 1 R 2 R 3 group, where R 1 and R 2 of Each is described separately herein, and R 3 is H or C 1 -C 6 is an alkyl group, preferably in this context R 1 , R 2 , R 3 is C 1 -C 3 Each of the above groups may be directly attached to the substituted moiety, or alternatively the substituent is an optionally substituted (CH 2 ) m - or alternatively optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m -or-(CH 2 CH 2 O) m The -(CH) group of an alkylene group may be linked to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety), which may be substituted with any one or more of the above-mentioned substituents.2 ) m -or-(CH 2 ) n The - group or other chain, such as the ethylene glycol chain identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen, or C 1 -C 6 (Preferably C 1 -C 3 ) alkyl group (optionally containing one or two hydroxyl groups, one or two ether groups (OC 1 -C 6 group), up to three halo groups (preferably F), or may be substituted at the side chain of an amino acid as otherwise described herein), and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane group (often containing one or two C 0 -C 6 In certain embodiments, the alkylene group (often a single methylene group) has one or two optionally substituted C 1 -C 6 Alkyl groups, preferably C 1 -C 4 Substituted with an alkyl group, most often a methyl or O-methyl group, or an amino acid side chain as otherwise described herein. Moieties in the molecules in this disclosure may be optionally substituted with up to 5 substituents, preferably up to 3 substituents. In most cases, substituted moieties in this disclosure are substituted with 1 or 2 substituents.

[0429] The term "substituted," where each substituent is independent of any other substituent, shall, within the context of its use, be understood to include any of the following: 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C 1 -C 6 Esters (oxyesters or carbonylesters), C 1 -C6 Keto, urethane-OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 , nitro, cyano, and and amines (especially C 1 -C 6 Alkylene-NR 1 R 2 , mono or di-C 1 -C 6 "Alkyl substituted amines" also refer to alkyl substituted amines, including those which may be optionally substituted with one or two hydroxyl groups. Each of these groups contains 1 to 6 carbon atoms, unless otherwise indicated within the context. In certain embodiments, preferred substituents are, for example, -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m - (where m and n are 1, 2, 3, 4, 5 or 6, as the context requires), -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 O.C.(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 , -(OCH 2 ) n OH, -(CH 2 O) n COOH, C 1 -C 6 Alkyl, -(OCH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 O) n C(O)-(C 1 -C 6 Alkyl), -(OCH 2 ) n NHC(O) -R 1 , -(CH 2 O) n C(O)-NR 1 R 2 , -S(O) 2 -R S , -S(O)-R S (R S is C 1 -C 6 Alkyl or -(CH 2 ) m -NR 1 R 2 group), NO 2 , C.N. or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of use of the substituent. 1 and R 2 are H or C in the context 1 -C 6 The term "substituted" is also intended to mean, within the chemical context of the compound specified and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. The alkylene group may also be substituted as otherwise disclosed herein, and is preferably an optionally substituted C 1 -C6 an alkyl group (preferably methyl, ethyl or hydroxymethyl or hydroxyethyl, thereby providing a chiral center), the side chain of an amino acid group as otherwise described herein, an amide group as described above, or a urethane group, OC(O)-NR 1 R 2 A group, wherein R 1 and R 2 may be substituted with groups as otherwise described herein, but many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or less, and preferably one or two substituents. It is noted that in compounds where substitution is required at a particular position of the molecule (mainly for valence reasons) but no substitution is indicated, the substituent is assumed or understood to be H, unless otherwise indicated in the context of the substitution.

[0430] The term "aryl" or "aromatic", in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), which may be attached to a compound in accordance with the present disclosure at any available stable position on the ring or as otherwise specified in the chemical structure presented. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen or sulfur atoms in the ring, such as heterocyclic aromatic ring systems, e.g., imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, among others, which may be optionally substituted as described above.Among the heteroaryl groups which may be mentioned are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine. , pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from among nitrogen, sulfur, and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, among others, all of which may be optionally substituted.

[0431] The term "substituted aryl" refers to a group consisting of at least one aromatic ring or Aryl groups refer to aromatic carbocycles composed of multiple fused rings, at least one of which is aromatic, in which the ring is substituted with one or more substituents. For example, an aryl group can include a substituent selected from the following: -(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, wherein the alkyl group on said amine is optionally one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C 1 -C 6 alkyl, preferably CH 3 , CF 3 , OMe, OCF 3 , NO 2 , or CN group (each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), optionally substituted phenyl group (the phenyl group itself is preferably substituted with a linker attached to a PTM group containing a ULM group) and / or F, Cl, OH, COOH, CH 3 , CF 3 , OMe, OCF 3 , NO 2or substituted with at least one of the following groups: CN group (ortho-, meta- and / or para-positions of the phenyl ring, preferably para-position), optionally substituted naphthyl group, 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 isothiazole including methyl substituted isothiazole, optionally substituted pyrrole including methyl substituted pyrrole, optionally substituted imidazole including methyl imidazole, optionally substituted benzimidazole or methoxybenzylimidazole. optionally substituted oximidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo- (preferably F) or methyl-substituted pyridine groups or oxapyridine groups, where the pyridine group is attached to the phenyl group by an oxygen, 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.

[0432] "Carboxyl" is - C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, while these generic substituents have the same meaning as in the corresponding group definitions defined herein.

[0433] The term "heteroaryl" or "hetaryl" includes, but is not limited to, optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted (CH 2 ) m -OC 1 -C 6 An alkyl group or an optionally substituted (CH 2 ) m -C(O)-OC 1 -C 6 It may refer to a 1,2,3-triazole substituted with an alkyl group, an optionally substituted pyridine (2, 3, or 4-pyridine), or a group according to the following chemical structure:

[0434] [ka]

[0435] During the ceremony, S c is CHR SS , N.R. URE , or O, R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6 alkyl), each group optionally containing one or two hydrogen atoms. substituted with xyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; and Y C is N or CRYC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 It is an acetylene group which is an alkyl group.

[0436] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing aryl or heteroaryl, respectively, as defined above, and alkyl, and / or heteroalkyl, and / or carbocyclic and / or heterocycloalkyl ring systems.

[0437] As used herein, the term "arylalkyl" refers to any of the aryl groups defined above. An arylalkyl group refers to an aryl group as defined above appended to an alkyl group. An arylalkyl group is attached to a parent moiety through an alkyl group, which alkyl group is from 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as described above.

[0438] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described herein above.

[0439] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxyl, isoxyl, isoquinolinyl, isothiazol ... Examples of such alkyl groups include sazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane.

[0440] Heterocyclic groups include 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, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO 2 -Alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, oxo (=O), and -SO 2-heteroaryl. Such heterocyclic groups may have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene or cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0441] The term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having from 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, but is not limited to any one of these. The term "substituted cycloalkyl" refers to, but is not limited in any manner to, monocyclic or polycyclic alkyl groups substituted with one or more substituents, such as, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, and these generic substituents have the same meaning as the definition of the corresponding group provided in this Description.

[0442] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its ring structure is replaced with 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 ring carbon atom of its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, which groups contain one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as the definition of the corresponding group provided in this Description.

[0443] The term "hydrocarbyl" is intended to mean a compound that contains carbon and hydrogen and may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0444] As used herein, the term "independently" is used to indicate that the variable that is independently applied varies independently from application to application.

[0445] The term "lower alkyl" refers to methyl, ethyl, or propyl. The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0446] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A and Rn can be independently covalently linked to a linker, and / or a linker attached to one or more PTM, ULM, ILM or ILM' groups. Exemplary MLM In certain additional embodiments, the MLM of the bifunctional compound comprises chemical moieties such as, for example, substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.

[0447] In additional embodiments, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as either cis or trans configurations.

[0448] In yet additional embodiments, the MLM comprises structural features as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

[0449] In certain preferred embodiments, the MLM is a substituted imidazoline derivative represented by formula (A-1), or a thiazoloimidazoline derivative represented by formula (A-2), or a spiroindolinone derivative represented by formula (A-3), or a pyrrolidine derivative represented by formula (A-4), or a piperidinone / morpholinone derivative represented by formula (A-5), or an isoquinolinone derivative represented by formula (A-6), or a pyrrolopyrimidine / imidazolopyridine derivative represented by formula (A-7), or a pyrrolopyrrolidinone / imidazolopyrrolidinone derivative represented by formula (A-8).

[0450] [ka]

[0451] [ka]

[0452] In the above formulas (A-1) to (A-8), X in the formulae (A-1) to (A-8) is carbon, oxygen, sulfur, sulfoxide, sulfone, or NR a is selected from the group consisting of R a are independently H or an alkyl group having 1 to 6 carbon atoms; In formulae (A-1) to (A-8), Y and Z are independently carbon or nitrogen; A, A' and A'' in formulae (A-1) to (A-8) are independently selected from C, N, O or S, or may be 1 or 2 atoms forming a fused bicyclic ring or forming a 6,5- and 5,5-fused aromatic bicyclic group; R in formula (A-1) to formula (A-8) 1 , R 2 is independently selected from the group consisting of an aryl group or a heteroaryl group having 1 or 2 heteroatoms independently selected from sulfur or nitrogen, and the aryl or heteroaryl group is It may be monocyclic or bicyclic, or may be unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: Halogen, -CN, C 1 ~C 6 Alkyl group, C 3 ~C 6 Cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons, and dialkylamine containing 2 to 6 carbons; R in formula (A-1) to formula (A-8) 3 , R 4 is H, methyl and C 1 ~C 6 independently selected from the group consisting of alkyl, R in formula (A-1) to formula (A-8) 5is selected from the group consisting of an aryl group or a heteroaryl group, the heteroaryl group having 1 or 2 heteroatoms independently selected from sulfur or nitrogen, the aryl group or heteroaryl group may be monocyclic or bicyclic or may be unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: Halogen, -CN, C 1 ~C 6 Alkyl group, C 3 ~C 6 Cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons, dialkylamine containing 2 to 6 carbons, alkyl ether (C 2 ~C 6 ), alkyl ketones (C 3 ~C 6 ), morpholinyl, alkyl ester (C 3 ~C 6 ), alkyl cyanide (C 3 ~C 6 ); R in formula (A-1) to formula (A-8) 6 is H or -C(=O)R b where: R in formula (A-1) to formula (A-8) b is alkyl, cycloalkyl, mono-, di- or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piperidinyl, 4-NR c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl, R in formula (A-1) to formula (A-8) cis an alkyl, fluorine-substituted alkyl, cyanoalkyl, hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidoalkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, mono-, di- and tri-substituted aryl or heteroaryl, CH 2 CH 2 R d , and C.H. 2 CH 2 CH 2 R d wherein: R in formula (A-1) to formula (A-8) d is an alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO 2 - selected from the group consisting of alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R in formula (A-1) to formula (A-8) 7 , H, C 1 ~C 6 selected from the group consisting of alkyl, cyclic alkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, 5- or 6-membered substituted heteroaryl or aryl; R in formula (A-1) to formula (A-8) 8 -R e -C(O)-R f , -R e -alkoxy, -R e -aryl, -R e -heteroaryl, and -R e -C(O)-R f -C(O)-R g wherein: R in formula (A-1) to formula (A-8) e is an alkylene containing 1 to 6 carbons or a bond; R in formula (A-1) to formula (A-8) f is a 4- to 7-membered substituted heterocycle; R in formula (A-1) to formula (A-8) gis selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocycle; R in formula (A-1) to formula (A-8) 9 is selected from the group consisting of mono-, di- or tri-substituents on the fused bicyclic aromatic ring in formula (A-3), the substituents being independently selected from the group consisting of halogen, alkene, alkyne, alkyl, substituted or unsubstituted with Cl or F; R in formula (A-1) to formula (A-8) 10 is a group consisting of aryl groups or heteroaryl groups wherein the heteroaryl group may contain one or two heteroatoms such as sulfur or nitrogen, the aryl or heteroaryl group may be monocyclic or bicyclic, and the aryl or heteroaryl group may be selected from halogen, F, Cl, -CN, an alkene, an alkyne, C 1 ~C 6 Alkyl group, C 1 ~C 6 may be unsubstituted or substituted with 1 to 3 substituents including cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons; R in formula (A-1) to formula (A-8) 11 is -C(O)-N(R h )(R i ) in which R h and R i is selected from the group consisting of: H, C 1 ~C 6 Alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heteroaryl, mono-, di- or tri-substituted aryl or heteroaryl, alkyl carboxylic acid, heteroaryl carboxylic acid, alkyl carboxylic acid, fluorine-substituted alkyl carboxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl, R in formula (A-1) to formula (A-8) h and Ri H, 4-hydroxycyclohexane, monohydroxy and dihydroxy substituted alkyl (C 3 ~C 6 ), 3-hydroxycyclobutane, phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acids; R in formula (A-1) to formula (A-8) 12 and R 13 is H, lower alkyl (C 1 ~C 6 ), lower alkenyl (C 2 ~C 6 ), lower alkynyl (C 2 ~C 6 ), cycloalkyl (4-, 5- and 6-membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl, and heteroaryl; R 12 and R 13 may be joined to form 5- and 6-membered rings with or without ring substitution; R in formula (A-1) to formula (A-8) 14 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 in formula (A-1) to formula (A-8) 15 is CN, R in formula (A-1) to formula (A-8) 16 is C 1 ~C 6 Alkyl, C 1 ~C 6 Cycloalkyl, C 2 ~C 6 Alkenyl, C in which one or more hydrogens are replaced by fluorine 1~6 Alkyl or C 3~6 Cycloalkyl, 1 CH 2 is S(=O), -S or -S(=O) 2 Alkyl or cycloalkyl substituted with, terminal CH 3is S(=O) 2 N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O) 2 (alkyl), -C(=O) 2 (alkyl), alkyl or cycloalkyl substituted with -O(alkyl), C with hydrogen replaced by hydroxyl group 1 ~C 6 and wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is selected from the group consisting of a halogen atom, a 3- to 7-membered cycloalkyl or heterocycloalkyl group, optionally containing a -(C=0)- group, or a 5- to 6-membered aryl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group may contain 1 to 3 heteroatoms independently selected from O, N or S, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is selected from the group consisting of a halogen atom, a C 1 ~C 6 Alkyl groups, hydroxylated C 1 ~C 6 Alkyl, thioether-containing C 1 ~C 6 may be unsubstituted or substituted with 1 to 3 substituents independently selected from alkyl, ether, sulfone, sulfoxide, fluorine-substituted ether, or cyano groups; R in formula (A-1) to formula (A-8) 17 is (CH 2 )nC(O)NR k R l wherein R k and R l , H, C 1 ~C 6 Alkyl, Hydroxylated C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyalkyl, C in which one or more hydrogens are replaced by fluorine 1 ~C 6 Alkyl, C with one carbon replaced by S(O) 1 ~C 6 Alkyl, S(O)(O), C with one or more hydrogens replaced by fluorine 1~C 6 alkoxyalkyl, C where hydrogen is substituted with a cyano group 1~6 alkyl, 5- and 6-membered aryl or hetero aryl, alkylaryl having an alkyl group containing 1 to 6 carbons, and alkylheteroaryl having an alkyl group containing 1 to 6 carbons, independently selected, and the aryl group or heteroaryl group may be further substituted, R of formula (A-1) to formula (A-8) 18 is selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, and the substitution is preferably -N(C 1-4 alkyl)(cycloalkyl), -N(C 1-4 alkyl)alkyl-cycloalkyl, and -N(C 1-4 alkyl)[(alkyl)-(heterocyclic substituted)-cycloalkyl], R of formula (A-1) to formula (A-8) 19 is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and these aryl groups and heteroaryl groups may be substituted with halogen, C 1 ~C 6 alkyl, C 1 ~C 6 cycloalkyl, CF 3 , F, CN, alkyne, alkylsulfone, and the halogen substitution may be mono-substituted, di-substituted or tri-substituted, R of formula (A-1) to formula (A-8) 20 and R 21 are C 1 ~C 6 alkyl, C 1 ~C 6 cycloalkyl, C 1 ~C 6 alkoxy, hydroxylated C 1 ~C 6 alkoxy, and fluorine-substituted C 1 ~C 6 alkoxy, independently selected, wherein R 20 and R 21may be further linked to form 5-, 6-, and 7-membered rings or heterocycles, which may be further substituted; R in formula (A-1) to formula (A-8) 22 , H, C 1 ~C 6 Alkyl, C 1 ~C 6 is selected from the group consisting of cycloalkyl, carboxylic acid, carboxylic ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea, and nitrogen-containing 5-membered heterocycle, wherein the 5-membered heterocycle is further selected from the group consisting of C 1 ~C 6 may be substituted with alkyl, alkoxy, fluorine-substituted alkyl, CN, and alkylsulfone; R in formula (A-1) to formula (A-8) 23 is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl)-heteroaryl, wherein the aryl or heteroaryl group is selected from halogen, C 1 ~C 6 Alkyl, Hydroxylated C 1 ~C 6 Alkyl, cycloalkyl, fluorine-substituted C 1 ~C 6 R in formula (A-1) to formula (A-8) may be substituted with alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide. 24 is -CH 2 -(C 1-6 alkyl), -CH 2 -Cycloalkyl, -CH 2 -aryl, CH 2 -heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl, and substituted cycloalkyl; R in formula (A-1) to formula (A-8) 25 is C 1-6 Alkyl, C 1-6 and selected from the group consisting of alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5, 6 and 7 membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocycles, and these saturated heterocycles are selected from the group consisting of C 1 ~C 6 Alkyl, fluorine-substituted C 1 ~C 6 may be substituted with alkyl, alkoxy, aryl and heteroaryl groups; R in formula (A-1) to formula (A-8) 26 is C 1-6 Alkyl, C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is selected from the group consisting of -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH 2 , -NH-alkyl, NH-C(O)alkyl, -NH-S(O) 2 -Alkyl, and -S(O) 2 - optionally substituted with alkyl; R in formula (A-1) to formula (A-8) 27 is selected from the group consisting of aryl, heteroaryl, and bicyclic heteroaryl, and the aryl or heteroaryl group is 1 ~C 6 Alkyl, alkoxy, NH 2 , NH-alkyl, halogen, or -CN, which may be independently mono-, di-, or tri-substituted; R in formula (A-1) to formula (A-8) 28is selected from the group consisting of aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine, where the cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further substituted with -OH, alkoxy, mono-, di- or tri-substituted, including halogen, -CN, alkylsulfone, and fluorine-substituted alkyl groups; and R in formula (A-1) to formula (A-8) 1” is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0453] In certain embodiments, R f and R g The heterocycle in the formula (I) is a substituted pyrrolidine, substituted piperidine, or substituted piperizine.

[0454] More specifically, non-limiting examples of MLMs include those shown below, as well as "hybrid" molecules that result from combining one or more of the different properties shown in the molecules below.

[0455] Using the MLMs of Formulas A-1 through A-8, the following PROTACs can be prepared to target specific proteins for degradation, where "L" is a connector (i.e., linker group) and "PTM" is a ligand that binds to the target protein.

[0456] In certain embodiments, the present disclosure provides a bifunctional molecule comprising a structure selected from the group consisting of:

[0457] [ka]

[0458] [ka]

[0459] In the formula, X, R a , Y, Z, A, A', A'', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R b , R c , R d , R 7 , R e , R f , R g , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , 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’’ is as defined for formulas (A-1) to (A-8) in this specification.

[0460] In certain embodiments, the present disclosure provides bifunctional or chimeric molecules having the following structure: PTM-L-MLM, where the PTM is a protein target binding moiety linked to the MLM by L, where L is a bond (i.e., absent) or a chemical linker. In certain embodiments, the MLM has a structure selected from the group consisting of A-1-1, A-1-2, A-1-3, and A-1-4,

[0461] [ka]

[0462] During the ceremony, Formulae A-1-1 to A-1-4 (i.e., A-1-1, A-1-2, A-1-3, and A-1-4) R1' and R2' are F, Cl, Br, I, acetylene, CN, CF 3 , and NO 2 are independently selected from the group consisting of R3' is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CH 2 OCH 3 , and -OCH(CH 3 ) 2 is selected from the group consisting of R4' in A-1-1 to A-1-4 is H, halogen, -CH 3 , -CF 3 , -OCH 3 , -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -cyclopropyl, -CN, -C(CH 3 ) 2 OH, -C(CH 3 ) 2 OCH 2 CH 3 , -C(CH 3 ) 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 2 CH 3 , -C(CH 3 ) 2 CH 2 OCH 2 CH 2 OH, -C(CH 3 ) 2 CH 2 OCH 2 CH 3 , -C(CH 3 ) 2 CN, -C(CH3 ) 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 formulae A-1-1 to A-1-4 is halogen, -cyclopropyl, -S(O) 2 CH 3 , -S(O) 2 CH 2 CH 3 , 1-pyrrolidinyl, -NH 2 , -N(CH 3 ) 2 , and -NHC(CH 3 ) 3 and R6' of formulas A-1-1 to A-1-4 is selected from the structures depicted below, where the linker attachment point is indicated as "*".

[0463] Apart from R6' as a point for linker attachment, R4' can also serve as a linker attachment site. When R4' is the linker attachment site, the linker will be attached to the terminal atom of the R4' group shown above.

[0464] In certain embodiments, the linker bond of formula A-1-1 to formula A-1-4 is at least one of R4' or R6', or both.

[0465] In a specific embodiment, R6' of formulae A-1-1 to A-1-4 is H,

[0466] [ka]

[0467] [ka]

[0468] where "*" indicates the point of attachment of the linker. In certain embodiments, the linker of formula A-4-1 through formula A-4-6 is attached to at least one of R1', R2', R3', R4', R5', R6', or a combination thereof.

[0469] In certain embodiments, the present disclosure provides bifunctional or chimeric molecules having the structure PTM-L-MLM, where PTM is a protein target binding moiety linked to MLM by L, where L is a bond (i.e., absent) or a chemical linker. In certain embodiments, MLM has 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:

[0470] [ka]

[0471] During the ceremony, R7' in A-4-1 to A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6) is a constituent element selected from the group consisting of halogen, mono-substituted, and di- or tri-substituted halogen. R8' in formulae A-4-1 to A-4-6 is H, -F, -Cl, -Br, -I, -CN, -NO 2, ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C 1-6 Alkyl, other C 1-6 Alkenyl and C 1-6 alkynyl, mono-substituted, di-substituted or tri-substituted; R9' in formulae 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 H, -OCH 3 , -OCH 2 CH 3 and halogen; R10' and R11' in formulae A-4-1 to A-4-6 are each 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 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 2CH 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 NRR'', 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, wherein the heterocycle may be optionally substituted with alkyl, hydroxyl, COOR' and COR', wherein R' and R'' are independently selected from the group consisting of H, alkyl, alkyl substituted with halogen, hydroxyl, NH 2 , NH(alkyl), N(alkyl) 2, oxo, carboxy, cycloalkyl, and heteroaryl; m, n, and p are independently 0 to 6; R12' in formulae A-4-1 to A-4-6 is -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl), -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl). 2 , -S(O)-(alkyl), S(O) 2 -(alkyl), -C(O)-(cyclic amine), and -O-aryl-(alkyl), -O-aryl-(alkoxy); R1″ in formulae A-4-1 to A-4-6 is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0472] In any of the aspects or embodiments described herein, it may be alkyl, alkoxy, etc., lower alkyl or lower alkoxy.

[0473] In certain embodiments, the linker attachment position of formulas A-4-1 to A-4-6 is at least one of Z, R8', R9', R10', R11'', R12'', or R1''.

[0474] The methods used to design the chimeric molecules presented in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLMs using Formula A-2, Formula A-3, Formula A-5, Formula A-6, Formula A-7 and Formula A-8, where the solvent exposed areas within the MLMs may be coupled to a linker "L", which is attached to a target protein ligand "PTM" to construct a PROTAC.

[0475] Examples of MDM2 binding moieties include, but are not limited to, the following: HDM2 / MDM2 inhibitors have been shown 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 ro. The compound described below in "Ute to chemical proteomics," Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908 The compounds identified include (or may additionally include) nutrin-3, nutrin-2, and nutrin-1 (derivatized), and all derivatives and analogs thereof.

[0476] [ka]

[0477] (derivatized, where a linker group L or -(L-MLM) group is attached, for example, at a methoxy group or as a hydroxyl group),

[0478] [ka]

[0479] (derivatized, with a linker group L or -(L-MLM) group attached, for example, at a methoxy or hydroxyl group), and

[0480] [ka]

[0481] (derivatized, the linker group L or the -(L-MLM) group is, for example, or as hydroxyl groups). Exemplary CLM Neo-imide compounds In one aspect, the present disclosure provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures:

[0482] [ka]

[0483] [ka]

[0484] During the ceremony, W in formula (a) to formula (e) is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; X in formula (a) to formula (e) is O, S, or H. 2 are independently selected from the group Y in the formulas (a) to (e) is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (e) is O, S or H. 2 where X and Z are independently selected from the group 2 It should not be, G and G' in formula (a) to formula (e) are H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH optionally substituted with R'. 2 -heterocyclyl, and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a) to (e) each represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A in formula (a) to formula (e) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) to (e) includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n R", -aryl, -hetaryl, -alkyl (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" of formulas (a) through (e) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl, each of which is optionally substituted; In formulas (a) to (e), n is an integer of 1 to 10 (e.g., 1 to 4), Formula (a) to Formula (e)

[0485] [ka]

[0486] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and R in formulas (a) to (e) n is a substituted or unsubstituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, propoxy, pentoxy, or hexoxy) containing 1 to 4 independent functional groups, optionally substituted alkoxy groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, propoxy, pentoxy, or hexoxy), where the alkoxy groups are halogen, cycloalkyl (e.g., C 3 -C 6 cycloalkyl), or aryl (e.g., C 5 -C 7 aryl)) or containing an atom. Exemplary CLM In any of the compounds described herein, the CLM comprises a chemical structure selected from the following group:

[0487] [ka]

[0488] [ka]

[0489] During the ceremony, W in formula (a) to formula (e) is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; X in formula (a) to formula (e) is O, S, or H. 2 are independently selected from the group Y in formula (a) to formula (e) is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (e) is O, S or H. 2 where X and Z are independently selected from the group 2 It should not be, G and G' in formula (a) to formula (e) are H, alkyl (linear, branched), OH, R'OCOOR, R'OCONRR", CH optionally substituted with R'. 2-heterocyclyl, and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a) to (e) each represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A in formula (a) to formula (e) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, H and F; R in formulas (a) to (e) includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -hetaryl, -alkyl (straight chain, branched chain, any substituted with), -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" of formulas (a) through (e) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, and heterocyclyl, each of which is optionally substituted; In formulas (a) to (e), n is an integer of 1 to 10 (e.g., 1 to 4), Formula (a) to Formula (e)

[0490] [ka]

[0491] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and Rn in formulas (a) to (e) is one to four independent functional groups, an optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy), where the alkoxyl is a halogen, a cycloalkyl (e.g., C 3 -C 6 cycloalkyl), or aryl (e.g., C 5 -C 7 aryl), or atoms, and optionally, one of which is modified to covalently bond to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0492] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the following group:

[0493] [ka]

[0494] During the ceremony, W in formula (g) is CH 2 , C═O, NH and N-alkyl, and R in formula (g) is selected from the group consisting of H, methyl, alkyl (e.g., C 1 ~C 6 alkyl (straight chain, branched chain, optionally substituted); In formula (g),

[0495] [ka]

[0496] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and Rn in formula (g) is one to four independently selected functional groups, an optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy), where the alkoxyl is a halogen, a cycloalkyl (e.g., C 3 -C 6 cycloalkyl), or aryl (e.g., C 5 -C 7 aryl), or atoms, and optionally, one of which is modified to covalently bond to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0497] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A and Rn of Formula (a)-Formula (g) can be independently covalently linked to a linker, and / or a linker attached to one or more PTM, ULM, CLM or CLM' groups.

[0498] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules that result from combining one or more of the different properties shown in the molecules below.

[0499] [ka]

[0500] [ka]

[0501] [ka]

[0502] [ka]

[0503] [ka]

[0504] [ka]

[0505] [ka]

[0506] [ka]

[0507] [ka]

[0508] [ka]

[0509] In any of the compounds described herein, the CLM comprises a chemical structure selected from the following group:

[0510] [ka]

[0511] [ka]

[0512] During the ceremony, W in formula (h) to formula (ab) is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; Q of formula (h) to formula (ab) 1 , Q 2 , Q 3 , Q4 , Q 5 are independently R', N or N- represents a carbon C substituted with a group independently selected from oxide, R in formula (h) to formula (ab) 1 H, CN, C 1 ~C 3 alkyl, R in formula (h) to formula (ab) 2 H, CN, C 1 ~C 3 Alkyl, CHF 2 , C.F. 3 , CHO, R in formula (h) to formula (ab) 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R in formula (h) to formula (ab) 4 is selected from H, alkyl, and substituted alkyl; R in formula (h) to formula (ab) 5 is H or lower alkyl, X in formulae (h) to (ab) is C, CH or N; R' in formulas (h) to (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R in formulae (h) to (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy, or halogenated lower alkyl; Formulas (h) to (ab)

[0513] [ka]

[0514] is a single bond or a double bond, and The CLM is covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0515] In any aspect or embodiment described herein, the CLM or CLM′ may be an R group (e.g., R, R 1 , R 2 , R 3 , R 4 or R'), W, X, or Q groups (e.g., Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 ) to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof.

[0516] In any of the embodiments described herein, CLM or CLM′ is selected from the group consisting of W, X, R, R of formula (h) to formula (ab). 1 , R 2 , R 3 , R 4 , R 5 , R', Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof via

[0517] In any of the embodiments described herein, W, X, R of formula (h) to formula (ab) 1 , R 2 , R 3 , R 4 , R', Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 may be independently covalently attached to a linker and / or to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0518] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds resulting from a combination of properties of one or more of the following compounds: [ka]

[0519] [ka]

[0520] During the ceremony, W in formula (ac) to formula (an) is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; R in formula (ac) to formula (an) 1 H, CN, C 1 ~C 3 is selected from the group of alkyl, R in formula (ac) to formula (an) 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R in formulas (ac) to (an) is H;

[0521] [ka]

[0522] is a single bond or a double bond, and R in formula (ac) to formula (an) n contains a functional group or atom.

[0523] In any of the embodiments described herein, W, R of formula (ac) to formula (an) 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently bonded to a linker and / or to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0524] In any of the embodiments described herein, R of formula (ac) to formula (an) 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently bonded to a linker and / or to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0525] In any of the embodiments described herein, Q of formula (ac) to formula (an) 1 , Q 2 , Q 3 , Q 4 and Rn may independently be covalently bonded to a linker and / or to a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0526] In any aspect or embodiment described herein, R of formula (ac) to formula (an) n is modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0527] In any aspect or embodiment described herein, the CLM is selected from:

[0528] [ka]

[0529] In the formula, R' is a halogen and R 1 is as described above for formulae (h) to (ab) or (ac) to (an).

[0530] In certain instances, the CLM may be an imide that binds to cereblon E3 ligase. These imides and linker attachment points may be, but are not limited to, the following structures:

[0531] [ka]

[0532] In the formula, R' is a halogen. Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM and comprises the chemical structure of ULM-a:

[0533] [ka]

[0534] During the ceremony, the dashed line indicates attachment of at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., a ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical linker moiety, linking at least one PTM, a ULM' or VLM' or CLM' or ILM' or MLM' to the other end of the linker; X in the formula ULM-a 1 , X 2 are bond, O, and NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO 2 are independently selected from the group R in the formula ULM-a Y3 , R Y4 are H, straight or branched chain C 1-6 alkyl, optionally with one or more halo, optionally substituted C 1~6 Alkoxyl (e.g., optionally 0 to 3 R P substituted by a group, R in the formula ULM-a Pare 1, 2 or 3 groups, each of which is H, halo, -OH, C 1-3 independently selected from the group consisting of alkyl, W of formula ULM-a 3 is optionally substituted -TN(R 1a R 1b )X 3 , optionally replaced -TN(R 1a R 1b ), 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, X in the formula ULM-a 3 is C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b each represents a straight or branched chain C optionally substituted with H, one or more halo or -OH groups; 1 -C 6 Alkyl group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 )C=O, N(R Y3 R Y4 )C=S,N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO 2 T of formula ULM-a is independently selected from the group consisting of X 1 is covalently bound to W of formula ULM-a 4 is optionally substituted -N R 1 -T-aryl, optionally substituted -N R 1-T-heteroaryl group or an optionally substituted -N R 1 -T-heterocycle, wherein -N R 1 X 2 is covalently bonded to R 1 is H or CH 3 , preferably H.

[0535] In any of the embodiments described herein, T is optionally substituted alkyl, -(CH 2 ) n - groups, wherein each one of the methylene groups is selected from the group of linear or branched C -C groups optionally substituted with halogen, methyl, one or more halogens or -OH groups. 1 -C 6 Optionally substituted with one or two substituents selected from the group of alkyl groups, or optionally substituted amino acid side chains, and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.

[0536] In certain embodiments, W of formula ULM-a 4 teeth,

[0537] [ka]

[0538] where R 14a , R 14b are each independently selected from the group: H, haloalkyl, or optionally substituted alkyl.

[0539] In any of the embodiments, W of formula ULM-a 5 is selected from the group consisting of phenyl and 5-10 membered heteroaryl; R in the formula ULM-a 15 H, halogen, CN, OH, NO 2 , N, R 14a R 14b , OR 14a ,CONR 14aR 14b , N.R. 14a COR 14b , S.O. 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; and in additional embodiments, W for use in the present disclosure is selected from the group of: 4 Substituents may also be any W group present in the specified compounds disclosed herein. 4 The substituents are also specifically included (without being limited to the particular compounds disclosed). 4 Each of the substituents may be any number of W 3 They may be used in conjunction with substituents, which are also disclosed herein.

[0540] In certain additional embodiments, ULM-a has 0-3 R in the pyrrolidine moiety. P Each R P are independently H, halo, -OH, C 1-3 Alkyl, C=O.

[0541] In any of the embodiments described herein, W of formula ULM-a 3 , W 4 may be independently covalently linked to a linker that is attached to one or more PTM groups, and where the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that links at least one PTM or ULM', or both, to a ULM.

[0542] In certain embodiments, the ULM is VHL and is represented by the structure:

[0543] [ka]

[0544] During the ceremony, W in formula ULM-b 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0545] [ka]

[0546] is selected from the group R in the formula ULM-b 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R in the formula ULM-b 11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0547] [ka]

[0548] is selected from the group R in the formula ULM-b 12 is selected from the group of H or optionally substituted alkyl; R in the formula ULM-b 13 is selected from the group: 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 in the formula ULM-b 14a、 R 14bare each independently selected from the group: H, haloalkyl, or optionally substituted alkyl; W in formula ULM-b 5 is selected from the group of phenyl or 5-10 membered heteroaryl, R of formula ULM-b 15 H, halogen, CN, OH, NO 2 , N, R 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , S.O. 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; each of which is optionally substituted; R in the formula ULM-b 16 is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; and o of formula ULM-b is 0, 1, 2, 3, or 4; R in the formula ULM-b 18 is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and In formula ULM-b, p is 0, 1, 2, 3, or 4, and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that links at least one PTM or ULM', or both, to ULM.

[0549] In certain embodiments, R of formula ULM-b 15 teeth,

[0550] [ka]

[0551] where R 17 is H, halo, optionally substituted C 3~6 Cycloalkyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkenyl, and C 1~6 haloalkyl and Xa is S or O.

[0552] In certain embodiments, R of formula ULM-b 17 is selected from the group of methyl, ethyl, isopropyl and cyclopropyl.

[0553] In certain additional embodiments, R of formula ULM-b 15 is selected from the group consisting of:

[0554] [ka]

[0555] In certain embodiments, R of formula ULM-b 11 is selected from the group consisting of:

[0556] [ka]

[0557] In certain embodiments, ULM has a chemical structure selected from the group consisting of:

[0558] [ka]

[0559] During the ceremony, R in formula ULM-c, formula ULM-d, and formula ULM-e 1is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R in formula ULM-c, formula ULM-d, and formula ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R in formula ULM-c, formula ULM-d, and formula ULM-e 15 H, halogen, CN, O H, NO 2、 optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl; X in formula ULM-c, formula ULM-d, and formula ULM-e is C, CH 2 or C=O, R in formula ULM-c, formula ULM-d, and formula ULM-e 3 is absent, a bond, or an optionally substituted 5- or 6-membered heteroaryl; and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that links at least one PTM or ULM', or both, to ULM.

[0560] In certain embodiments, ULM comprises a group according to the following chemical structure:

[0561] [ka]

[0562] During the ceremony, R in the formula ULM-f 14ais H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R in the formula ULM-f 9 is H, R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 teeth,

[0563] [ka]

[0564] or optionally substituted heteroaryl; In the formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R in the formula ULM-f 12 is H, C=O, R in the formula ULM-f 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in the formula ULM-f 15 H, halogen, Cl, CN, OH, NO 2、 optionally substituted heteroaryl, optionally substituted aryl,

[0565] [ka]

[0566] and wherein the dashed line in formula ULM-f indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that links at least one PTM or ULM', or both, to ULM.

[0567] In certain embodiments, ULM is selected from the following structures:

[0568] [ka]

[0569] [ka]

[0570] In the formula, n is 0 or 1. In certain embodiments, ULM is selected from the following structures:

[0571] [ka]

[0572] [ka]

[0573] [ka]

[0574] [ka]

[0575] wherein the phenyl rings of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, and where the dashed lines indicate the sites of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that links at least one PTM or ULM', or both, to ULM-a.

[0576] In one embodiment, the phenyl ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 is functionalized as an ester, which can be made part of a prodrug.

[0577] In certain embodiments, the hydroxyl group on the pyrrolidine ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 each include an ester-linked prodrug moiety.

[0578] In any of the aspects or embodiments described herein, ULM, and, if present, ULM', or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof, is each independently a group according to the chemical structure:

[0579] [ka]

[0580] During the ceremony, ULM-g R 1’ is an optionally substituted C 1 -C 6 Alkyl groups, optionally substituted -(CH 2 ) n OH, optionally substituted -(CH 2 ) n SH, optionally substituted (CH 2 ) n -O-(C1 -C 6 ) alkyl group, optionally substituted (CH 2 ) n -WCOCW-(C 0 -C 6 ) alkyl groups containing an epoxide moiety, W C O C W , where each W is independently H or C 1 -C 3 Alkyl groups, 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 O.C.(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 -(OCH 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)-R1 , optionally substituted -(CH 2 O) n C(O)-NR 1 R 2 , -(CH 2 CH 2 O) n H, optionally substituted -(CH 2 CH 2 O) n COOH, optionally substituted -(OCH 2 CH 2 ) n O-(C 1 -C 6アルキル ), 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 S(O)R S , NO 2 , CN or halogen (F, Cl, Br, I, preferably F or Cl), ULM-g R 1 and R 2 are each independently H, or C, which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). 1 -C 6 is an alkyl group, ULM-g R S is C 1 -C 6 an alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or -(CH 2 ) m NR 1 R 2 It is based on X and X' in ULM-g are each independently CO, CS, -S(O), or S(O). 2 (preferably X and X' are both C=O); ULM-g R 2’ is an optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v ( SO 2 ) w Alkyl groups, optionally substituted -(CH 2 ) n -(C=O) u (NR 1 ) v ( SO 2 ) w NR 1N R 2 N group, 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 N R 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 optionally substituted -NR 1 -(CH 2 ) n -(C=O) v NR 1 (SO 2 ) w -heterocycle, optionally substituted -X R2’ -Alkyl group; optionally substituted -X R2’ -aryl group; optionally substituted -X R2’ -heteroaryl group; optionally substituted -X R2’ -heterocyclic group; optionally substituted; ULM-g R 3’ is an optionally substituted alkyl, an optionally substituted -(CH 2 ) n - (O) u (NR 1 ) v (SO 2 )w -alkyl, optionally substituted -(CH 2 ) n -C( O) u (NR 1 ) v (SO 2 ) w -NR 1N R 2N , optionally substituted -(CH 2 ) n - C(O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , optionally substituted -(C H 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 (SO2 ) 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, any Substituted with -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -aryl group, any -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -Heteroary an optionally substituted -(CH 2 ) n -(V) n’ -(CH 2 )n -(V) n’ -Complex ring ’ 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’ -Alkyl group; optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -heteroaryl group; optionally substituted -X R3’ -heterocyclic group; optionally substituted; ULM-g R 1N and R 2N each independently represents H, C optionally substituted with one or two hydroxyl groups, or up to three halogen groups; 1 -C 6 Alkyl, 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 and ULM-g R 1 is the same as above, ULM-g R 1 and R 1’are each independently H or C 1 -C 3 is an alkyl group, and X of ULM-g is R2’ and X R3’ are each 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 is a cycloalkyl group, v is H, halo, or optionally substituted C 1 -C 3 is an alkyl group, Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' of ULM-g is independently 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w of ULM-g is independently 0 or 1; and ULM-g R 1’ , R 2’ , R 3’ any one or more of X and X' are optionally modified to be covalently attached to the PTM group through a linker group if the PTM is not a ULM', and R 1’ , R 2’ , R 3’ Any one or more of X, X′ are optionally modified to be covalently linked to each other directly or through a linker group.

[0581] In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, is each independently a group according to the following chemical structure, or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof:

[0582] [ka]

[0583] During the ceremony, ULM-h R 1’ , R 2’ and R 3’ are the same as above, and X is a C=O, C=S, -S(O) group, or S(O) 2 is preferably a C=O group, and ULM-h R 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or to each of R 1’ , R 2’ , R 3’ Any one or more of are optionally modified and are covalently attached to each other directly or through a linker group.

[0584] In any of the aspects or embodiments described herein, ULM, and, if present, ULM', or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof, each independently corresponds to the following chemical structure:

[0585] [ka]

[0586] During the ceremony, ULM-I R 1’ , R2’ , and R 3’ any one or more of which are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or to each of R 1’ , R 2’ , R 3’ Any one or more of are optionally modified and are covalently attached to each other directly or through a linker group.

[0587] In a further aspect of the disclosure, R of ULM-g to ULM-i 1’ The hydroxyl group, Preferably, R is a group that can be metabolized to a hydroxyl group or a carboxylic acid group, thereby providing a prodrug form of the active compound. 1’ Examples of groups include, for example, -(CH 2 ) n OH, (CH 2 ) n -O-(C 1 -C 6 ) alkyl group, -(CH 2 ) n COOH, -(CH 2 O) n H, optionally substituted -(CH 2 ) n O.C.(O)-(C 1 -C 6 alkyl), or optionally substituted -(CH 2 ) n C(O)-O-(C 1 -C 6 alkyl), where n is 0 or 1. 1’ is or contains a carboxylic acid group, a hydroxyl group or an amine group, each of which may be optionally substituted, which may be further chemically modified to provide a covalent bond to a linker group that is attached to a PTM group (including a ULM' group); X and X' of ULM-g and ULM-h, when present, are preferably C=O, C=S, -S(O) groups or S(O)2 is a group, more preferably a C=O group, ULM-g~ULM-i R 2’ is preferably an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or an optionally substituted -NR 1 -T-heterocycle, wherein R 1 is H or CH 3 is preferably H, and T is optionally substituted -(CH 2 ) n - group, wherein each one of the methylene groups is preferably a halogen, an amino acid side chain as otherwise described herein, or a C 1 -C 3 T may be optionally substituted with one or two substituents selected from alkyl groups, preferably one or two methyl groups which may be optionally substituted, and n is 0 to 6, such as 0, 1, 2 or 3, such as 0 or 1. Alternatively, T may also be -(CH 2 O) n - group, -(OCH 2 ) n - group, -(CH 2 CH 2 O) n - group, -(OCH 2 CH 2 ) n - groups, all of which are optionally substituted.

[0588] ULM-g~ULM-i R 2’ Preferred aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, which can be optionally substituted with a linker group to which a PTM group (including a ULM′ group) is attached, a halogen (preferably F or Cl), an amine, a mono- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO2 or CN groups (each of which may be substituted at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position), an optionally substituted phenyl group (which itself is optionally attached to a PTM via a linker group (including a ULM' group)), and / or F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 or at least one of a CN group (at the ortho-, meta- and / or para-position of the phenyl ring, preferably at the para-position), 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, an optionally substituted isothiazole, including a methyl substituted isothiazole, an optionally substituted pyrrole, including a methyl substituted pyrrole, an optionally substituted imidazole, including a methyl imidazole, an optionally substituted benzimidazole or a methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl substituted triazole groups, optionally substituted pyridine groups including halo- (preferably F) or methyl substituted pyridine groups or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, optionally linked to a PTM group via an optionally substituted group according to the chemical structure;

[0589] [ka]

[0590] During the ceremony, ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 a heterocyclic group selected from the group consisting of an alkyl group, preferably methyl, or a halo group, preferably F or Cl, benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably is 0 or 1), or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (each of which groups, when substituted, is preferably substituted with methyl or halo (F, Br, Cl), and each of which groups may be optionally attached to a PTM group (including a ULM' group) via a linker group).

[0591] In certain preferred embodiments, ULM-g to ULM-i

[0592] [ka]

[0593] teeth,

[0594] [ka]

[0595] It is based on In the formula, R of ULM-g to ULM-i PRO is the same as above.

[0596] ULM-g~ULM-i R 2’ Preferred heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3- or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or a group according to the chemical structure:

[0597] [ka]

[0598] During the ceremony, ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a And wherein R of ULM-g to ULM-i a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), each of which can be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0599] ULM-g~ULM-i R 2’ Preferred heterocyclic groups for include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which is optionally substituted. or may be a group according to the following chemical structure:

[0600] [ka]

[0601] Preferably

[0602] [ka]

[0603] basis, During the ceremony, ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 alkyl, or an optionally substituted aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, and Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of these groups can optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0604] Preferred R of ULM-g to ULM-i 2’ Substituents include those R found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and in the drawings accompanying this specification. 2’ The substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). 2’ Each of the substituents may be any number of R 3’ They may be used in conjunction with substituents, which are also disclosed herein.

[0605] ULM-g~ULM-i R 3’ is preferably an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted -T-heterocycle, Ru-NR 1 -T-aryl, optionally substituted -NR 1-T-heteroaryl, or optionally substituted -NR 1 In a preferred embodiment, R 1 is H or C 1 -C 3 Alkyl group, preferably H or CH 3 , T is optionally substituted -(CH 2 ) n - group, wherein each one of the methylene groups is preferably a halogen, C 1 -C 6 T may be optionally substituted with one or two substituents selected from an alkyl group (straight chain, branched chain, optionally substituted) or the side chain of an amino acid as otherwise described herein, preferably methyl, optionally substituted, and n is 0-6, e.g., 0, 1, 2, or 3, such as 0 or 1. Alternatively, T may also be -(CH 2 O) n - group, -(OCH 2 ) n - group, -(CH 2 CH 2 O) n - group, -(OCH 2 CH 2 ) n - groups, each of which is optionally substituted.

[0606] ULM-g~ULM-i R 3’ Preferred aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, or naphthyl groups may be optionally substituted with linker groups and / or halogens (preferably F or Cl), amines, mono- or dialkylamines (preferably dimethylamine), amide groups (preferably -(CH 2 ) m -NR 1 C(O)R 2 group, wherein m, R 1 oh YobiR 2 is the same as above), halo (often F or Cl), OH, CH 3 , C.F.3 , OMe, OCF 3 , NO 2 , CN or S(O) 2 R S Group(R S is C 1 -C 6 an alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or (CH 2 ) m NR 1 R 2 groups), each of which may be substituted at the ortho-, meta-, and / or para-positions (preferably the para-position) of the phenyl ring, or is optionally bonded to a PTM group (including a ULM' group) via an aryl (preferably phenyl), heteroaryl, or heterocycle. Preferably, the substituent phenyl group is an optionally substituted phenyl group (i.e., the substituent phenyl group itself is preferably free of F, Cl, OH, SH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2, CN, or a linker group attached to a PTM group (including a ULM' group), where the substitution occurs at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), a naphthyl group which may be optionally substituted including as described above, 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, an optionally substituted pyrrole including a methyl substituted pyrrole, an optionally substituted imidazole including a methyl substituted imidazole, a benzylic imidazole or a methoxybenzylic imidazole). The PTM group is optionally substituted with a ULM' group, such as aryl, oximidazole or methyloximidazole, an optionally substituted diazole group including a methyldiazole group, an optionally substituted triazole group including a methyl-substituted triazole group, a pyridine group including a halo (preferably F) or methyl-substituted pyridine group or an oxapyridine group (wherein the pyridine group is bonded to the phenyl group by an oxygen), or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane). Each aryl, heteroaryl, or heterocycle group may be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0607] ULM-g~ULM-i R 3’Preferred heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted (CH 2 ) m -OC 1 -C 6 An alkyl group or an optionally substituted (CH 2 ) m -C(O)-OC 1 -C 6 alkyl substituted 1,2,3-triazoles), optionally substituted pyridines (2, 3, or 4-pyridine), or a group according to the following chemical structure:

[0608] [ka]

[0609] During the ceremony, ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 R in ULM-g to ULM-i is an acetylene group. SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R of ULM-g through ULM-i is URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and Y of ULM-g through ULM-i is C is N or CR YC where R YCH, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 Each of said heteroaryl groups can be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0610] ULM-g~ULM-i R 3’ Preferred heterocyclic groups for include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, or thiane, each of which may be optionally substituted or may be a group according to the chemical structure:

[0611] [ka]

[0612] Preferably

[0613] [ka]

[0614] base, During the ceremony, ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6Alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 a heterocyclic group selected from the group consisting of an alkyl group, preferably methyl, or a halo group, preferably F or Cl, benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, and Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of said heterocyclic groups may be optionally attached to a PTM group (including a ULM' group) via a linker group.

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

[0616] In certain alternative preferred embodiments, R of ULM-g to ULM-i 2’ is an optionally substituted -NR 1 -X R2’ -Alkyl group, -NR 1 -X R2’ -aryl group; optionally substituted -NR1 -X R2’ -HET, optionally substituted -NR 1 -X R2’ -aryl-HET or optionally substituted -NR 1 -X R2’ -HET-aryl, ULM-g~ULM-i R 1 is H or C 1 -C 3 is an alkyl group (preferably H), ULM-g~ULM-i X R2’ is optionally replaced by - ( CH 2 ) n -,- ( CH 2 ) n -CH(X v )=CH(X v )-(cis or trans), -(CH 2 ) n -CH≡CH-, -(CH 2 CH 2 O) n - or C 3 -C 6 is a cycloalkyl group, and X in ULM-g to ULM-i is v is H, halo, or optionally one or two hydroxyl groups. C substituted with silyl or up to three halogen groups 1 -C 3 is an alkyl group, Alkyl of ULM-g to ULM-i is optionally substituted C 1 -C 10 Alkyl (preferably C 1 -C 6 alkyl) groups (in certain preferred embodiments, the alkyl groups are terminally terminated with a halo group, often Cl or Br); Aryl of ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and HET of ULM-g to ULM-i is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each of which, when substituted, is preferably C 1 -C 3 substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according to the following chemical structure:

[0617] [ka]

[0618] ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 R in ULM-g to ULM-i is an acetylene group. SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6 alkyl), each group being optionally Heterocycles which are optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, such as piperazine, each of which is optionally substituted. lysine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc. ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alki A cyclic group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 a heterocyclic group selected from the group consisting of an alkyl group, preferably methyl, or a halo group, preferably F or Cl, benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0619] Each of the above groups may be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0620] In certain alternative embodiments of the present disclosure, R of ULM-g to ULM-i 3’ is an optionally substituted -(CH 2 ) n -(V) n’ -(CH 2 ) n -(V) n’ -R S3’ Ki, Ren -(CH 2 ) n -N(R 1’)(C=O) m’ -(V) n’ -R S3’ Group, optionally substituted -X R3’ -alkyl group, optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or an optionally substituted -X R3’ -HET-aryl group, During the ceremony, R S3’ is an optionally substituted alkyl group (C 1 -C 10 , preferably C 1 -C 6 alkyl), an optionally substituted aryl group or a HET group; R 1’ is H or C 1 -C 3 is an alkyl group (preferably H), V is O, S or NR 1’ and X R3’ is -(CH 2 ) n -, -(CH 2 CH 2 O) n -,- ( CH 2 ) n -CH(X v )=CH(X v )-(cis or trans), - ( CH 2 ) n -CH≡CH-, or C 3 -C 6 cycloalkyl groups, all of which are optionally substituted; X v is H, halo, or C optionally substituted with one or two hydroxyl groups or up to three halogen groups; 1 -C 3 is an alkyl group, Alkyl is an optionally substituted C 1 -C 10 Alkyl (preferably C 1 -C6 alkyl) groups (in certain preferred embodiments, the alkyl groups are terminally terminated with a halo group, often Cl or Br); Aryl is an optionally substituted phenyl or naphthyl group, preferably a phenyl group, and HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolyl, azine, azaindolizine, quinoline (when substituted, each preferably C 1 -C 3 substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according to the structure:

[0621] [ka]

[0622] ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a And , where R a is H or C 1 -C 6Alkyl group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 0 -C 6 alkyl), each group being optionally or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alki A cyclic group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, also is optionally substituted aryl (phenyl or naphthyl), heteroaryl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 a heterocyclic group selected from the group consisting of an alkyl group, preferably a methyl group, or a halo group, preferably substituted with F or Cl), benzofuran, indole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' of ULM-g to ULM-i is 0 or 1, and Each n' of ULM-g to ULM-i is 0 or 1, wherein each of said compounds, preferably on an alkyl, aryl or Het group, is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0623] In an alternative embodiment, R of ULM-g through ULM-i 3 ' is -(CH 2 ) n -a Reel, -(CH 2 CH 2 O) n -aryl, -(CH 2 ) n -HET or -(CH 2 CH 2 O) n -HET, During the ceremony, The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, the substituents being preferably —(CH 2 ) n OH, itself CN, halo (up to three halo groups), OH, -(CH 2 ) n O(C 1 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6 C optionally further substituted with alkyl)amine 1 -C 6 alkyl, where the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups; or The aryl group of ULM-g to ULM-i is —(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 ) alkyl, -(CH 2 ) n -O-(CH 2 ) n -(C 1 -C 6 ) alkyl, -(CH 2 ) n -C(O)(C 0 -C 6 ) alkyl, -(CH 2 ) n -C(O)O(C 0 -C6 ) alkyl, -(CH 2 ) n -OC(O)(C 0 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6 The alkyl group on the amine is substituted with one or two hydroxyl groups, or up to three halo (preferably F, Cl) groups, CN, NO 2 , optionally substituted -(CH 2 ) n -(V) m’ - ( CH 2 ) n -(V) m’ -(C 1 -C 6 ) alkyl group, -(V) m’ -(CH 2 CH 2 O) n -R PEG groups, where V is O, S, or NR 1’ and R 1’ is H or C 1 -C 3 is an alkyl group (preferably H), and R PEG is H or optionally substituted C 1 -C 6 an alkyl group (including those optionally substituted with carboxyl groups); or The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each is preferably C 1 -C 3 and optionally substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a heterocycle, including heteroaryl, selected from the group consisting of a group conforming to the following chemical structure:

[0624] [ka]

[0625] ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 0 -C 6 alkyl), each group being optionally or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alki A cyclic group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 Alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, pipera azine, morpholine, quinoline (each preferably C 1 -C 3 a heterocyclic group selected from the group consisting of an alkyl group, preferably methyl, or a halo group, preferably F or Cl, benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1 -C 3 substituted with an alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the structure:

[0626] [ka]

[0627] ULM-g~ULM-i S c is CHR SS , N.R. URE or O, ULM-g~ULM-i R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 0 -C 6 alkyl), each group being optionally Heterocycles which are optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidin, each of which is optionally substituted. azine, piperazine, etc. ULM-g~ULM-i Y C is N or CR YC where R YC H, OH, CN, NO 2, halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or C 1 -C 6 Alki A cyclic group (preferably C 1 -C 3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1 -C 6 alkyl, or an optionally substituted aryl, heteroaryl or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 each independently represents H, optionally substituted C 1 -C 3 are alkyl groups or together form a keto group, Each m' of ULM-g to ULM-i is independently 0 or 1; and each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); wherein each of said compounds, preferably said aryl group or HET group, is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0628] In yet additional embodiments, preferred compounds include those according to the following chemical structure, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, each of which is optionally attached to a PTM group (including a ULM' group) via a linker group:

[0629] [ka]

[0630] During the ceremony, ULM-i R 1’ is OH or a group that is metabolized to OH in the patient or subject, ULM-i R 2’ is -NH-CH 2 -aryl-HET- (preferably methyl substituted) a phenyl bonded directly to a thiazole; ULM-i R 3’ -CHR CR3’ -NH-C(O)-R 3P1 Group or -CHR CR3’ -R 3P2 It is based on ULM-i R CR3’ is C 1 -C 4 an alkyl group, preferably methyl, isopropyl, or tert-butyl; ULM-i R 3P1 is C 1 -C 3 Alkyl (preferably methyl), optionally substituted oxetane groups (preferably methyl-substituted -(CH 2 ) n OCH 3 group, where n is 1 or 2 (preferably 2), or

[0631] [ka]

[0632] group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (attached to the carbonyl at the 2- or 3-position), ULM-i R 3P2 teeth,

[0633] [ka]

[0634] It is based on Aryl of ULM-i is phenyl; HET of ULM-i is an optionally substituted thiazole or isothiazole; and ULM-i R HET is H or a halo group (preferably H) It is.

[0635] In certain embodiments, the bifunctional compound comprises a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure, or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof:

[0636] [ka]

[0637] During the ceremony, Each R in ULM-j 5 and R 6 are independently OH, SH, or optionally substituted alkyl, or R 5 , R 6 and the carbon atom to which they are attached forms a carbonyl, ULM-j R 7 is H or optionally substituted alkyl, E of ULM-j is a bond, C=O, or C=S; G of ULM-j is a bond, optionally substituted alkyl, —COOH, or C═J; J in ULM-j is O or NR 8 and ULM-j R 8 is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, or

[0638] [ka]

[0639] and ULM-j R 9 and R 10 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide bonded 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; ULM-j R 11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

[0640] [ka]

[0641] and ULM-j R 12 is H or optionally substituted alkyl, ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate; Each R in ULM-j 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl; ULM-j R 15is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R in ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; Each R in ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 the groups can be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH, ULM-j Z 1 , Z 2 , Z 3 and Z 4 are independently C or N, and The o of ULM-j is 0, 1, 2, 3, or 4.

[0642] In certain embodiments, G of ULM-j is C=J, J is O and R 7 is H, and each R 14 is H and o is 0.

[0643] In certain embodiments, G of ULM-j is C=J, J is O and R 7 is H, and each R 14 is H and R 15 is an optionally substituted heteroaryl and o is 0. In other examples, E is C=O and M is

[0644] [ka]

[0645] It is. In certain embodiments, E of ULM-j is C═O and R 11 is an optionally substituted heterocyclic or

[0646] [ka]

[0647] and M is

[0648] [ka]

[0649] It is. In certain embodiments, E of ULM-j is C=O and M is

[0650] [ka]

[0651] and R 11 teeth

[0652] [ka]

[0653] And each R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0654] In certain embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0655] [ka]

[0656] During the ceremony, G of ULM-k is C=J, J is O, ULM-k R 7 is H, Each R of ULM-k 14 is H, The o of ULM-k is 0, ULM-k R 15 teeth

[0657] [ka]

[0658] and ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

[0659] In another example, the R 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0660] In other embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0661] [ka]

[0662] During the ceremony, G of ULM-k is C=J, J is O, ULM-k R 7 is H, Each R of ULM-k 14 is H, ULM-k's o is 0, and ULM-k R 15 is selected from the group consisting of:

[0663] [ka]

[0664] In the formula, R of ULM-k 30 is H or optionally substituted alkyl. In other embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0665] [ka]

[0666] During the ceremony, E of ULM-k is C=O, The M in ULM-k is

[0667] [ka]

[0668] and ULM-k R 11 is selected from the group consisting of:

[0669] [ka]

[0670] In yet another embodiment, the compound of the following chemical structure:

[0671] [ka]

[0672] wherein E of ULM-k is C=O; ULM-k R 11 teeth

[0673] [ka]

[0674] and The M in ULM-k is

[0675] [ka]

[0676] and ULM-k's q is 1 or 2; ULM-k R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

[0677] [ka]

[0678] and ULM-k R 21 is H or optionally substituted alkyl, and ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

[0679] In any embodiment described herein, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0680] [ka]

[0681] [ka]

[0682] [ka]

[0683] In certain embodiments, R of ULM-j or ULM-k 11is selected from the group consisting of:

[0684] [ka]

[0685] [ka]

[0686] [ka]

[0687] In certain embodiments, ULM (or ULM′, when present) is a group according to the following chemical structure:

[0688] [ka]

[0689] During the ceremony, X of ULM-l is O or S; Y of ULM-l is H, methyl or ethyl; ULM-l R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0690] [ka]

[0691] and ULM-l R 9 is H, ULM-l R 10is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl; ULM-l R 11 is an optionally substituted heteroaromatic, an optionally substituted heterocyclic, an optionally substituted aryl, or

[0692] [ka]

[0693] and ULM-l R 12 is H or optionally substituted alkyl, and ULM-l R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate.

[0694] In some embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0695] [ka]

[0696] During the ceremony, Y of ULM-m is H, methyol or ethyl; ULM-m R 9 is H, R 10 isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl, ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocycle.

[0697] In other embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0698] [ka]

[0699] During the ceremony, ULM-n R 17 is methyl, ethyl, or cyclopropyl, and ULM-n R 9 , R 10 , and R 11 is as defined above. In other examples, R 9 is H, and ULM-n R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0700] In any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Further, in any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be linked to a PTM directly via a bond or by a chemical linker.

[0701] In certain embodiments of the disclosure, the ULM moiety is selected from the group consisting of: [ka]

[0702]

change

[0703]

change

[0704]

change

[0705]

change

[0706]

change

[0707]

change

[0708]

change

[0709]

change

[0710]

change

[0711]

change

[0712]

change

[0713]

change

[0714]

change

[0715]

change

[0716]

change

[0717]

change

[0718]

change

[0719]

change

[0720]

change

[0721]

change

[0722]

change

[0723] [ka]

[0724] The VLM may be attached to the PTM via a linker as described herein, at any suitable location, including, for example, an aryl, heteroaryl, phenyl, or phenyl of an indole group, and optionally via any suitable functional group, such as an amine, ester, ether, alkyl, or alkoxy. Exemplary Linkers In certain embodiments, the compounds described herein include one or more PTMs that are chemically bonded or linked to one or more ULMs (e.g., at least one of a CLM, a VLM, a MLM, an ILM, or a combination thereof) via a chemical linker (L). In certain embodiments, the linker group L is a group that includes one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or- (A L ) q -), A 1 is a group attached to the PTM, L ) q is a group linked to ULM.

[0725] In certain embodiments, the linker group L is -(A L ) q - is selected from (A L ) q is a group attached to a ULM moiety, a PTM moiety, or a combination thereof, and the linker's q is an integer equal to or greater than 1; Each A L is a bond, CR L1 R L2 , O, S, SO, SO 2 , N.R. L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R.L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , optionally 0 to 6 R L1 and / or R L2 C substituted with group 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with group 5-13 spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with group 3-11 Heterocyclyl, optionally 0 to 8 R L1 and / or R L2 C substituted with group 5-13 spiroheterocycloalkyl, optionally 0 to 6 R L1 and / or R L2 aryl substituted with a group, optionally 0 to 6 R L1 and / or R L2 heteroaryl substituted with a aryl group, where R L1 or R L2 each independently represents 0 to 4 R L5 Cycloalkyl substituted with a group and and / or heterocyclyl moieties, and R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or C 1-8 Alkyl, OC 1-8 Alkyl, SC1-8 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)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl) 2 , C.C.-C. 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=CH(C 1-8 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 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 Alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 Alkyl) 2 , CONH.C. 1-8 Alkyl, CON(C 1-8 Alkyl)2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 Alkyl)CON(C 1-8 Alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 Alkyl) 2 , N.H.C.O.N. 2 , N(C 1-8 Alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 Alkyl)SO 2 N(C 1-8 Alkyl) 2 , N.H.S.O. 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 Alkyl) 2 , N.H.S.O. 2 NH 2 It is.

[0726] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0727] In certain embodiments, for example when the linker q is greater than 2, (A L ) q is a group attached to ULM, A L 1 and (A L ) q are linked via a linker (L) structural unit.

[0728] In certain embodiments, for example, when the q of the linker is 2, (A L ) q A L 1 and is a group attached to ULM.

[0729] In certain embodiments, for example when the linker q is 1, the linker group L has the structure -A L 1and A L 1 is a group attached to the ULM and ABM moieties.

[0730] In certain embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxyl)-, -NR(CH 2 ) n -(lower alkoxy)-OCH 2 -, -NR(CH 2 ) n -(lower alkoxyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(cycloalkyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(heterocycloalkyl)-, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heterocycloalkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -Aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(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)l-, -NR(CH 2 CH 2 ) n -(cycloalkyl)-O-(heterocycle)-CH 2、 -NR(CH 2 CH 2 ) n -(heterocyclic ring)-(complex elementary ring)-CH 2 , -N(R1R2)-(heterocycle)-CH 2 ; during the ceremony n in the linker can be 0 to 10; R of the linker can be H, lower alkyl; The linkers R1 and R2 can form a ring with the N to which they are attached.

[0731] In certain embodiments, the linker (L) comprises 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(CH2 ) 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 -;

[0732] [ka]

[0733] [ka]

[0734] [ka]

[0735] During the ceremony, each of m, n, o, p, q, and r of the linker is independently 0, 1, 2, 3, 4, 5, or 6; If the number is zero, there are no NO or OO bonds. R of the linker is H, methyl and ethyl; X of the linker is H and F;

[0736] [ka]

[0737] wherein m in the linker may be 2, 3, 4, or 5;

[0738] [ka]

[0739] [ka]

[0740] [ka]

[0741] [ka]

[0742] [ka]

[0743] [ka]

[0744] [ka]

[0745] [ka]

[0746] [ka]

[0747] wherein each of m and n in the linker may independently be 0, 1, 2, 3, 4, 5, or 6.

[0748] In some embodiments, the linker (L) is selected from the group consisting of:

[0749] [ka]

[0750] [ka]

[0751] [ka]

[0752] [ka]

[0753] During the ceremony, each m and n is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the linker (L) is selected from the group consisting of:

[0754] [ka]

[0755] [ka]

[0756] [ka]

[0757] In some embodiments, the linker (L) is selected from the group consisting of:

[0758] [ka]

[0759] [ka]

[0760] [ka]

[0761] [ka]

[0762] [ka]

[0763]

change

[0764]

change

[0765]

change

[0766]

change

[0767]

change

[0768]

change

[0769]

change

[0770]

change

[0771]

change

[0772]

change

[0773]

change

[0774] [ka]

[0775] [ka]

[0776] [ka]

[0777] [ka]

[0778] [ka]

[0779] [ka]

[0780] [ka]

[0781] [ka]

[0782] wherein m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0783] In some embodiments, the linker (L) is selected from the group consisting of:

[0784] [ka]

[0785]

change

[0786]

change

[0787]

change

[0788]

change

[0789]

change

[0790]

change

[0791]

change

[0792]

change

[0793]

change

[0794]

change

[0795] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety.

[0796] [ka]

[0797] During the ceremony, W L1 and W L2 are each independently R Q and each R is a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with Q are independently H, halo, OH, CN, CF 3 , C 1 -C 6 Alkyl (straight chain, branched chain, optionally substituted), C 1 -C 6 Alkoxy (straight chain, branched chain, optionally substituted), or two R groups forming, together with the atom to which they are attached, a 4-8 membered ring system containing 0-4 heteroatoms Q It is based on Y L1 each independently represents a bond, C 1 -C 6 Alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are O, or C 1 -C 6 substituted with alkoxy (straight chain, branched chain, optionally substituted); n is 0 to 10, and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0798] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety.

[0799] [ka]

[0800] During the ceremony, W L1 and W L2 each independently represents an aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each of which is optionally R Q Each R Q are independently H, halo, OH, CN, CF 3 , Hydroxyl, Nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1 -C 6 Alkyl (straight chain, branched chain, optionally substituted), C 1 -C 6 Alkoxy (straight chain, branched chain, optionally substituted), OC 1-3 Alkyl (optionally substituted with one or more -F), OH, NH 2 , N.R. Y1 R Y2 , CN, or two R which together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms Q It is based on Y L1 are each independently a bond, NR YL1 ,O.S.,NR. YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO 2 , C 1 -C 6 Alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are O, C 1 -C 6 substituted with alkoxy (straight chain, branched chain, optionally substituted); Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 R Q Each R Q are independently H, C 1~6 Alkyl (straight chain, branched chain, optionally with one or more halo, C 1-6alkoxyl), or two R which, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms Q It is based on R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight chain, branched chain, optionally with one or more halo, C 1-6 alkoxyl), or R which together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms 1 , R 2 and n is 0 to 10, and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0801] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or an optionally substituted alkyl group 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.

[0802] 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 ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0803] In another embodiment, the disclosure is directed to a compound comprising a PTM group as described above, which binds to a target protein or polypeptide (e.g., RAF), is ubiquitinated by a ubiquitin ligase, and is chemically linked directly to a ULM group or through a linker moiety, L. Alternatively, the PTM is alternatively a ULM' group, which is also a ubiquitin ligase binding moiety, which may be the same as or different from the ULM group described above, which is linked through a linker moiety or directly to the ULM group, and L is a linker moiety as described above, which may or may not be present, chemically linking (covalently linking) the ULM to the PTM, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[0804] In certain embodiments, the linker group, L, is a group that comprises one or more covalently linked structural units independently selected from the group consisting of:

[0805] [ka]

[0806] X is O, N, S, S(O) and SO 2 n is an integer from 1 to 5, 5; R L1 is hydrogen or alkyl,

[0807] [ka]

[0808] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

[0809] [ka]

[0810] is selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; and the phenyl ring fragment can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In some embodiments, the linker group L comprises up to 10 covalently linked structural units as described above.

[0811] The ULM and PTM groups may be covalently attached to the linker group via any group that is appropriate and stable for the linker chemistry, and in preferred embodiments of the disclosure, the linker is independently covalently attached to the ULM and PTM groups, preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which may be inserted anywhere on the ULM and PTM groups to provide maximum binding of the ULM group to the ubiquitin ligase and maximum binding of the PTM group to the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein to be degraded may also be the ubiquitin ligase itself.) In certain preferred embodiments, the linker may be attached to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group on the ULM and / or PTM group. Exemplary PTMs In a preferred embodiment of the present disclosure, the PTM group is a group that binds to a target protein. The target of the PTM group is diverse, and the target is selected from proteins expressed in cells, at least a portion of whose sequence is present in the cell and can be bound to the PTM group. The term "protein" includes oligonucleotide sequences and polypeptide sequences of sufficient length that can be bound to a PTM group according to the present disclosure. As otherwise described herein, any protein in a eukaryotic cell system or a microbial system, including a virus, a bacterium, or a fungus, is a target of ubiquitination regulated by the disclosed compounds. Preferably, the target protein is a eukaryotic cell protein.

[0812] PTM groups according to the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), and include the following non-limiting examples of small molecule target protein moieties: RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressant compounds, and compounds specifically targeting the aryl hydrocarbon receptor (AHR). The compositions described below exemplify some of the components of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target a protein of interest. These binding moieties are attached, preferably through a linker, to a ubiquitin ligase binding moiety to present the target protein (to which the protein target moiety is attached) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0813] Any protein that can be bound to a protein targeting moiety or PTM group and acted upon or degraded by a ubiquitin ligase (e.g., RAF) is a target protein in accordance with the present disclosure. In general, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, as well as proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolytic activity, biosynthesis, kinase activity, redox activity, transferase activity, hydrolytic activity, lyase activity, isomerase activity, ligase activity, enzyme control activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, control of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (protein transport activity), and the like. Proteins of interest include proteins involved in the integral function of cells, including proteins involved in cellular function (including cellular function, nuclear transport, ion transport activity, channel transport activity, carrier activity, permeation activity, secretion activity, electron transport activity), phagocytosis, chaperone regulation activity, nucleic acid binding activity, transcription regulation activity, extracellular integration and biosynthesis activity, translation regulation activity. Proteins of interest include proteins from eukaryotes (e.g., c-RAF, A-RAF, and / or B-RAF) and prokaryotes, including humans and other animals as targets for drug therapy, including livestock animals, microorganisms for determining targets for antibiotics and other antimicrobial agents, and plants, and especially viruses (e.g., v-RAF and / or v-Mil), among many others.

[0814] The present disclosure may be used to treat many disease states and / or conditions, including any disease state and / or condition in which a protein is deregulated and in which a patient would benefit from protein degradation.

[0815] In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or salt form thereof described herein, and a pharma- ceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent. The therapeutic composition can be used to modulate protein degradation in a patient or subject, such as an animal, such as a human, and treat or ameliorate a disease state or condition modulated via the degraded protein. In certain embodiments, the therapeutic composition described herein can be used to cause targeted protein degradation for the treatment or amelioration of a disease, such as cancer, heart-face-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome. In certain additional embodiments, the disease is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma.

[0816] In an alternative aspect, the present disclosure relates to a method of treating a pathology or ameliorating a disease symptom or condition in a subject in need thereof by degrading a protein or polypeptide, the pathology or condition being modulated through degrading the protein or polypeptide, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound as described above, optionally in combination with a pharma- ceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent, the composition being effective in treating or ameliorating a disease or disorder or a symptom thereof in the subject. This disclosure Method byBy administering an effective amount of at least one compound described herein using the method of the present invention, many disease states or conditions can be treated, including cancer, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome, etc. The disease state or condition can be a disease caused by a microbial organism or an exogenous factor, such as a virus (e.g., murine retrovirus or avian retrovirus, e.g., avian retrovirus MH2), bacteria, fungi, protozoa, or other microbial factor, or can be a disease state caused by overexpression of a protein and / or the presence of a constitutively activated protein that gives rise to the disease state and / or condition.

[0817] In another aspect, the present description provides methods for identifying the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0818] The term "target protein" is used herein below to describe a protein or polypeptide to which the disclosed compounds bind and are targeted for degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target a protein of interest. These binding moieties are linked to at least one ULM group (e.g., VLM, CLM, ILM, and / or IL) via at least one linker group, L. MLM).

[0819] The target protein that can be bound to the protein targeting moiety and that can be bound to the ubiquitin ligase binding moiety and degraded by the ligase includes any protein or peptide, including fragments thereof, analogs thereof, and / or homologs thereof. Target proteins include proteins and peptides that have any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, conservation, transport, and signal transduction. More specifically, many of the drug targets for human therapy are protein targets to which the protein targeting moiety can be bound and incorporated into the compounds according to the present disclosure. These proteins include proteins that can be used to restore function in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners of the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalane cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e. Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza neuraminidase, hepatitis B virus reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38MAP kinase, Ras / Raf / MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase.Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel.Still further target proteins include acetyl-Coa carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0820] These various protein targets may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the disclosed compounds, the activity level of the protein can be altered for therapeutic end results. .

[0821] 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 / presents the protein or polypeptide in close proximity to ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR) in particular. The compositions described below exemplify some of the components of small molecule target proteins.

[0822] Exemplary protein targeting moieties according to the present disclosure include RAF inhibitors, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0823] The following compositions are illustrative of some of these types of small molecule target protein binding moieties. These small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. The references cited herein below are incorporated herein by reference in their entirety.

[0824] In any aspect or embodiment described herein, the PTM targets and / or binds RAF. For example, in any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structures consisting of PTM-Ia or PTM-Ib below:

[0825] [ka]

[0826] [ka]

[0827] During the ceremony, The double dashed bond is an aromatic bond, V PTM , W PTM , X PTM , Y PTM , Z PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, N; C, N, C, CH, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, N, C; X PTM35 , X PTM36 , X PTM37 , and X PTM38 is independently selected from CH and N; R PTM1 is covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, a MLM, a ULM', a CLM', an ILM', a VLM', a MLM', or a combination thereof; R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM3 is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH 3 , N.H.C.H. 3 or M1-CH2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle, and R PTM5 teeth,

[0828] [ka]

[0829] is selected from the group consisting of: In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structures consisting of PTM-IIa or PTM-IIb:

[0830] [ka]

[0831] [ka]

[0832] During the ceremony, X PTM1 , X PTM2 , X PTM3 , X PTM4 , X PTM5 , and X PTM6 is independently selected from CH or N; R PTM5ais a bond, an optionally substituted amine, an optionally substituted amide (e.g., optionally substituted with an alkyl group, a methyl group, an ethyl group, a propyl group, or a butyl group), H,

[0833] [ka]

[0834] -NHC(O)R PTM5 selected from the group consisting of; R PTM5 teeth,

[0835] [ka]

[0836] is selected from the group consisting of: R PTM6a and R PTM6b are each hydrogen, halogen, or optionally substituted C 1 -C 6アルキル (straight chain, branched chain, optionally substituted); R PTM6 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM8 , R PTM9 or R PTM10is absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O or NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle, and R PTM8 , R PTM9 or R PTM10 At least one of is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[0837] In certain embodiments, the PTM may comprise a chemical group selected from the group of chemical structures consisting of:

[0838] [ka]

[0839] In the formula, R PTM5 , R PTM6a , R PTM6b , R PTM6 , R PTM7 , R PTM8 , R PTM9 , R PTM10 , R PTM11 is as described herein.

[0840] In some embodiments, R PTM9is the covalent bond site, R PTM7 and R PTM8 is R PTM7 and R PTM8 can be covalently linked together in such a way as to form a bicyclic group having the ring to which is attached.

[0841] In other embodiments, R PTM8 is the covalent bond site, R PTM9 and R PTM10 is R PTM9 and R PTM10 can be linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached.

[0842] In a further embodiment, R PTM10 is the covalent bond site, R PTM8 and R PTM9 is R PTM8 and R PTM9 can be covalently linked together in such a way as to form a bicyclic group having the ring to which is attached.

[0843] In any aspect or embodiment described herein, the PTM is III,

[0844] [ka]

[0845] During the ceremony, X PTM7 , X PTM8 , X PTM9 , X PTM10 , X PTM11 , X PTM12 , X PTM13 , X PTM14 , X PTM15 , X PTM16 , X PTM17 , X PTM18 , X PTM19 , X PTM20are independently CH or N; R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 is absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH 3 , N.H.C.H. 3 or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R PTM20 is a small group containing less than four non-hydrogen atoms, R PTM21 is trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH 3 , N.H.C.H. 3 , dimethylamino or M1-CH 2 -CH 2 -M2, wherein M1 is CH 2 , O or NH, M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle, and R PTM12 , R PTM13 and R PTM16 At least one of is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[0846] In some embodiments, R PTM12 is the covalent bond site, R PTM13 and R PTM14 is R PTM13 and R PTM14and / or R can be covalently linked together in such a way as to form a bicyclic group having a ring to which R is attached. PTM15 and R PTM16 is R PTM15 and R PTM16 can be linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached.

[0847] In other embodiments, R PTM13 is the covalent bond site, R PTM12 and R PTM16 is R PTM12 and R PTM16 and / or R can be covalently linked together in such a way as to form a bicyclic group having a ring to which R is attached. PTM15 and R PTM16 is R PTM15 and R PTM16 can be linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached.

[0848] In a further embodiment, R PTM16 is the covalent bond site, R PTM12 and R PTM13 is R PTM12 and R PTM13 and / or R can be covalently linked together in such a way as to form a bicyclic group having a ring to which R is attached. PTM13 and R PTM14 is R PTM13 and R PTM14 can be linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached.

[0849] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structures consisting of PTM-IVa or PTM-IVb:

[0850] [ka]

[0851] During the ceremony, X PTM21 , X PTM22 , X PTM23 , X PTM24 , X PTM25 , X PTM26 , X PTM27 , X PTM28 , X PTM29 , X PTM30 , X PTM31 , X PTM32 , X PTM33 , X PTM34 are independent...

Claims

1. Chemical structure: ULM-L-PTM or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, having During the ceremony, (a) L is a group represented by the formula -(A L ) q - A chemical bond moiety represented by the formula: (A L ) q is a group connecting the ULM and the PTM, q is 1 to 20; Each A L Independently, CR L1 R L2 , O, N.R. L3 ,CONR L3 , CO, CR L1 =CR L2 , C≡C, 1 to 6 R L1 C optionally substituted with a group 3-11 Cycloalkyl and 1 to 6 R L1 C optionally substituted with a group 3-11 heterocyclyl, provided that there is no N-O or O-O bond; Each R L1 and R L2 are independently H, C 1-8 Alkyl, and C 3-11 is cycloalkyl, (b) the ULM is （１） 【Chemistry 1】 Cereblon E3 ubiquitin ligase binding moiety (CLM), represented by Here, W is CH ２ or C=O, X and Z are both O; G is H, Q １ , Q ２ , Q ３ , and Q ４ are each independently CH, CR or N; A is H, n is 1 or 2; Each R is independently H, C １－４ Alkyl, halo, C １－４ Alkoxy, OH, NH ２ or CN, where R is modified to covalently bond to L; 【Chemistry 2】 represents a bond which may be stereospecific or non-stereospecific, or （２） 【Chemistry 3】 The von Hippel-Lindau ligase binding moiety (VLM) is represented by Here, R １ is isopropyl or tert-butyl, R １４ａ is H, methyl, or hydroxymethyl; R １５ teeth, 【Chemistry 4】 and X is CH2, R ３ is non-existent or 【Chemistry 5】 and 【Chemistry 6】 indicates the attachment point of L, (c) the PTM has the following chemical structure: PTM-IIa 【Chemistry 7】 is a RAF (rapidly accelerated fibrosarcoma) protein targeting moiety represented by During the ceremony, X ＰＴＭ１ is C, X PTM2 , X PTM3 , X PTM4 , X PTM5 and X PTM6 are independently selected from C and N; R PTM5a is 【Chemistry 8】 and R ＰＴＭ５ teeth, 【Chemistry 9】 is selected from R ＰＴＭ６ａ and R ＰＴＭ６ｂ are each independently selected from hydrogen and a halogen; R ＰＴＭ６ is hydrogen, R ＰＴＭ７ , R ＰＴＭ８ , R ＰＴＭ９ , R ＰＴＭ１０ and R ＰＴＭ１１ is absent or hydrogen, R ＰＴＭ８ , R ＰＴＭ９ Or R ＰＴＭ１０ at least one of is a bond to L; A bifunctional compound, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof.

2. R ＰＴＭ５ teeth, 【Chemistry 10】 2. The bifunctional compound of claim 1, wherein:

3. R ＰＴＭ９ is a bond to L, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof.

4. The PTM is 【Chemistry 11】 2. The bifunctional compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, selected from:

5. The ULM is 【Chemistry 12】 is selected from wherein R 14a is methyl or hydroxymethyl; 【Chemistry 13】 A bifunctional compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein indicates a point of attachment.

6. The ULM is 【Chemistry 14】 having a chemical structure represented by During the ceremony, W is C=O; A is H, 【Chemistry 15】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; 5. The bifunctional compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein n is 1, and wherein R is covalently attached to a chemical linking moiety (L).

7. The ULM is 【Chemistry 16】 5. The bifunctional compound of claim 1, having a chemical structure represented by:

8. The L is represented by the following formula: -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 -、 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 where 8. The bifunctional compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein each m, n, o, p, q, and r of the chemical linking moieties is independently 0, 1, or 2, with the proviso that when the number is zero, there is no N-O or O-O bond. 【Request 9】 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 2. The bifunctional compound of claim 1, selected from: 【Request 10】 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 2. The bifunctional compound of claim 1, selected from:

11. A composition comprising an effective amount of a bifunctional compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, enantiomer, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

12. 12. A composition comprising a pharma- ceutically acceptable carrier and an effective amount of a bifunctional compound according to any one of claims 1 to 11, or at least one of its pharma- ceutically acceptable salts, enantiomers, or stereoisomers, for treating a disease or disorder in a subject, the method comprising administering said composition to a subject in need thereof, wherein said bifunctional compound is effective to treat or ameliorate at least one symptom of said disease or disorder.

13. The composition of claim 12, wherein the disease or disorder is associated with accumulation and aggregation of BRaf.

14. The disease or disorder is (i) cancer; (ii) Cardio-facial-skin syndrome; (iii) Neurofibromatosis type 1; (iv) Costello syndrome; (v) Noonan syndrome; or (vi) Lesions, electrocardiogram abnormalities, ocular hypertelorism, pulmonary valve stenosis, genital anomalies, growth retardation, and hearing loss (LEOPARD) syndrome associated with accumulation and aggregation of RAF.

14. The composition according to claim 12 or 13.

15. 15. The composition of claim 14, wherein the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; non-small cell lung cancer; ovarian cancer; thyroid cancer; pilocytic astrocytoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma.

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