Compounds and methods for targeted degradation of RAF (rapidly accelerated fibrosarcoma) polypeptides

Abstract

To provide bifunctional compounds, which find utility as modulators of RAF (rapidly accelerated fibrosarcoma, such as c-RAF, A-RAF and / or B-RAF; the target protein).SOLUTION: The present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitor-of-Apotosis Proteins or MDM2 (mouse double-minute homolog 2) ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein.SELECTED DRAWING: None

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, 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 incorporated herein by reference in their entireties. Additionally, all references cited herein are incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with government support under Grant No. NIH R35CA197589 issued by the National Institutes of Health. The government has certain rights in this invention.

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

[0003] Most small molecule drugs bind closely to enzymes or receptors in well-defined pockets. However, targeting protein-protein interactions using small molecules is notoriously difficult due to the large protein contact surfaces and the shallow, groove-like or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination. Therefore, their specificity for specific protein substrates makes them more attractive therapeutic targets than general proteasome inhibitors. Developing ligands for E3 ligases has proven challenging, 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 remains largely unexplored. For example, since the discovery of nutrin, the first small molecule E3 ligase inhibitor of mouse double minute 2 homolog MDM2 (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 p53 inactivation has been proposed as an important pathway for tumor cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310). Mutations in p53 have been found in approximately 50% of cancer patients (M. Hollstein, et al. Science (1991), 233, 49-53), whereas downregulation of p53 by MDM2 through protein-protein interaction with p53 has been frequently observed in patients with wild-type p53 (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 and cellular stress, p53 levels increase, and MDM2 levels also increase through 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] Several mechanisms explain the downregulation of p53 by MDM2. First, MDM2 binds to the N-terminal domain of p53, inhibiting the expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). Second, MDM2 shuttles p53 from the nucleus to the cytoplasm, promoting its proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Finally, MDM2 possesses intrinsic E3 ligase activity, which ubiquitinates p53, leading to its degradation via the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). Because MDM2 functions as an E3 ligase, recruiting MDM2 to disease-causing proteins and exercising its ubiquitination and degradation activities is a very attractive therapeutic approach. This is a drug development method.

[0006] One E3 ligase with attractive therapeutic potential is the von Hippel-Lindau (von Von Hippel-Lindau (VHL) tumor suppressor is the substrate-recognition subunit of the E3 ligase complex VCB, which further comprises elongins B and C, Cul2, and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the angiogenic growth factor VEGF and the erythroid-inducible cytokine erythropoietin in response to low oxygen levels. The first small molecule ligand of VHL to the substrate-recognition subunit of the E3 ligase has been generated, and its crystal structure has been obtained, confirming that this compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0007] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs 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 numerous other proteins. Through a mechanism that is 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 then regulates numerous developmental processes, such as limb and otic vesicle formation. It has been conclusively concluded that this ubiquitin ligase complex is important for limb development 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 an E3 ligase-specific domain and a baculoviral IAP repeat (BIR) domain, which 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). Therefore, through caspase binding, 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 (AVPI) of mature SMAC 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 (incorporated herein by reference) function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, these patent publications describe the use of bifunctional or proteolytic targeting chimeras (PROTACs). describes bifunctional (ubiquitin cleavage targeting chimeric) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds.

[0011] There is an ongoing need in the art for effective treatment of diseases associated with the 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) target only 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 available 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 available 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, nonspecific 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 modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is their potential for broad pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein class or family. Additionally, the present disclosure 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-facio-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, and LEOPARD (lentiginous moles, electrocardiogram abnormalities, hypertelorism, pulmonary valve stenosis, genital abnormalities, growth retardation, and hearing loss) syndrome.

[0014] Thus, in one aspect, the disclosure provides bifunctional compounds, 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 bringing the target protein / polypeptide into proximity with the ubiquitin ligase, which acts to degrade (and inhibit) the protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) binds to a von Hippel-Lindau E3 ubiquitin The bifunctional compound may be a venous hemoglobin (VHL) binding moiety (VLM), a cereblon E3 ubiquitin ligase binding moiety (CLM), 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 the bifunctional compound may be as follows:

[0015] [ka]

[0016] The respective positions 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 position 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] wherein PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group, connecting 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 an MDM2 (mouse double minute 2 homolog) 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 chemical linker group) that connects 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 to VHL E3 ligase, CLM is a ceroblon E3 ubiquitin ligase binding moiety that binds to cereblon, MLM is an MDM2 E3 ubiquitin ligase binding moiety, and ILM is an IAP binding moiety that binds to 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 is selected from the amino acids alanine (A), valine (V), proline (P), and isoleucine (I), or non-naturally occurring versions thereof. In additional embodiments, the amino acids of the AVPI tetrapeptide fragment are linked to one another through amide bonds (i.e., -C(O)NH- or -NHC(O)-).

[0024] In certain embodiments, the compounds described herein comprise independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations 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 some 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, which is incorporated herein in its entirety.

[0028] In certain embodiments, the MLM can be nutrine or a derivative thereof. Additionally, other contemplated 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, wherein 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 C-N bond or a C-C bond. Examples of CLMs include pomalidomide, lenalidomide, and thalidomide, as well as their derivatives. Derivatives of the formula (I) are not limited to the formula (I).

[0033] In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to regulate protein degradation in a patient or subject, e.g., an animal, such as a human, and treat or ameliorate a disease state or condition mediated by 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 present 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, a PTM and a CLM, or a PTM and an 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 proteins bound to the PTM for degradation. Similarly, a PTM can be linked to a VLM or a CLM or an MLM or an 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 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 for a disease state or condition, which is regulated via the target protein by reducing the level of that protein in the patient's cells.

[0034] In yet another aspect, the description provides a method of treating or ameliorating a disease, disorder, or 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 pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

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

[0036] The general areas 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 particular 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 explanation of the drawings]

[0038] [Figure 1A] Diagram of the general principles of PROTAC function. An exemplary PROTAC includes a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and an optional linker moiety (L; black line) connecting the PTM and ULM. [Figure 1B]Diagram of the general principles of PROTAC function. The functional applications of PROTACs described herein are illustrated. Briefly, ULM recognizes and binds to specific E3 ubiquitin ligases, and PTMs bind to and recruit target proteins, bringing them into close proximity to the E3 ubiquitin ligase. Typically, E3 ubiquitin ligases, complexed with E2 ubiquitin-binding proteins, catalyze the attachment of ubiquitin (dark circle) via an isopeptide bond to lysines on target proteins, either alone or via the E2 protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 2] Table 42. Exemplary protein targeting moieties and compounds of the present disclosure. [Figure 3] Table 43. Data for exemplary protein targeting moieties and compounds of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0039] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations 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 herein are expressly incorporated by reference in their entirety.

[0040] Described herein are compositions and methods related to the surprising and unexpected discovery that an E3 ubiquitin ligase protein (e.g., inhibitor of apoptosis protein (IAP), von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon E3 ubiquitin ligase, or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinates a target protein when the two proteins are brought into close proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein to the target protein. Accordingly, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety (ULM) linked to a protein target binding moiety (PTM), which results in ubiquitination of the 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 present disclosure provides compounds comprising 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), which can bind to a ubiquitin ligase, such as an 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 the 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, unless the context clearly dictates otherwise (e.g., for a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), the It is understood that each intervening value between the upper and lower limits of a range and any other stated range, to the tenth of the unit of the lower limit, or in that stated range, is encompassed within the scope of the invention. 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 range. 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 phrase "and / or" should be understood to mean "either or both" of the elements so conjoined. That is, in some instances, the elements are present conjunctivly and in other instances, they are present disjointly. Multiple elements listed with "and / or" should be construed in the same manner; that is, "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or not 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 to only B (optionally including elements other than A), in yet another embodiment 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 more than one, and optionally including additional unlisted items. Only terms clearly implied to the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," shall 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 exclusive terms, such as "either," "one of," "only one of," or "exactly one of."

[0048] In the claims, as well as in the foregoing 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 Section 2111.03 of the United States Patent and Trademark Office Guidelines for Patent Examination.

[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 presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, regardless of whether those specifically identified elements are related. 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, in one embodiment, refer to at least one A, optionally including multiple A's, and no B (optionally including elements other than B). In another embodiment, it refers to at least one B, optionally including multiple B's, and no A (optionally including elements other than A's). In yet another embodiment, it can refer to at least one A, optionally including multiple A's, and at least one B, optionally including multiple B's (optionally including other elements).

[0050] It will also be understood that in particular methods described herein that include multiple steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context indicates otherwise.

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

[0052] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, and includes 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 thereof, including prodrugs and / or deuterated forms, where appropriate in the context. Contemplated deuterated small molecules are small molecules in which one or more of the hydrogen atoms contained in the drug molecule have been replaced with deuterium.

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

[0054] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them 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, subsequently targeting 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, a third ubiquitin is attached to the second, 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 a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation but may instead change their cellular location or function, for example, through binding to other proteins that contain domains capable of ubiquitin binding. Further complicating the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is the lysine used to generate polyubiquitin, which is recognized by the proteasome.

[0055] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of an infection, condition, or pathology specific to a particular animal, e.g., a human patient, the term patient refers to that particular animal, including domestic animals, e.g., dogs or cats, or livestock, e.g., horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by 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 an MDM2 (mouse double minute 2 homologue) 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 wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of moieties in the compounds 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 the context indicates otherwise. For example, the term ULM encompasses all ULMs, including those that bind to IAPs (i.e., ILMs), MDM2 (i.e., MLMs), cereblon (i.e., CLMs), and VHL (i.e., VLMs). In addition, ILMs The term encompasses all potential IAP E3 ubiquitin ligase-binding moieties, the term MLM encompasses all potential MDM2 E3 ubiquitin ligase-binding moieties, the term VLM encompasses all potential VHL-binding moieties, and the term CLM encompasses all potential cereblon-binding moieties.

[0058] In another aspect, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for controlling protein activity by inducing target protein degradation. In certain embodiments, the compounds comprise an ILM or VLM or CLM or MLM linked, directly or indirectly, e.g., covalently, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the ILM / VLM / CLM / MLM and PTM are linked or connected via a chemical linker (L). The ILM binds to 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, bringing the target protein and ubiquitin ligase protein into close proximity, thereby promoting target protein degradation 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). 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 comprise multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that specifically bind to multiple / different E3 ubiquitin ligases, e.g., VHL, IAP, cereblon, and / or MDM2), or combinations thereof. In any of the embodiments, the PTM and ULM (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 still 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 ULM directly, via a chemical linker (L), or both. In certain additional embodiments, a compound comprising multiple ULMs further comprises multiple PTMs. In even 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, a compound may comprise multiple ULMs and / or multiple ULMs'. In further embodiments, a compound comprising at least two different ULMs, multiple ULMs, and / or multiple ULMs' further comprises at least one PTM linked to a ULM or ULM' 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 additional 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, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

[0064] In additional embodiments, the present disclosure provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salt forms, such as acid and base salt forms. Exemplary 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-naturally occurring 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 together form a 5- to 8-membered ring, which is optionally further fused to 1 to 2 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R for formulas (I), (II), (III), (IV), and (V) 7 is a cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl , aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is further optionally 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 further optionally substituted with 1 to 3 substituents as described above.

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

[0069] [ka]

[0070] During the ceremony, R1 in formula (VI) is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3-C 1O -cycloalkyl, which are unsubstituted or substituted; R2 in formula (VI) is H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, or C3-C 1O -cycloalkyl, which are unsubstituted or substituted; R3 in formula (VI) is H, -CF3, -C2H 5、 independently selected from C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, -CH2-Z, or any R2 and R3 together form a heterocyclic ring, Each Z in formula (VI) is H, —OH, F, Cl, —CH 3、 -CF 3、 independently selected from —CH2Cl, —CH2F, or —CH2OH; R4 in formula (VI) is C1-C 16 straight or branched chain alkyl, C1-C 16 -Alkenyl, C1-C 16 -Alkynyl, C3-C 10 -cycloalkyl, -(CH2) 0-6 -Z 1、 -(CH2) 0-6 -aryl, and -(CH2) 0-6 -het, wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; R5 in formula (VI) is H, C 1-10 -Alkyl, aryl, phenyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -Alkyl-aryl, -(CH2) 0-6 -C 3-7 -Cycloalkyl-(CH2) 0-6 -phenyl, -(CH2) 0-4 -CH[(CH2) 1-4 -phenyl] 2、 Indanyl, -C (O)-C 1-10 -Alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-(CH2) 0-6 -phenyl, -(CH2) 0-6 -C(O)-phenyl, -(CH2) 0-6 -het, -C(O)-(CH2) 1-6 -het, or R5 is selected from a residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl, and aryl substituents are unsubstituted or substituted; Z1 in formula (VI) is —N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 1O)-C(O)-(CH2) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH2) 0-6 -phenyl, -N(R 10 )-C(O)(CH2) 1-6 -het, -C(O)-N(R 11 )(R 12 ), -C(O)-OC 1-10 -Alkyl, -C(O)-O-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -phenyl, -C(O)-O-(CH2) 1-6 -het, -OC(O)-C 1-10 -Alkyl, -OC(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -het is independently selected from alkyl, cycloalkyl, and phenyl, and is 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, wherein the heterocyclic ring or fused ring system is unsubstituted or substituted on the carbon or nitrogen atoms; R in formula (VI) 10 -H, -CH 3、 selected from —CF3, —CH2OH, or —CH2Cl; R in formula (VI) 11 and R 12 is H, C 1-4 -Alkyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl, (CH2) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R11 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 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 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, and wherein each alkyl is independently unsubstituted or substituted; R in formula (VII) d is Re-Q-(R f ) p (R g ) q、 and Ar1-D-Ar2, R in formula (VII) c is selected from the group of H or any R c and R d together form a cycloalkyl or het, and R c and R d is cycloalkyl or het When formed, R5 is attached to the formed ring at a C atom or an 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 selected from the group N, O, S, S(O) and S(O)2; Ar1 and Ar2 in formula (VII) are independently selected from the group 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, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, aryl, phenyl-phenyl Nyl, -(CH2) 1-6 -het, -O-(CH2) 1-6 -het, -OR 13 , -C(0)-R 13 , -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -SR 13 , -S(O)-R 13 , -S(O)2-R 13 , -S(O)2-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, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted; -SO2-C 1-2 -Alkyl, -SO2-C 1-2 -Alkylphenyl, -OC 1-4 -alkyl or any R g and R f together form a ring selected from het or aryl; D in formula (VII) is -CO-, -C(O)-C 1-7 -Alkylene or arylene, -CF2-, -O-, -S(O) r where r is 0 to 2 1,3-dioxalanes, or C 1-7-alkyl-OH, where alkyl, alkylene or arylene is unsubstituted or has one or more halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -alkyl, or -CF3, or each D is N(R h ), and 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, -SO2-C 1-10 -Alkyl, or -SO2-(C 0-10 -alkylaryl), R6, R7, R8 and R9 in formula (VII) are each independently H, -C 1-10 -Alkyl, -C 1-10 -alkoxy, aryl-C 1-10 -Alkoxy, -OH, -OC 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, -(CH2) 1-6 -het, -O-(CH2) 1-6 -het, -OR 13、 -C(O)-R 13、 -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -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 14wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted, and any of R, R, R, and R optionally together form a ring system; R in formula (VII) 13 and R 14 is H, C 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -(CH2) 0-6 -(CH) 0-1 -(aryl) 1-2、 -C(O)-C 1-10 -Alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6 -aryl, -C(O)-(CH2) 0-6 -O-Fluorenyl, -C(O)-NH-(CH2) 0-6 -aryl, -C(O)-(CH2) 0-6 -aryl, -C(O)-(CH2) 0-6 -het, -C(S)-C 1-10 -Alkyl, -C(S)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(S)-O-(CH2) 0-6 -aryl, -C(S)-(CH2) 0-6 -O-Fluorenyl, -C(S)-NH-(CH2) 0-6 -aryl, -C(S)-(CH2) 0-6 -aryl, or -C(S)-(CH2) 1-6 -het, wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted. : or any R 13 and R 14 forms het with the nitrogen atom, In the formula, R in formula (VII) 13 and R 14 The alkyl substituents in are unsubstituted or substituted, and if substituted, are C 1-10 -Alkyl, halogen, OH, -OC 1-6 -Alkyl, -SC 1-6-substituted by one or more substituents selected from -alkyl, -CF3, 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 some 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 chemically linking the ILM and the second ILM. In some embodiments, the at least one additional linker group to the ILM of Formula (VI) or a non-natural mimetic thereof chemically links a group selected from R4 and R5. 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 described in Ndubaku, C., et al. Antagonism of c-IAP and XIAP proteins are required for efficient Induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4(7)(2009)), 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 rings, fused rings, aryls, and heteroaryls; and 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 formula (IX) below (derived from the chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010)), 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 in formula (IX) 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) (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,

[0089] [ka]

[0090] During the ceremony, R in formula (X) 1 is selected from H, -CHOH, -CHCHOH, -CHNH, -CHCHNH; X in formula (X) is selected from S or CH2; R in formula (X) 2is selected from:

[0091] [ka]

[0092] R in formula (X) 3 and R 4 are independently selected from H or Me. In any of the compounds described herein, the ILM can have the structure of formula (XI) below (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, R in formula (XI) 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 the chemical species cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15(5-6), 210-9 (2010)), 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 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)). It can have the structure of 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 10 is 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 are 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 selected from CH2 and O, and

[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 Patent 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) 1 is selected from:

[0130] [ka]

[0131] [ka]

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

[0133] [ka]

[0134] X is selected from CH2 and O; and

[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; of 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 selected from the group of O or CH2.

[0151] In any of the compounds described herein, the ILM may be of formula (XVIII) (Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, based on IAP ligands described in 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 ligand 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 six-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] X in formula (XX) is selected from CH2, 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, and

[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 pharmaceutically 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 are independently 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) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and During the ceremony, v is an integer from 1 to 3, -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 OH, NR 24 R 25 OR26 are independently selected from -CH2CHR 21 COR 2 R 21 is NR 24 R 25 is selected from the group -CH2R 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, -CH2(OCH2CH2O) m CH3, or a polyamine chain such as spermine or spermidine; OR 26 R 26 is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen, or NH; and m is an integer from 1 to 8; R of formula (XXII) or formula (XXIII) 3 and R 4 are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXII) or formula (XXIII) 5 , R 6 , R 7 and R 8are 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 pharmaceutically 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 point of attachment of a PTM, L, or ULM, e.g., an ILM. In any of the compounds described herein, the ILM may be of formula (XXIV) or formula (XXVI) (see International Patent Application Publication No. WO 2015 / 006524 and Perez HL, derived from the IAP ligands described in "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 ILM is a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0185] [ka]

[0186] During the ceremony, R of formula (XXIV), formula (XXV) or formula (XXVI) 1is 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, and the substituent attached to the S atom of the thioalkyl is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and During the ceremony, v is an integer between 1 and 3 , -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 OH, NR 24 R 25 OR 26 are independently selected from -CH2CHR 21 COR 2 R 21 is NR 24 R 25 is selected from -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, the optional substituents including alkyl and halogen; NR 24 R 25 R24 is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2(OCH2CH2O) m CH3, or a polyamine chain such as spermine or spermidine; OR 26 R 26 is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen, or NH; and m is an integer from 1 to 8; R of formula (XXIV), formula (XXV) or formula (XXVI) 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, 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 comprising:

[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 have the structure of a pharmaceutically acceptable salt, tautomer, or the like. 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 SR 70 wherein R is independently selected from 60 and R 61 teeth , H or methyl; R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 is selected from During the ceremony, v is an integer from 1 to 3, -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 OH, NR 24 R 25 OR 26 are independently selected from -CH2CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH2R 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 24is selected from hydrogen or optionally substituted alkyl; NR 24 R 25 R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3, or polyamine chains such as spermine or spermidine -[CH2CH2(CH2)δNH]ΨCH2CH2(CH2)ωNH2 Selected, In the formula, δ=0 to 2, Ψ=1 to 3, and ω=0 to 2. OR 26 R 26 is optionally substituted alkyl, the optional substituents being OH, halogen, or NH; and m is an integer from 1 to 8; R of formula (XXVII) and formula (XXVIII) 3 and R 4 are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXVII) and formula (XXVIII) 5 , R 6 , R 7 and R 8 are 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 formulas (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 11 are 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 17are 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 SR 70 wherein R is independently selected from 60 and R 6 1 is selected from H or methyl, and R 70 is an optionally substituted alkyl, an optionally substituted branched alkyl, an optionally substituted heterocyclyl, -(CH2) vCOR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and During the ceremony, v is an integer from 1 to 3, -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 O H, NR 24 R 25 OR 26 are independently selected from -CH2CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH2R 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, -CH2CH2(OCH2CH2) m CH3, or -[CH2CH2(CH2)δNH]ΨCH2CH2(CH2)ω of polyamine chains such as spermine or spermidine r NH2, In the formula, δ=0 to 2, Ψ=1 to 3, and ω=0 to 2. OR 26 R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen, or NH; m is an integer from 1 to 8; R of formula (XXIX) to formula (XXXII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and R of formula (XXIX) to formula (XXXII) 31 is 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] 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] During the ceremony, 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, and R of formula (XXXIII)6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R in formula (XXXIII) 32 is (C1-C4 alkylene)-R 33 wherein R 33 is selected from hydrogen, aryl, heteroaryl, or cycloalkyl, optionally further substituted; X in formula (XXXIII) is selected from:

[0219] [ka]

[0220] Z and Z′ of 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 the point of attachment to the compound, and X is selected from:

[0233] [ka]

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

[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, and A is -C(O)R 3 and R 3 is -C(O)R 3 , OH, NHCN, NHSO2R 10 , NHOR 11 or N( R 12 )(R 13 ) and NHSO2R 10 and NHOR 11 R 10 and F 11 is independently selected from hydrogen, optionally substituted -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or heterocycloalkyl; N(R 12 )(R 13 )R 12 and R 13 is hydrogen, -C1-C4 alkyl, -(C 1-C4) alkylene)-NH-(C1-C4 alkyl), and -(C1-C4 alkyl independently selected from: R 12and R 13 together with the nitrogen atom to which they are commonly attached form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O and S, said saturated heterocycle optionally being 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 pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;

[0247] [ka]

[0248] During the ceremony, In 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) 1and R 2 is independently selected from 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) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 wherein v is an integer of 1 to 3; -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 OH, NR 24 R 25 OR 26 are independently selected from -CH2CHR 21 COR 22 R 21 is NR 24 R 25 is selected from -CH2R 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, -CH2(OCH2CH 20 ) m CH3, or a polyamine chain; R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen, or NH; -(CR 10 R 11) m - m is an integer from 1 to 8, R of formula (XXXIV) or formula (XXXV) 3 and R 4 are independently 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 are 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 R18 is hydrogen, halogen, optionally substituted alkyl, or OR 19 are independently selected from OR 19 R 19 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 10 R 11 ) m m and n in - are independently 0, 1, 2, 3, or 4, and -(CR 10 R 11 ) m - o and p are independently 0, 1, 2, or 3; -(CR 10 R 11 ) m q is 0, 1, 2, 3, or 4 and r is 0 or 1; -(CR 10 R 11 ) m -t is 1, 2 or 3.

[0255] In any of the compounds described herein, the ILM can have the structure of formula (XXXVI) (derived from the IAP ligands described in WO 2014 / 025759), or a non-natural mimetic thereof, and / or a pharmaceutically 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 -(CR21 R 22 ) m -,

[0260] [ka]

[0261] is selected from Y and Z in formula (XXXVI) are each independently —O—, —NR 6 - independently selected from or absent, V in formula (XXXVI) is selected from -N- or -CH-; W in formula (XXXVI) is selected from -CH- or -N-; R in formula (XXXVI) 1 is 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 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or preferably methyl;

[0262] [ka]

[0263] R 9 and R 10are 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 WO 2014 / 011712), or a non-naturally occurring mimetic thereof, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof;

[0274] [ka]

[0275] [ka]

[0276] During the ceremony, X in formula (XXXVII) and 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 are independently selected from or 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 4 are 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 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or 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 R17 are independently selected from hydrogen, halogen, or optionally substituted alkyl; R of formula (XXXVII) and formula (XXXVIII) 50 and R 51 are 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 2is 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 WO 2013 / 071039), or a non-natural mimetic thereof;

[0293] [ka]

[0294] During the ceremony, R of 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 of formula (XXXIX) and formula (XL) 6 and R 8 are 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, NHSOR 10 , NHOR 11 or N(R 12 )(R 13 ) and NHS02R 10 and NHOR 11 R 10 and R 11 is independently selected from -C1-C4 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 which is selected from hydrogen, —C1-C4 alkyl, —(C1-C4 alkylene)-NH—(C1-C4 alkyl), benzyl, —(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)CH3, -CH(benzyl)-COOH, -C1-C4 alkoxy, and -(C1-C4 alkylene)-O-(C1-C4 hydroxyalkyl), or N(R 12 )(R 13 )R 12 and R 13 together with the nitrogen atom to which they are commonly attached form a saturated heterocyclyl optionally containing one additional heteroatom selected from N, O and S, said saturated heterocycle optionally being 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, NR A , or C(R 8a )(R 8b ) and W in formula (XLI) 2 are O, S, NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or both S, R in formula (XLI) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); Selected, X 1 But, O, NR A , S, S(O), or S(O)2, then X 2 teeth, C(R 2a R 2b ) and or X in formula (XLI) 1 is CR 2c R 2d Selected from X 2 is CR 2a R 2b and R 2c and R2a 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 is selected from CH2, and X 2 is C=0, C=C(R C )2, or C=NR C where each R c are independently selected from H, —CN, —OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), —C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), —C1-C6 alkyl-(substituted or unsubstituted aryl), or —C1-C6 alkyl-(substituted or unsubstituted heteroaryl); NR A R A is selected from H, C1-C6 alkyl, —C(═O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d and CR 2a R 2b R 2a , R 2b , R 2c , R 2dis H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R B are independently selected from -C(=O)R B R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl). are selected independently from m in formula (XLI) is selected from 0, 1 or 2; -U- in formula (XLI) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLI) 3 is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLI) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3, or -OR 5 is selected from -NHR 5 , -N(R 5 )2, -N+(R 5 )3, and -OR 5 Each R 5 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, and —C-C alkyl-(C-C cycloalkyl); or R in formula (XLI) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached, or R in formula (XLI) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLI) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 selected from heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 Each R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl)2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) Pindependently 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 are independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C 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 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. death, or R 8c and R 8d is as defined above, and R 8a and R 8btogether with the atoms 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 atoms 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 1 to 3 R 9 is replaced by R 8a , R 8b , R 8c and R 8d Each R 9 are independently selected from halogen, —OH, —SH, (C═O), CN, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C fluoroalkoxy, —NH, —NH(C-C alkyl), —NH(C-C alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C-C alkyl, —S(═O)2CH3, —NH(C-C alkyl)-OH, —NH(C-C alkyl)-O—(C-C alkyl), —O(C-C alkyl)-NH2; —O(C-C alkyl)-NH—(C-C alkyl), and —O(C-C alkyl)-N—(C-C alkyl)2, or two R 9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, which may be unsubstituted or substituted with halogen, -OH, or C1-C3 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 WO 2013 / 071039), or a non-natural mimetic thereof:

[0318] [ka]

[0319] During the ceremony, W in formula (XLII) 1 are O, S, NR A , or C(R 8a )(R 8b ) and W in formula (XLII) 2 are O, S, NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or both S, R in formula (XLII) 1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); are 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 When is selected from S, S(O) or S(O)2, X 2 is CR 2c R 2d and X 3is CR 2a R 2b and or X in formula (XLII) 1 If is O, then X 2 is CR 2c R 2d and NR A and X 3 is CR 2a R 2b and or X in formula (XLII) 1 If is CH3, X 2 , O, NR A , S, S(O), or S(O)2, and X 3 is CR 2a R 2b and X in formula (XLII) 1 is CR 2e R 2f and X 2 is 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 are both CH2, and X in formula (XLII) 2 is C=0, C=C(R C )2, or C=NR C where each R Cis independently H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl). and selected, 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 is 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 is CR 2e R 2f and NR A R A is selected from H, C1-C6 alkyl, —C(═O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R B are independently selected from -C(=O)R B R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), or -NR D R E is selected from NR D R E R D and R Eis H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl). are selected independently from m in formula (XLII) is selected from 0, 1 or 2; -U- in formula (XLII) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLII) 3 is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLII) 4 -NHR 5 , -N(R 5 )2, -N+(R 5 )3 OR -OR 5 is selected from -NHR 5 , -N(R 5 )2, -N + (R 5 )3, and -OR 5 Each R 5 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, and —C-C alkyl-(C-C cycloalkyl); or R in formula (XLII) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached, or R in formula (XLII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 selected from heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 Each R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl)2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P 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 are independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 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 atoms 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 atoms 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 1 to 3 R 9 is replaced by R 8a , R 8b , R 8c and R 8d Each R 9are independently selected from halogen, —OH, —SH, (C═O), CN, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C fluoroalkoxy, —NH, —NH(C-C alkyl), —NH(C-C alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C-C alkyl, —S(═O)2CH3, —NH(C-C alkyl)-OH, —NH(C-C alkyl)-O—(C-C alkyl), —O(C-C alkyl)-NH2; —O(C-C alkyl)-NH—(C-C alkyl), and —O(C-C alkyl)-N—(C-C alkyl)2, or two R 9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, which may be unsubstituted or substituted with halogen, -OH, or C1-C3 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 WO 2013 / 071039), or a non-natural mimetic thereof:

[0321] [ka]

[0322] During the ceremony, W in formula (XLIII) 1 are O, S, NR A , or C(R 8a )(R 8b ) and W in formula (XLIII) 2 are O, S, NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or both S, R in formula (XLIII) 1is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) is selected from X in formula (XLIII) 1 But NR A , S, S(O), or S(O)2, X in formula (XLIII) 2 is CR 2c R 2d and X of formula (XLIII) 3 is CR 2a R 2b and or X in formula (XLIII) 1 is O, then X in formula (XLIII) 2 , O, NR A , S, S(O), or S(O)2, and X of formula (XLIII) 3 is CR 2a R 2b and or X in formula (XLIII) 1 is CR 2e R 2f and X in formula (XLIII) 2 is CR 2c R 2d If R 2e and R 2c together form a bond, and X in formula (XLIII) 3 is CR 2a R 2b and or X in formula (XLIII) 1 and X 2is 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 is CR 2a R 2b and or X in formula (XLIII) 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 is CR 2e R 2f and NR A R A is H, C1-C6 alkyl, —C(═O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b , and C.R. 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl) , —C1-C6 alkyl-(substituted or unsubstituted aryl), —C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and —C(═O)R B are independently selected from -C(=O)R B R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl). 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)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLIII) 3 is C1-C3 alkyl or C1-C3 fluoroalkyl; R in formula (XLIII) 4-NHR 5 , -N(R 5 )2, -N+(R 5 )3 OR -OR 5 and -NHR 5 , -N(R 5 )2, -N + (R 5 )3, and -OR 5 Each R 5 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, and —C-C alkyl-(C-C cycloalkyl); or R in formula (XLIII) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms 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)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 selected from heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7, -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 Each R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3 -C 10 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl)2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P 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 are independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 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 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 atoms 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 atoms 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 1 to 3 R 9 is replaced by R 8a , R 8b , R 8c and R 8d Each R 9 are independently selected from halogen, —OH, —SH, (C═O), CN, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C fluoroalkoxy, —NH, —NH(C-C alkyl), —NH(C-C alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C-C alkyl, —S(═O)2CH3, —NH(C-C alkyl)-OH, —NH(C-C alkyl)-O—(C-C alkyl), —O(C-C alkyl)-NH2; —O(C-C alkyl)-NH—(C-C alkyl), and —O(C-C alkyl)-N—(C-C alkyl)2, or two R 9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, which may be unsubstituted or substituted with halogen, -OH, or C1-C3 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, NR A , or C(R 8a )(R 8b ) and W in formula (XLIV)2 are O, S, NR A , or C(R 8c )(R 8d ), where W 1 and W 2 are not both O or both S, W in formula (XLIV) 3 are O, S, NR A , or C(R 8e )(R 8f ), where W 1 , W 2 and W 3 does not contain two adjacent oxygen or sulfur atoms, R in formula (XLIV) 1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); are selected from X in formula (XLIV) 1 When is O, X in formula (XLIV) 2 is CR 2c R 2d and N.R. A X of formula (XLIV) is selected from 3 is CR 2a R 2b and or X in formula (XLIV) 1 is CH2, X in formula (XLIV) 2 , O, NR A , S, S(O), or S(O)2, and X of formula (XLIV) 3 is CR 2a R 2b and or X in formula (XLIV) 1 is CR 2e R 2f and X in formula (XLIV) 2 is CR 2cR 2d If R 2e and R 2c together form a bond, and X in formula (XLIV) 3 is CR 2a R 2b and or X in formula (XLIV) 1 and X 3 are both CH2, and X in formula (XLII) 2 is C=0, C=C(R C )2, or C=NR C where each R C are independently selected from H, -CN, -OH, alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); Selected, 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 is CR 2a R 2b and or X in formula (XLIV) 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 (VLIV) 1 is CR 2e R 2f and NR A R A is selected from H, C1-C6 alkyl, —C(═O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , 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 C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O)R B are independently selected from -C(=O)R B R Bis substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 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 C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl). are selected independently from m in formula (XLIV) is selected from 0, 1 or 2; -U- in formula (XLIV) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, or -NHS(=O)2NH-; R in formula (XLIV) 3 is selected from C1-C3 alkyl, or C1-C3 fluoroalkyl; R in formula (XLIV) 4 -NHR 5 , -N(R 5 )2, -N + (R 5 )3, or -OR 5 is selected from -NHR 5 , -N(R5 )2, -N + (R 5 )3, and -OR 5 Each R 5 is independently selected from H, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, and —C-C alkyl-(C-C cycloalkyl); or R in formula (XLIV) 3 and R 5 form a substituted or unsubstituted 5- to 7-membered ring together with the atoms to which they are attached, or R in formula (XLIII) 3 is attached to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLIII) 6 is -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7 , -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1 -C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 selected from heterocycloalkyl, or substituted or unsubstituted heteroaryl; -NHC(=O)R 7 , -C(=O)NHR 7 , -NHS(=O)2R 7 , -S(=O)2NHR 7 ;-NHC(=O)NHR 7 , -NHS(=O)2NHR 7, -(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ;-(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 Each R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C 10 Heterocycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), -(CH2) p -CH(substituted or unsubstituted aryl)2, -(CH2) p -CH(substituted or unsubstituted heteroaryl)2, -(CH2) P 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 , R8c , R 8d , R 8e , and R 8f are independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C 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 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 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 atoms 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 heteroaryl ring containing 1 to 3 heteroatoms selected from S, O, and N. Forming a reel ring, or C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8c , R 8d , R 8e , and R 8f is as defined above, and R 8a and R 8b together with the atoms 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 atoms 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 atoms 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 1 to 3 R 9 is replaced by R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f Each R 9are independently selected from halogen, —OH, —SH, (C═O), CN, C-C alkyl, C-C fluoroalkyl, C-C alkoxy, C-C fluoroalkoxy, —NH, —NH(C-C alkyl), —NH(C-C alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C-C alkyl, —S(═O)2CH3, —NH(C-C alkyl)-OH, —NH(C-C alkyl)-O—(C-C alkyl), —O(C-C alkyl)-NH2; —O(C-C alkyl)-NH—(C-C alkyl), and —O(C-C alkyl)-N—(C-C alkyl)2, or two R 9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring, which may be unsubstituted or substituted with halogen, -OH, or C1-C3 alkyl.

[0326] In any of the compounds described herein, the ILM may be a compound 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, derived from the IAP ligand described in 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 R4 are 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] wherein R in formula (XLVIII) 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] 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] 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] is chemically bonded to a linker group L at the area indicated by

[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 ligand 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] wherein 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-naturally occurring 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 formulas (LIX) and (LX) is one or two substituents independently selected from H, halogen, or cyano, and L in formulas (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, systemic 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 may be any of the compounds described in Wang, J, et al., Discovery of novel second mitochondrial-derived activators of caspase mimetics. The IAP ligands described in "IAP inhibitors as selective inhibitors or apoptosis protein inhibitors," J. Pharmacol. Exp. Ther., 349(2):319-29 (2014), or the structure of a non-natural mimetic thereof, may have a structure selected from the group consisting of:

[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 variables that are independently applied vary 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-C 10 , more preferably C1-C6, or alternatively C1-C3 alkyl groups, which may be optionally substituted. Examples of alkyl groups include 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 with a halogen substituent (often chlorine or bromine) at its distal end, thereby forming a covalent bond between the compound containing the moiety and the protein.

[0424] The term "alkenyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0425] The term "alkynyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0426] The term "alkylene," when used, refers to an optionally substituted -(CH) n -group (n is generally an integer from 0 to 6). When substituted, alkylene groups are preferably substituted at one or more of the methylene groups with C1-C6 alkyl groups (including cyclopropyl or t-butyl groups), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or amino acid side chains as otherwise disclosed herein. In certain embodiments, 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 to 10, preferably 1 to 6, often 1 to 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 still other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as the side chain group of a natural or unnatural amino acid, 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. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with an H. Thus, a range of carbon atoms from C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with an H replacing the carbon for C0.

[0428] The terms "substituted" or "optionally substituted" shall mean, within context, independently at any carbon (or nitrogen) position on a molecule, 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 that may themselves be further substituted) and include, as substituents, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (especially alkyl, and especially methyl groups, such as trifluoromethyl, preferably 1, 2, or 3 halogens), alkyl groups (preferably C1-C2), and the like. 10 , more preferably C 1-6 ), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioethers (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), esters or thioesters (preferably C1-C6 alkyl or aryl), including alkylene esters (where the attachment is on the alkylene group rather than the ester functionality, and is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), an amine (including a 5- or 6-membered cyclic alkylene amine, further including a C1-C6 alkyl amine or a C1-C6 dialkyl amine, wherein the alkyl group may be substituted with one or two hydroxyl groups), or an optionally substituted -N Examples of suitable substituents include (C0-C6 alkyl)C(O)(O-C1-C6 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), hydrazine, amide, which preferably has one or two C1-C6 alkyl groups (including carboxamide, which is optionally substituted with one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, where R1 and R2 are Each is as otherwise described herein, and R3 is H or a C1-C6 alkyl group, preferably in this context R1, R2, R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly bonded to the substituted moiety, or alternatively, the substituent may be an optionally substituted (CH2) m - or alternatively optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) m The alkylene group -(CH) may be linked through a - group 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. m -or-(CH2) n-groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on alkylene groups include halogens or C1-C6 (preferably C1-C3) alkyl groups (optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chains of amino acids as otherwise described herein), and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C0-C6 alkyl substituents, which may also be further substituted). In certain embodiments, alkylene groups (often a single methylene group) are substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids as otherwise described herein. Moieties in molecules in the present disclosure may optionally be substituted with up to five substituents, preferably up to three substituents. In most cases, moieties that are substituted in this disclosure are substituted with one or two substituents.

[0429] The term "substituted" (each substituent is independent of any other substituent), within the context of its use, includes C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and The term "C1-C6 alkylene-NR1R2" also refers to alkyl groups, such as C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl-substituted amines, which may optionally be 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, -(CH2) m- (where m and n are 1, 2, 3, 4, 5 or 6, as the context requires), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O) -R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 groups), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of the use of the substituent. R1 and R2 are each, within context, H or a C1-C6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" is also intended to mean, within the chemical context of the specified compound and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. Alkylene groups may also be substituted as otherwise disclosed herein, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, 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, an O-C(O)-NR1R2 group, where R1 and R2 are as otherwise described herein, although many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds where substitution is required at a particular position in the molecule (primarily for valence reasons) but no substitution is indicated, the substituent is assumed or understood to be H unless the context of the substitution suggests otherwise.

[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 can 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 provided chemical structure. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as heteroaromatic ring systems, e.g., imidazole, furyl, pyrrole, furanyl, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, among others, which can be optionally substituted as described above.Among the heteroaryl groups that 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 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 An aryl group refers to an aromatic carbocycle composed of multiple fused rings, at least one of which is aromatic, where the ring is substituted with one or more substituents. For example, an aryl group can include a substituent selected from the following: -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2)n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl group on the amine optionally contains one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups, each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position, an optionally substituted phenyl group, wherein the phenyl group and / or substituted with at least one of F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN groups (at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, an optionally substituted oxazole, including methyl-substituted oxazole. substituted oxazoles, optionally substituted thiazoles including methyl-substituted thiazoles, optionally substituted isothiazoles including methyl-substituted isothiazoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, 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 furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines, and combinations thereof.

[0432] "Carboxyl" means -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, while these generic substituents have the same meaning as 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 substituted, triisopropylsilyl group, optionally substituted (CH m -O-C1-C6 alkyl group, or optionally substituted (CH2) m It may refer to a 1,2,3-triazole substituted with a —C(O)—O—C1-C6 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 HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1 an acetylene group, which is a -C6 alkyl group (preferably a C1-C3 alkyl); R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally containing one or two hydrogen atoms; substituted with an xyl group or up to three halo 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 C is N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl).

[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. "arylalkyl" refers to an aryl group, as defined above, appended to an alkyl group. An arylalkyl group is attached to the parent moiety through an alkyl group, which alkyl group is 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 their 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, isoxazolyl, and benzothiazolyl. Examples 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 can be optionally substituted with members selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can 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 either heterocyclic ring is fused to a benzene ring or a 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 does not include any The term "substituted cycloalkyl" refers to, but is not limited in any way to, a monocyclic or polycyclic alkyl group 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, and 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 containing carbon and hydrogen, which 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 variables that are independently applied vary 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 a chemical moiety such as, for example, a substituted imidazoline, a substituted spiro-indolinone, a substituted pyrrolidine, a substituted piperidinone, a substituted morpholinone, a substituted pyrrolopyrimidine, a substituted imidazolopyridine, a substituted thiazoloimidazoline, a substituted pyrrolopyrrolidinone, and a substituted isoquinolinone.

[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 still additional embodiments, the MLM comprises structural features as found 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 / morphulinone 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 formulas (A-1) to (A-8) is carbon, oxygen, sulfur, sulfoxide, sulfone, and NR a is selected from the group consisting of R a are independently H or an alkyl group having 1 to 6 carbon atoms; Y and Z in formulas (A-1) to (A-8) are independently carbon or nitrogen; A, A' and A'' in formula (A-1) to formula (A-8) are independently selected from C, N, O or S, or may be 1 or 2 atoms forming a fused bicyclic ring or forming a 6,5- and 5,5-fused aromatic bicyclic group; R1 and R2 in formulas (A-1) to (A-8) are independently selected from the group consisting of aryl groups or heteroaryl groups, and the heteroaryl group has one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group is It may be monocyclic or bicyclic, and may be unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons, amide containing 2 to 6 carbons, and dialkylamine containing 2 to 6 carbons; R3 and R4 in formulas (A-1) to (A-8) are independently selected from the group consisting of H, methyl, and C1 to C6 alkyl; R5 in formulas (A-1) to (A-8) is selected from the group consisting of an aryl group or a heteroaryl group, the heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl group or heteroaryl group may be monocyclic or bicyclic, or may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of: Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy containing 1-6 carbons, fluorine-substituted alkoxy containing 1-6 carbons, sulfoxide containing 1-6 carbons, sulfone containing 1-6 carbons, ketone containing 2-6 carbons, amide containing 2-6 carbons, dialkylamine containing 2-6 carbons, alkyl ether (C2-C6), alkyl ketone (C3-C6), morpholinyl, alkyl ester (C3-C6), alkyl cyanide (C3-C6); R6 in formulas (A-1) to (A-8) is H or -C(=O)R b where: R in formulas (A-1) to (A-8) b is alkyl, cycloalkyl, mono-, di- or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl, 4-NR c -morpholinyl, 4-R c -1-piperidinyl, and 3-R c -1-piperidinyl, wherein R in formulas (A-1) to (A-8) c is alkyl, fluorine-substituted alkyl, cyanoalkyl, hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amidoalkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, mono-, di- and tri-substituted aryl or heteroaryl, CH2CH2R d , and CH2CH2CH2R d wherein: R in formulas (A-1) to (A-8) d is selected from the group consisting of alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R7 in formulas (A-1) to (A-8) is selected from the group consisting of H, C1 to C6 alkyl, cyclic alkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, and 5- or 6-membered substituted heteroaryl or aryl; R8 in formulas (A-1) to (A-8) is -R e -C(O)-R f , -R e -alkoxy, -R e -aryl, -R e -heteroaryl, and -R e -C(O)-R f -C(O)-R g wherein: R in formulas (A-1) to (A-8) e is an alkylene containing 1 to 6 carbons or a bond; R in formulas (A-1) to (A-8) f is a substituted 4- to 7-membered heterocycle, R in formulas (A-1) to (A-8) g is selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocycle; R9 in Formulas (A-1) to (A-8) is selected from the group consisting of one, two, or three substituents on the fused bicyclic aromatic ring in Formula (A-3), and the substituents are independently selected from the group consisting of halogen, alkene, alkyne, and alkyl, substituted or unsubstituted with Cl or F; R in formulas (A-1) to (A-8) 10 is a group consisting of aryl 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 unsubstituted or substituted with 1 to 3 substituents including halogen, F, Cl, -CN, alkene, alkyne, C1-C6 alkyl group, C1-C6 cycloalkyl, -OH, alkoxy containing 1 to 6 carbons, fluorine-substituted alkoxy containing 1 to 6 carbons, sulfoxide containing 1 to 6 carbons, sulfone containing 1 to 6 carbons, ketone containing 2 to 6 carbons; R in formulas (A-1) to (A-8) 11 is -C(O)-N(R h )(R i ) where R h and R i is selected from the group consisting of: H, C1-C6 alkyl, alkoxy-substituted alkyl, sulfone-substituted alkyl, aryl, heteroaryl, mono-, di- or tri-substituted aryl or heteroaryl, alkylcarboxylic acid, heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted alkylcarboxylic acid, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl, R in formulas (A-1) to (A-8) h and R i are independently selected from the group consisting of H, 4-hydroxycyclohexane, monohydroxy and dihydroxy substituted alkyl (C3-C6), 3-hydroxycyclobutane, phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic acid, which are joined to form a ring; R in formulas (A-1) to (A-8) 12 and R 13 are independently selected from H, lower alkyl (C1-C6), lower alkenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4-, 5-, and 6-membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl, and heteroaryl; R 12 and R 13may be joined to form 5- and 6-membered rings with or without ring substitution; R in formulas (A-1) to (A-8) 14 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl; R in formulas (A-1) to (A-8) 15 is CN, R in formulas (A-1) to (A-8) 16 is C1-C6 alkyl, C1-C6 cycloalkyl, C2-C6 alkenyl, C in which one or more hydrogen atoms are replaced by fluorine atoms. 1~6 Alkyl or C 3~6 Cycloalkyl, alkyl or cycloalkyl in which one CH2 is replaced by S(=O), -S or -S(=O)2, alkyl or cycloalkyl in which a terminal CH3 is replaced by S(=O)2N(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O)2(alkyl), -C(=O)2(alkyl), -O(alkyl), C1-C6 alkyl or alkyl-cycloalkyl in which a hydrogen is replaced by a hydroxyl group, 3-7 membered cycloalkyl or heterocycloalkyl optionally containing a -(C=0)- group, or 5-6 membered aryl the heterocycloalkyl or heteroaryl group can contain 1 to 3 heteroatoms independently selected from O, N, or S; the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group can be unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, hydroxylated C1-C6 alkyl, thioether-containing C1-C6 alkyl, ether, sulfone, sulfoxide, fluorine-substituted ether, or cyano; R in formulas (A-1) to (A-8) 17 is (CH2)nC(O)NR k R lwherein R k and R l is H, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxyalkyl, C1-C6 alkyl in which one or more hydrogens are replaced by fluorine, C1-C6 alkyl in which one carbon is replaced by S(O), S(O)(O), C1-C6 alkoxyalkyl in which one or more hydrogens are replaced by fluorine, C in which hydrogen is replaced by a cyano group 1~6 Alkyl, 5- and 6-membered aryl or hetero and independently selected from alkyl, alkylaryl having an alkyl group containing 1 to 6 carbons, and alkylheteroaryl having an alkyl group containing 1 to 6 carbons, wherein the aryl or heteroaryl group can be further substituted; R in formulas (A-1) to (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 in formulas (A-1) to (A-8) 19 is selected from the group consisting of aryl, heteroaryl, and bicyclic heteroaryl, and these aryl and heteroaryl groups can be substituted with halogen, C1-C6 alkyl, C1-C6 cycloalkyl, CF3, F, CN, alkyne, alkylsulfone, and the halogen substitution can be mono-, di-, or tri-substituted; R in formulas (A-1) to (A-8) 20 and R 21 is independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, hydroxylated C1-C6 alkoxy, and fluorine-substituted C1-C6 alkoxy, wherein R 20 and R 21 may be further linked to form 5-, 6-, and 7-membered rings or heterocycles, which may be further substituted; R in formulas (A-1) to (A-8) 22 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 cycloalkyl, carboxylic acid, carboxylic ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea, and nitrogen-containing 5-membered heterocycle, which may be further substituted with C1-C6 alkyl, alkoxy, fluorine-substituted alkyl, CN, and alkylsulfone; R in formulas (A-1) to (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, and -N(alkyl)-heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with halogen, C1-C6 alkyl, hydroxylated C1-C6 alkyl, cycloalkyl, fluorine-substituted C1-C6 alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide; R in Formulas (A-1) to (A-8) 24 is -CH2-(C 1-6 -alkyl), -CH-cycloalkyl, -CH-aryl, CH-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 formulas (A-1) to (A-8) 25 is C 1-6 Alkyl, C 1-6selected 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 may be substituted with C1-C6 alkyl, fluorine-substituted C1-C6 alkyl, alkoxy, aryl and heteroaryl groups; R in formulas (A-1) to (A-8) 26 is C 1-6 Alkyl, C 3-6 cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)-alkyl, and -S(O)-alkyl; R in formulas (A-1) to (A-8) 27 is selected from the group consisting of aryl, heteroaryl, and bicyclic heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with C1-C6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or -CN, and the substitutions may be independently mono-, di-, and tri-substituted; R in formulas (A-1) to (A-8) 28 is 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, wherein 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 formulas (A-1) to (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 in Formula (A-1) to Formula (A-8) f and R g The heterocycle in the formula (I) is a substituted pyrrolidine, a substituted piperidine, or a 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 to 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'', R1, R2, R3, R4, R5, R6, R b , R c , R d , R7, R e , R f , R g , R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R k , R l , R18 , 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 in the present specification with respect to formulas (A-1) to (A-8).

[0460] In certain embodiments, the present specification provides bifunctional or chimeric molecules having the following 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, 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, Formula A-1-1 to Formula A-1-4 (i.e., A-1-1, A-1-2, A-1-3, and A-1-4) R1' and R2' are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF3, and NO2; R3' is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, and -OCH(CH3)2; R4' in A-1-1 to A-1-4 is H, halogen, -CH3, -CF3, -OCH3, -C(CH3)3, -CH(CH3)2, -cyclopropyl, -CN, -C(CH3)2OH, -C(CH3)2OCH2CH3, -C(CH3)2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CH2OCH2CH2OH, -C(CH3)2C selected from the group consisting of H2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C(CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O2)CH2CH3, -NHC(CH3)3, -N(CH3)2, pyrrolidinyl, and 4-morpholinyl; R5' in Formulae A-1-1 to A-1-4 is selected from the group consisting of halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1-pyrrolidinyl, -NH2, -N(CH3)2, and -NHC(CH3)3; and R6' in formulae A-1-1 to A-1-4 is selected from the structures represented below, where the linker attachment point is indicated as "*".

[0463] Aside from R6' as the 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 certain embodiments, 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, the 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 component 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, -NO2, ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C 1-6 Alkyl and other C 1-6 Alkenyl and C 1-6 alkynyl, monosubstituted, disubstituted or trisubstituted; 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 formulae A-4-1 to A-4-6 is selected from the group consisting of H, —OCH 3 , —OCH 2 CH 3 , and halogen; R10' and R11' in formulas A-4-1 to A-4-6 are H, (CH2) n -R', (CH2) n -NR'R'', (CH2) n -NR'COR'', (CH2) n -NR'SO2R'', (CH2) n -COOH, (CH2) n -COOR', (CH) n -CONR'R'', (CH2) n -OR', (CH2) n -SR', (CH2) n -SOR', (CH2) n -CH(OH)-R', (CH2) n -COR', (CH2) n SO2R', (CH2) n -SONR'R'', (CH2) n SO2NR'R'', (CH2O ) m -(CH2) n -R', (CH2CH2O) m -(CH2) n -OH, (CH2CH2O) m -(CH2) n -OR', (CH2CH2O) m -(CH2) n -NR'R'', (CH2CH2O) m -(CH2) n -NR'COR'', (CH2CH2O) m (CH2) n -NR'SO2R', (CH2CH2O) m (CH2) n -COOH, (CH2 CH2O)m (CH2) n -COOR'、(CH2CH2O) m -(CH2) n -CONR'R''、(CH2CH2O) m -(CH2) n SO2R'、(CH2CH2O) m -(CH2) n -COR'、(CH2CH2O) m -(CH2) n -SONR'R''、(CH2CH2O) m -(CH2) n SO2NR'R''、(CH2) p -(CH2CH2 Oh) m -(CH2) n R'、(CH2)p-(CH2CH2O) m -(CH2) n -OH、(CH2) p -(CH2CH2O) m -(CH2) n -OR',(CH2) p -(CH2CH2O) m -(CH2) n -NR'R''、(CH2) p -(CH2CH2O) m -(CH2) n -NR'COR''、(CH2) p -(CH2CH2O) m -(CH2) n -NR'SO2R''、(CH2) p -(CH2CH2O) m -(CH2) n -COOH、(CH2) p -(CH2CH2O) m -(CH2) n -COOR'、(CH2) p -(CH2CH2O) m -(CH2) n -CONR'R''、(CH2)p-(CH2CH2O) m -(CH2) n SO2R'、(CH2) p -(CH2CH2O) m -(CH2) n-COR', (CH2) p -(CH2CH2O) m -(CH2) n -SONR'R'', (CH2) p -(CH2CH2O) m -(CH2) n SO2NRR'', aryl-(CH2) n -COOH, and heteroaryl-alkyl-CO-alkyl-NR'R''m (wherein alkyl can be substituted with OR'), and heteroaryl-(CH2) n -heterocycle, wherein the heterocycle can be optionally substituted with alkyl, hydroxyl, COOR', and COR', wherein R' and R'' are selected from H, alkyl, alkyl substituted with halogen, hydroxyl, NH, NH(alkyl), N(alkyl), oxo, carboxy, cycloalkyl, and heteroaryl; and m, n, and p are independently 0-6; R12' in formulae A-4-1 to A-4-6 is selected from the group consisting of -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl), -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl), -S(O)-(alkyl), S(O)-(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, alkyl, alkoxy, etc. may be 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 regions within the MLM may be coupled to a linker "L," which is then attached to a target protein ligand "PTM" to construct a PROTAC.

[0475] Examples of MDM2 binding moieties include, but are not limited to: 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 compounds described below in "Ute to chemical proteomics," Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908 The compounds identified include (or include in addition to) 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, with 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 -(L-MLM) group is, for example, or attached as a hydroxyl group). 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 formulas (a) to (e) is independently selected from the group consisting of CH, CHR, C=O, SO, NH, and N-alkyl; X in formula (a) to formula (e) is independently selected from the group consisting of O, S, and H2; Y in formulas (a) to (e) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (e) is independently selected from the group consisting of O, S, and H2, provided that both X and Z cannot be H2; G and G' in formula (a) to formula (e) are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (e) represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A in formulas (a) to (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, the following: -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'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, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR 'COR”, -NR'C(=N-CN)NR'R”, -C(=N-CN)NR'R”, -NR'C(=N-CN)R”, -NR'C(=C-NO2)NR'R”, -SO2NR 'COR', -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, and -OCF3 R' and R" 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 contains 1 to 4 independent functional groups, optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl can be substituted with halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms. 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 formulas (a) to (e) is independently selected from the group consisting of CH, CHR, C=O, SO, NH, and N-alkyl; X in formula (a) to formula (e) is independently selected from the group consisting of O, S, and H2; Y in formulas (a) to (e) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z in formula (a) to formula (e) is independently selected from the group consisting of O, S, and H2, provided that both X and Z cannot be H2; G and G' in formula (a) to formula (e) are independently selected from the group consisting of H, alkyl (linear, branched), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (e) represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A in formulas (a) to (e) is independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, H, and F; R in formulas (a) through (e) includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -hetaryl, -alkyl (linear, branched, or 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, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, and -OCF3 R' and R" 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)-(e) contains 1 to 4 independent functional groups, optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl can be substituted with halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 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 independently selected from the group consisting of CH2, C=O, NH and N-alkyl; R in formula (g) is independently selected from H, methyl, alkyl (e.g., C1-C6 alkyl (straight chain, branched, optionally substituted)); In equation (g),

[0495] [ka]

[0496] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and Rn in formula (g) contains 1 to 4 independently selected functional groups, optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl can be substituted with halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 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 Formulas (a)-(g) can independently be 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 group consisting of:

[0510] [ka]

[0511] [ka]

[0512] During the ceremony, W in formulas (h) to (ab) is independently selected from CH, CHR, C=O, SO, NH and N-alkyl; Q1, Q2, Q3, Q4, and Q5 in formulas (h) to (ab) are independently R', N, or N- represents a carbon C substituted with a group independently selected from: R in formula (h) to formula (ab) 1is selected from H, CN, C1-C3 alkyl, R in formula (h) to formula (ab) 2 is selected from the group consisting of H, CN, C1-C3 alkyl, CHF2, CF3, and 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 formulas (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 formulas (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 or double bond, and The CLM is covalently attached 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, 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 group (e.g., Q1, Q2, Q3, Q4, or Q5) to a PTM, chemical linker group (L), ULM, CLM, CLM′, or combination thereof.

[0516] In any of the embodiments described herein, CLM or CLM′ is selected from W, X, R, R of formula (h) to formula (ab). 1 , R 2 , R 3 , R 4 , R 5 , R', Q1, Q2, Q3, Q4, and Q5 to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof.

[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', Q1, Q2, Q3, Q4, and Q5 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.

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

[0519] [ka]

[0520] During the ceremony, W in formulas (ac) to (an) is independently selected from the group consisting of CH, CHR, C=O, SO, NH and N-alkyl; R in formula (ac) to formula (an) 1 is selected from the group consisting of H, CN, and C1-C3 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 or 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 in formula (ac) to formula (an) 1 , R 2 , Q1, Q2, Q3, Q4, 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 , Q1, Q2, Q3, Q4, 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, Q1, Q2, Q3, Q4, and Rn of Formulas (ac) through (an) 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] where R' is a halogen and R 1 is as described above for formulas (h) to (ab) or formulas (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] wherein R' is a halogen. Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM and comprises the following chemical structure of ULM-a:

[0533] [ka]

[0534] During the ceremony, The dashed line indicates the 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 2are bond, O, and NR, respectively. Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO; 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 P are 1, 2 or 3 groups, each of which is H, halo, -OH, C 1-3 independently selected from the group of alkyl, Formula ULM-a W 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 are each H, a straight or branched chain C-C alkyl group optionally substituted with one or more halo or -OH groups, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO2, N(R Y3 R Y4 )C=O, N(R Y3 R Y4)C=S,N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO2, and T of formula ULM-a is independently selected from the group consisting of X 1 is covalently bound to Formula ULM-a W 4 is an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or optionally substituted -NR 1 -T-heterocycle, wherein -NR 1 is X 2 is covalently bonded to R 1 is H or CH3, preferably H.

[0535] In any of the embodiments described herein, T is optionally substituted alkyl, —(CH) n - groups, wherein each one of the methylene groups is selected from the group consisting of a halogen , methyl, a straight or branched C1-C6 alkyl group optionally substituted with one or more halogen or -OH groups, or an optionally substituted amino acid side chain, 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 5is selected from the group of phenyl or 5-10 membered heteroaryl; R in the formula ULM-a 15 H, halogen, CN, OH, NO2, N, R 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 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: 4 Substituents may also be present in the specified compounds disclosed herein. 4 Substituents are also specifically included (without limiting them 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 is optionally substituted with a group. 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 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 a ULM.

[0542] In certain embodiments, the ULM is VHL and is represented by the following 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 R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R in 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 formula ULM-b 12 is selected from the group of H or optionally substituted alkyl; R in formula ULM-b 13is 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 formula ULM-b 14a、 R 14b are 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, and R of formula ULM-b 15 H, halogen, CN, OH, NO2, N, R 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; (each optionally substituted); R in 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 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 the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to 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 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, R1 of formula ULM-c, formula ULM-d, and formula ULM-e is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R of formula ULM-c, formula ULM-d, and formula ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R of 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, or C=O; R3 of formula ULM-c, formula ULM-d, and formula ULM-e 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 linking at least one PTM or ULM', or both, to ULM.

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

[0561] [ka]

[0562] During the ceremony, R in the formula ULM-f14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f is H; R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 teeth,

[0563] [ka]

[0564] or optionally substituted heteroaryl; p of the formula ULM-f 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, halogens, 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 wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to 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 comprises an ester-linked prodrug moiety.

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

[0579] [ka]

[0580] During the ceremony, ULM-g R 1’ is an optionally substituted C1-C6 alkyl group, optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6) alkyl group, optionally substituted (CH2) n-WCOCW-(C0-C6) alkyl groups containing an epoxide moiety WCOCW, where each W is independently H or a C1-C3 alkyl group, optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)—(C1-C6 alkyl), optionally substituted —(CH2) n NHC(O)-R1, optionally substituted -(CH2) n C(O) -NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), optionally substituted —(CHO) n COOH, optionally substituted -(OCH2) n O—(C1-C6 alkyl), optionally substituted —(CHO) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O)-R1, optionally substituted -(CHO) n C(O)-NR1R2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2) n O-(C1-C 6アルキル ), optionally substituted -(CH2CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) n NHC(O)-R1, optionally substituted -(CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), R1 and R2 of ULM-g are each independently H or a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine); ULM-g R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or -(CH2) m is an NR1R2 group, X and X' of ULM-g are each independently CO, CS, -S(O), or S(O)2 (preferably, both X and X' are C=O); ULM-g R 2’ is an optionally substituted -(CH2) n -(C=O) u (NR1) v ( SO2) w Alkyl groups, optionally substituted -(CH2) n -(C=O) u (NR1) v ( SO2) w NR 1N R2N group, optionally substituted -(CH2) n -(C=O) u (NR1 ) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR1 ) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -(C=O) v N R1(SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1)v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) 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) n - (O) u (NR1) v (SO2) w -alkyl, optionally substituted -(CH2) n -C( O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -(CH2) n - C(O) u (NR1) v (SO2) w -NR1C(O)R1N , optionally substituted -(C H2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted- NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O)u (NR1) v (SO2) w -heterocycle, optionally substituted -O-(CH2)n-(C =O) u (NR1) v (SO2) w -Alkyl, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted —O—(CH2)n—(C═O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted —O—(CH2)n—(C═O) u (NR1) v (SO2) w -aryl, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl or optionally substituted -O-(CH) n -(C=O) u (NR1) v (SO2) w -heterocycle;-(CH2) n -(V) n’ -(CH2) n -(V) n’ - alkyl group, optionally Substituted with -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, any optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -Heteroary an optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -Complex ring’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -alkyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl group, optionally substituted -(CH) 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 are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups or up to three halogen groups, or optionally substituted -(CH2) n -aryl, -(CH2) n -heteroaryl, or -(CH2) n -heterocyclic group, V of ULM-g is O, S or NR1; R1 of ULM-g is the same as above, R1 and R of ULM-g 1’ are each independently H or a C1-C3 alkyl group, and X in ULM-g R2’ and X R3’ are each independently an optionally substituted —(CH) n -, -(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n-CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group, wherein X v is H, halo, or an optionally substituted C1-C3 alkyl group; Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; each m' in ULM-g is independently 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w in ULM-g is independently 0 or 1; and ULM-g R 1’ , R 2’ , R 3’ wherein any one or more of X and X' are optionally modified to be covalently linked to the PTM group through a linker group if the PTM is not a ULM', and R of each of the ULM and ULM' if the PTM is a ULM'. 1’ , R 2’ , R 3’ Any one or more of X, X, and 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′, are each independently a group according to the following chemical structure, or a pharmaceutically 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) group, more 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 of the ULM and ULM' if the PTM is a ULM'. 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 pharmaceutically 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’ , 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 of the ULM and ULM' if the PTM is a ULM'. 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 representing a prodrug form of the active compound. 1’ Examples of groups include, for example, -(CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), or optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), 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, and the hydroxyl group, carboxylic acid group, or amine 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) or —S(O) groups, more preferably C═O groups; ULM-g~ULM-i R 2’ is preferably an optionally substituted —NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or optionally substituted -NR 1 -T-heterocycle, wherein R 1 is H or CH, preferably H, and T is optionally substituted -(CH) n - group, wherein each one of the methylene groups one of the groups is optionally substituted with one or two substituents, preferably selected from halogen, an amino acid side chain as otherwise described herein, or a C1-C3 alkyl group, preferably one or two methyl groups, which may be optionally substituted, and n is 0 to 6, e.g., 0, 1, 2, or 3, such as 0 or 1. Alternatively, T may also be -(CHO) n -group, -(OCH2)n - group, -(CH2CH2O) n - group, -(OCH2CH2) 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 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 di-alkylamine (preferably dimethylamine), F, Cl, OH, COOH, a C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2 or CN group, each of which may be in the ortho-, meta-, and / or para-position of the phenyl ring, preferably and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, a methyl-substituted phenyl group, an optionally substituted phenyl group (which itself is optionally attached to a PTM via a linker group (including a ULM' group)), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, a methyl-substituted phenyl group, an optionally substituted phenyl group, an optionally substituted phenyl group (which itself is optionally attached to a PTM via a linker group (including a ULM' group)), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, a methyl-substituted phenyl group, an optionally ... optionally substituted oxazoles including substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methyl imidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyldiazole groups, methyl substituted optionally substituted triazole groups, including triazole groups bonded to a phenyl group, optionally substituted pyridine groups, including halo- (preferably F) or methyl-substituted pyridine groups or oxapyridine groups (wherein the pyridine group is bonded 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 substituted groups 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally being 1 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 C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or a heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidines, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and Each n 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 optionally be 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 the basis, 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 following 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 HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally being 1 a heterocycle optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, 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 YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1-C6 alkyl and an acetylene group, each of which groups 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 groups 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, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2are each independently H, an optionally substituted C1-C3 alkyl group, 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 each group 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 any of the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and the drawings accompanying this specification. 2’ Substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). These R 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, an optionally substituted -T- 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 a C1-C3 alkyl group, preferably H or CH3, T is an optionally substituted -(CH2 ) n - group, wherein each one of the methylene groups is optionally substituted with one or two substituents, preferably selected from halogen, a C1-C6 alkyl group (linear, branched, optionally substituted), or the side chain of an amino acid as otherwise described herein, preferably methyl, optionally substituted, and n is 0 to 6, e.g., 0, 1, 2, or 3 (such as 0 or 1). Alternatively, T can also be -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O)n - group, -(OCH2CH2) 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 linked to linker groups and / or halogens (preferably F or Cl), amines, mono- or dialkylamines (preferably dimethylamine), amide groups (preferably -(CH2) m -NR1C(O)R2 group, where m, R1 and and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN or S(O)2R S Group(R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or (CH2) mNR1R2 groups), each of which may be substituted at the ortho-, meta-, and / or para-positions (preferably the para-position) of the phenyl ring, or 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 substituted with at least one of F, Cl, OH, SH, COOH, CH, CF, OMe, OCF, NO, CN, or a linker group attached to a PTM group (including a ULM′ group), with the substitution occurring 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 those described above, an optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, optionally substituted thiazole, including methyl-substituted thiazole, optionally substituted pyrrole, including methyl-substituted pyrrole, methylisothiazolinone ... midazole, optionally substituted imidazole including benzylimidazole or methoxybenzylimidazole, oximidazole or methyloximidazole, optionally substituted diazole group including methyldiazole group, optionally substituted triazole group including methyl-substituted triazole group, pyridine group including halo (preferably F) or methyl-substituted pyridine group or oxapyridine group (the pyridine group is bonded to the phenyl group by oxygen), or optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane). Each aryl, heteroaryl, or heterocycle group may optionally be 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 m -O-C1-C6 alkyl group, or optionally substituted (CH2) m -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (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 HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group that is H or a C1-C6 alkyl group (preferably C1-C3 alkyl), and R of ULM-g to ULM-i SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), and R of ULM-g through ULM-i is URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), and each group is optionally substituted with one or two hydroxyl groups or up to three 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 to ULM-i is C is N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group that is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl). Each of said heteroaryl groups can optionally be 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] basis, During the ceremony, ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or a heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidines, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, 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), and each of said heterocyclic groups can optionally be 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 any of the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and the drawings accompanying this specification. 3’ Substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). These R 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 through ULM-i 2’ is an optionally substituted -NR1-X R2’ -Alkyl group, -NR1-X R2’ -aryl group; optionally substituted -NR1-X R2’ -HET, optionally substituted -NR1-X R2’-aryl-HET or optionally substituted -NR1-X R2’ -HET-aryl, wherein R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H), ULM-g~ULM-i X R2’ is an optionally substituted -(CH2) n -, -(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CHCHO) n -, or a C3-C6 cycloalkyl group, and X in ULM-g to ULM-i v is H, halo, or optionally one or two hydroxyl groups. a silyl group or a C1-C3 alkyl group substituted with up to three halogen groups; The alkyl of ULM-g to ULM-i is optionally substituted C1-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); Aryl in ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group), and HET of ULM-g through ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each is preferably substituted with a C1-C3 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group that is H or a C1-C6 alkyl group (preferably C1-C3 alkyl), and R of ULM-g to ULM-i SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally being 1 Heterocycles substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or optionally substituted, 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 CRYC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1-C6 alkyl an acetylene group, which is an alkyl group (preferably C1-C3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl, or a heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidines, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0619] Each of the foregoing groups may optionally be 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 through ULM-i 3’ is an optionally substituted -(CH2)n -(V) n’ -(CH2) n -(V) n’ -R S3’ Ki, Ren optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -R S3’ group, optionally substituted -X R3’ -Alkyl group, optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or optionally substituted -X R3’ -HET-aryl group, During the ceremony, R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), an optionally substituted aryl group or a HET group; R 1’ is H or a C1-C3 alkyl group (preferably H), V is O, S or NR 1’ and X R3’ is -(CH2) n -, -(CH2CH2O) n -, -(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, or C 3-C6 cycloalkyl groups, all of which are optionally substituted; X v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; Alkyl is an optionally substituted C-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); 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, indole, azaindolizine, azaindolizine, quinoline (each, if substituted, preferably substituted with a C1-C3 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally being 1 heterocycles substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or optionally substituted, 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 is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1-C6 alkyl an acetylene group, which is an alkyl group (preferably C1-C3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or is an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably a methyl group, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, 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' in ULM-g to ULM-i is 0 or 1, and Each n' in ULM-g to ULM-i is 0 or 1, wherein each of said compounds, preferably on an alkyl group, aryl group 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 -(CH2) n -a Reel, -(CH2CH2O) n -aryl, -(CH2) n -HET or -(CH2CH2O) n -HET, During the ceremony, The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, and the substituents are preferably —(CH) n OH, itself CN, halo (up to 3 halo groups), OH, -(CH2) nselected from C1-C6 alkyl optionally further substituted with O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) amine, wherein 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) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) amine, where the alkyl group on the amine is substituted with one or two hydroxyl groups, or up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted with -(CH2) n -(V) m’ -(CH2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG Based on optionally substituted, wherein V is O, S, or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), and R PEG is H or an optionally substituted C1-C6 alkyl group (including one optionally substituted with a carboxyl group), or the aryl groups of ULM-g through ULM-i are optionally substituted with a heterocycle, including heteroaryl, selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (each of which, when substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally being 1 heterocycles substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or optionally substituted, 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 is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1-C6 alkyl an acetylene group, which is an alkyl group (preferably C1-C3 alkyl), ULM-g~ULM-i R PROis H, optionally substituted C1-C6 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 a heterocyclic group selected from the group consisting of benzofuran, indole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; The HET of ULM-g through ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 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 HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally being 1 Heterocycles 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 YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C 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 C1-C6 alkyl an acetylene group, which is an alkyl group (preferably C1-C3 alkyl), ULM-g~ULM-i R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; Each m' in 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 pharmaceutically 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-CH2-aryl-HET- (preferably methyl substituted) a phenyl bonded directly to a thiazole bonded to a ULM-i R 3’ is -CHR CR3’ -NH-C(O)-R 3P1 group or -CHR CR3’ -R 3P2 It is the basis, ULM-i R CR3’ is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl; ULM-i R 3P1 is a C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably a methyl-substituted —(CH2) n OCH3 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 the basis, The aryl of ULM-i is phenyl, HET of ULM-i is an optionally substituted thiazole or isothiazole; and ULM-i R HET is H or a halo group (preferably H) 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 pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof:

[0636] [ka]

[0637] During the ceremony, each R5 and R6 of ULM-j is independently OH, SH, or optionally substituted alkyl, or R5, R6 and the carbon atom to which they are attached form a carbonyl; R7 of ULM-j is H or optionally substituted alkyl; E of ULM-j is a bond, C=O, or C=S, G of ULM-j is a bond, optionally substituted alkyl, —COOH, or C═J; J of ULM-j is O or N-R8, R8 of ULM-j is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, a heterocyclic substituted with

[0638] [ka]

[0639] and R9 and R of ULM-j 10 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl, or R, R 10and 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 of ULM-j 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl; ULM-j R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R of ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; Each R of ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 the groups can together form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH, Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; and The o in ULM-j is 0, 1, 2, 3, or 4.

[0642] In certain embodiments, G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and o is 0.

[0643] In certain embodiments, G of ULM-j is C=J, J is O, R7 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] 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] 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, where J is O, R7 of ULM-k 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 of ULM-k 17is 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, where J is O, R7 of ULM-k is H, Each R of ULM-k 14 is H, o of ULM-k is 0, and ULM-k R 15 is selected from the group consisting of:

[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 has 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 q of ULM-k 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 21is 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 11 is 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 in ULM-1 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 R9 of ULM-l is H, ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted 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 13is 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; R9 of ULM-m is H, R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or is 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 R9, R 10 , and R11 is as defined above. In other examples, R9 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 pharmaceutically 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] [ka]

[0703] [ka]

[0704] [ka]

[0705] [ka]

[0706] [ka]

[0707]

change

[0708]

change

[0709]

change

[0710]

change

[0711]

change

[0712]

change

[0713]

change

[0714]

change

[0715]

change

[0716]

change

[0717] [ka]

[0718] [ka]

[0719] [ka]

[0720] [ka]

[0721] [ka]

[0722] [ka]

[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, compounds described herein comprise 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 L1… (A L ) q -or-(A L ) q -), A1 is a group attached to the PTM, and (A L ) q is a group linked to ULM.

[0725] In certain embodiments, the linker group L is -(A L ) q - selected from (A L ) q is a group attached to a ULM moiety, a PTM moiety, or a combination thereof, and q in the linker is an integer greater than or equal to 1; Each A L is a bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , optionally 0 to 6 R L1 and / or R L2 C substituted with a group 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with a group 5-13 spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with a group 3-11 Heterocyclyl, optionally 0 to 8 R L1 and / or RL2 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 group, wherein R L1 or R L2 are each independently optionally bonded to other groups and optionally have 0 to 4 R L5 Cycloalkyl and and / or heterocyclyl moieties, and R L1 , R L2 , R L3 , R L4 and R L5 are independently H, halo, and C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[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, and A L 1 and (A L ) q are linked via a structural unit of a linker (L).

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

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

[0730] In certain embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(lower alkoxyl)-OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocycle)-CH 2、 -NR(CH2CH2) n -(heterocyclic)-(complex -N(R1R2)-(heterocycle)-CH2, -N(R1R2)-(heterocycle)-CH2; n of 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)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;-N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q-O(CH2) r -OCH2-;

[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] Here, each of m and n of 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] wherein 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] [ka]

[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]

change

[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, C-C alkyl (straight chain, branched, optionally substituted), C-C alkoxy (straight chain, branched, optionally substituted), or two R that together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms. Q It is the basis, Y L1 are each independently a bond, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms are substituted by O, or C1-C6 alkoxy (linear, branched, optionally substituted); n is 0 to 10, and Dashed lines indicate points of attachment to 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 L2are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally containing R Q Each R is replaced by Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-C6 alkyl (straight chain, branched chain, optionally substituted), C1-C6 alkoxy (straight chain, branched chain, optionally substituted), OC 1-3 Alkyl (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN, or two R that together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms Q It is the basis, Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms are substituted by O, C1-C6 alkoxy (linear, branched, 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 is replaced by Q are independently H, C 1~6 Alkyl (straight chain, branched chain, optionally with one or more halo, C 1-6 alkoxyl), or two R that together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms Q It is the basis, R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight chain, branched chain, optionally with one or more halo, C 1-6substituted with alkoxyl), or R that together with the atoms 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 Dashed lines indicate points of attachment to 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, and 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 bonding) the ULM and the PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

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

[0805] [ka]

[0806] X is selected from the group consisting of O, N, S, S(O) and SO2, n is an integer from 1 to 5, 5, and 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; in preferred embodiments of the present 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 for maximal binding of the ULM group to the ubiquitin ligase and maximal 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 targets of the PTM group are 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 to be able to 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 viruses, bacteria, or fungi, is a target for 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, but are not limited to, the following 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, immunosuppressive 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 pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins 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 by a ubiquitin ligase or degraded by a ubiquitin ligase (e.g., RAF) is a target protein in accordance with the present disclosure. Generally, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, and proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, redox activity, transferase activity, hydrolytic activity, lyase activity, isomerase activity, ligase activity, enzyme regulation activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation 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 transport, nuclear transport, ion transport activity, channel transport activity, carrier activity, permeation activity, secretion activity, and electron transport activity), phagocytosis, chaperone regulation activity, nucleic acid binding activity, transcriptional regulation activity, extracellular integration and biosynthesis activity, and translational regulation activity. Proteins of interest include proteins from eukaryotes (e.g., c-RAF, A-RAF, and / or B-RAF), including humans and other animals as targets for drug therapy, and prokaryotes, including livestock animals, microorganisms for determining targets for antibiotics and other antimicrobial agents, and plants, and particularly 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 the patient would benefit from protein degradation.

[0815] In additional aspects, the present disclosure provides therapeutic compositions comprising an effective amount of a compound described herein or a salt form thereof, a pharmaceutically acceptable carrier, excipient, or vehicle, and, optionally, an additional bioactive agent. The therapeutic compositions can be used to modulate protein degradation in a patient or subject, e.g., an animal, such as a human, and to treat or ameliorate a disease state or condition mediated by the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to induce targeted protein degradation for the treatment or amelioration of diseases, such as cancer, cardio-facial-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, and 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 for treating a pathology or ameliorating a disease symptom or condition in a subject in need thereof by degrading a protein or polypeptide, wherein the pathology or condition is regulated through degradation of 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 described above, optionally in combination with a pharmaceutically acceptable carrier, excipient, or vehicle, and optionally an additional bioactive agent, wherein the composition is effective to treat or ameliorate the disease or disorder or its symptoms in the subject. Using the methods of the present disclosure, many pathologies or conditions can be treated by administering an effective amount of at least one compound described herein, including cancer, cardio-facio-cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, and LEOPARD syndrome. The pathology or condition may be a disease caused by an exogenous factor, such as a microbial organism or a virus (e.g., a murine retrovirus or an avian retrovirus, e.g., avian retrovirus MH2), a bacterium, a fungus, a protozoan, or other microbial agent, or may be a pathology caused by overexpression of a protein and / or the presence of a constitutively activated protein that gives rise to the pathology and / or condition.

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

[0818] The term "target protein" is used hereinafter 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 pharmaceutically 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 via at least one linker group, L, to at least one ULM group (e.g., VLM, CLM, ILM, and / or MLM).

[0819] Target proteins that can be bound to a protein targeting moiety and to which a ubiquitin ligase binding moiety can bind and be degraded by the ligase include any protein or peptide, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, conservation, transport, and signal transduction. More specifically, many drug targets for human therapy are protein targets to which a protein targeting moiety can be bound and incorporated into 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, p38 MAP 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 II, 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 inhibitor, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-activated chloride channel ion 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 positions / presents the protein or polypeptide in proximity to a 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 that specifically target the aryl hydrocarbon receptor (AHR). 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 compositions below exemplify some of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically 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 by reference in their entirety.

[0824] In any aspect or embodiment described herein, the PTM targets and / or binds to 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, C; C, CH, C, N, 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, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof; R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2, where M1 is CH2, 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, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; RPTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2, where M1 is CH2, O and NH and 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 below:

[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 PTM5a is 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-C 6アルキル (straight chain, branched chain, optionally substituted); R PTM6 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH, NHCH, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH, NHCH, or M1-CH2-CH2-M2, where M1 is CH2, O, or NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM8 , R PTM9 or R PTM10 is independently selected from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH, NHCH, or M-CH-CH-M, where M is CH, O, and NH, and M is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; R PTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH, NHCH, or M-CH-CH-M, where M is CH, O, or NH and M is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM8 , R PTM9 or R PTM10is 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 PTM9 is 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 PTM9can 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 may be any of the following PTMs: 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 PTM20 are independently CH or N, R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 are independently selected from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, 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 PTM21is selected from the group consisting of trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH3, NHCH3, dimethylamino, or M1-CH2-CH2-M2, where M1 is CH2, O, or NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM12 , R PTM13 and R PTM16 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 PTM14 and / or R 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 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 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 below:

[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 independently CH or N, R PTM22 teeth,

[0852] [ka]

[0853] is selected from the group consisting of R PTM25a and R PTM25bare each independently selected from hydrogen, halogen, or C1-C6 alkyl (linear, branched, optionally substituted); R PTM23 , R PTM24 , R PTM28 , R PTM29 , R PTM30 , R PTM31 , R PTM32 is independently selected from the group consisting of absence, a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH, and M2 is hydrogen, alkyl (linear, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted), or heterocycle (optionally substituted); and R PTM25 is absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or SCH3; R PTM26 is absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or SCH3; R PTM27 is selected from the group consisting of absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3 or SCH3, and R PTM24 , R PTM29 or R PTM32 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.

[0854] In some embodiments, R PTM24 is the covalent bond site, R PTM31 and R PTM32 is R PTM31 and RPTM32 and / or R PTM29 and R PTM30 is R PTM29 and R PTM30 has a ring to which They can be linked together via a covalent bond in such a way as to form a bicyclic group.

[0855] In other embodiments, R PTM29 is the covalent bond site, R PTM24 and R PTM32 is R PTM24 and R PTM32 and / or R PTM31 and R PTM32 is R PTM31 and R PTM32 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.

[0856] In a further embodiment, R PTM32 is the covalent bond site, R PTM24 and R PTM29 is R PTM24 and R PTM29 and / or R PTM29 and R PTM30 is R PTM29 and R PTM30 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.

[0857] In any aspect or embodiment described herein, the PTM is selected from the group consisting of chemical structures PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8.

[0858] [ka]

[0859] [ka]

[0860] In any aspect or embodiment described herein, the ULM is selected from the group consisting of:

[0861] [ka]

[0862] [ka]

[0863] In the formula, R 14a is H, methyl or hydroxymethyl. therapeutic composition Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein, and a combination of effective amounts of one or more of the compounds otherwise described herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent a further aspect of the present disclosure.

[0864] The present disclosure includes compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein, where applicable. The acids used to prepare pharmaceutically acceptable acid addition salts of the above-described base compounds useful according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, perphosphate, acetate, lactate, citrate, percitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salts, among many others.

[0865] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives disclosed herein. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds, which are acidic in nature, are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other pharmaceutically acceptable organic amines.

[0866] The compounds described herein may be administered orally, parenterally, or topically in single or divided doses in accordance with the present disclosure. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and...

Claims

1. Chemical structure: ULM-L-PTM or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, having the formula: During the ceremony, the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; the PTM is a small molecule that includes a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; L is a bifunctional linking or chemical linking moiety that connects the ULM and the PTM. compound.

2. 2. The bifunctional compound of claim 1, wherein the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog 2 (MDM2) (MLM), and IAP (ILM).

3. the PTM is represented by chemical structure PTM-Ia or PTM-Ib; 【Chemistry 1-1】 【Chemistry 1-2】 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, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, CH, N; 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.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 ＰＴＭ３ is absent, hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH ３ , N.H.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 ＰＴＭ４ is hydrogen, halogen, aryl, methyl, ethyl, OCH ３ , N.H.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 ＰＴＭ５ teeth, 【Chemistry 2】 3. The bifunctional compound according to claim 1 or 2, selected from the group consisting of:

4. the PTM is represented by chemical structure PTM-IIa or PTM-IIb; 【Chemistry 3-1】 【Chemistry 3-2】 During the ceremony, X ＰＴＭ１ , X ＰＴＭ２ , X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ , and X ＰＴＭ６ is independently selected from CH or N; R ＰＴＭ５ is H, 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), an optionally substituted amine, 【Chemistry 4】 、 -NHC(O)R ＰＴＭ５ is selected from the group consisting of R ＰＴＭ５ teeth, 【Chemistry 5】 is selected from the group consisting of R ＰＴＭ６ａ and R ＰＴＭ６ｂ are hydrogen, halogen, or C １ -C ６ independently selected from alkyl (straight chain, branched chain, optionally substituted); R ＰＴＭ６ is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH ３ , N.H.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 ＰＴＭ７ is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH ３ , N.H.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 ＰＴＭ８ , R ＰＴＭ９ Or R ＰＴＭ１０ is absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH ３ , N.H.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.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 ＰＴＭ８ , R ＰＴＭ９ Or R ＰＴＭ１０ 3. The bifunctional compound of claim 1 or 2, wherein 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.

5. R ＰＴＭ９ is the covalent bond position, R ＰＴＭ７ and R ＰＴＭ８ is R ＰＴＭ７ and R ＰＴＭ８ are covalently linked together in such a way as to form a bicyclic group having the ring to which is attached, or R ＰＴＭ８ is a covalent bond site, R ＰＴＭ９ and R ＰＴＭ１０ is R ＰＴＭ９ and R ＰＴＭ１０ are covalently linked together in such a way as to form a bicyclic group having the ring to which is attached, or The bifunctional compound of claim 4, wherein when RPTM10 is a covalent binding position, RPTM8 and RPTM9 are linked together via a covalent bond in such a way as to form a bicyclic group having a ring to which RPTM8 and RPTM9 are attached.

6. the PTM is represented by chemical structure PTM-III; 【Chemistry 6】 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 ＰＴＭ２０ is 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.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.H. ３ , dimethylamino or M1-CH ２ -CH ２ -M2 (wherein M1 is CH ２ , O or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; R ＰＴＭ１２ , R ＰＴＭ１３ and R ＰＴＭ１６ 3. The bifunctional compound of claim 1 or 2, wherein 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.

7. R ＰＴＭ１２ is a covalent bond site, R ＰＴＭ１３ and R ＰＴＭ１４ is R ＰＴＭ１３ and R ＰＴＭ１４ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, and / or ＰＴＭ１５ and R ＰＴＭ１６ is R ＰＴＭ１５ and R ＰＴＭ１６ are linked together via a covalent bond in such a way as to form a bicyclic group having the ring to which is attached, R ＰＴＭ１３ is a covalent bond site, R ＰＴＭ１２ and R ＰＴＭ１６ is R ＰＴＭ１２ and R ＰＴＭ１６ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, and / or ＰＴＭ１５ and R ＰＴＭ１６ is R ＰＴＭ１５ and R ＰＴＭ１６ are covalently linked together in such a way as to form a bicyclic group having the ring to which is attached, or R ＰＴＭ１６ is a covalent bond site, R ＰＴＭ１２ and R ＰＴＭ１３ is R ＰＴＭ１２ and R ＰＴＭ１３ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, and / or ＰＴＭ１３ and R ＰＴＭ１４ is R ＰＴＭ１３ and R ＰＴＭ１４ The compound of claim 6, wherein:

8. the PTM is represented by chemical structure PTM-IVa or PTM-IVb; 【Chemistry 7-1】 【Chemistry 7-2】 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 is independently CH or N; R ＰＴＭ２２ teeth, 【Chemistry 8】 is selected from the group consisting of R ＰＴＭ２５ａ and R ＰＴＭ２５ｂ are hydrogen, halogen, or C １ -C ６ independently selected from alkyl (straight chain, branched chain, optionally substituted); R ＰＴＭ２３ , R ＰＴＭ２４ , R ＰＴＭ２８ , R ＰＴＭ２９ , R ＰＴＭ３０ , R ＰＴＭ３１ , R ＰＴＭ３２ is absent, a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight chain, branched chain, optionally substituted), OCH ３ , N.H.H. ３ or M1-CH ２ -CH ２ -M2 (wherein M1 is CH ２ , O and NH, and M2 is independently selected from the group consisting of hydrogen, alkyl (linear, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted) or heterocycle (optionally substituted); R ＰＴＭ２５ Absent, hydrogen, halogen, C １ -C ６ Alkyl (straight chain, branched chain, optionally substituted), OCH ３ , N.H.H. ３ or SCH ３ is selected from R ＰＴＭ２６ Absent, hydrogen, halogen, C １ -C ６ Alkyl (straight chain, branched chain, optionally substituted), OCH3, NHCH ３ or SCH ３ is selected from R ＰＴＭ２７ is absent, hydrogen, halogen, C １ -C ６ Alkyl (straight chain, branched chain, optionally substituted), OCH ３ , N.H.H. ３ or SCH ３ is selected from the group consisting of R ＰＴＭ２４ , R ＰＴＭ２９ , R ＰＴＭ３２ 3. The bifunctional compound of claim 1 or 2, wherein 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.

9. R ＰＴＭ２４ is the covalent bond position, R ＰＴＭ３１ and R ＰＴＭ３２ is R ＰＴＭ３１ and R ＰＴＭ３２ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, or ＰＴＭ２９ and R ＰＴＭ３０ is R ＰＴＭ２９ and R ＰＴＭ３０ together in such a way as to form a bicyclic group having the ring to which linked via a covalent bond, or R ＰＴＭ２９ is a covalent bond site, R ＰＴＭ２４ and R ＰＴＭ３２ is R ＰＴＭ２４ and R ＰＴＭ３２ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, and / or ＰＴＭ３１ and R ＰＴＭ３２ is R ＰＴＭ３１ and R ＰＴＭ３２ are covalently linked together in such a way as to form a bicyclic group having the ring to which R ＰＴＭ３２ is a covalent bond site, R ＰＴＭ２４ and R ＰＴＭ２９ is R ＰＴＭ２４ and R ＰＴＭ２９ are bonded together via a covalent bond in such a way as to form a bicyclic group having the ring to which R is attached, and / or ＰＴＭ２９ and R ＰＴＭ３０ is R ＰＴＭ２９ and R ＰＴＭ３０ 9. The bifunctional compound of claim 8, wherein:

10. The PTM is selected from the group consisting of PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8: 【Chemistry 9-1】 【Chemistry 9-2】 The bifunctional compound according to any one of claims 1 to 10, selected from the group consisting of:

11. The ULM is 【Chemistry 10-1】 【Chemistry 10-2】 is selected from the group consisting of In the formula, R １４ａ The bifunctional compound according to any one of claims 1 to 10, wherein is methyl or hydroxymethyl.

12. The ULM is a von Hippel-Lindau (VHL) ligase binding moiety (VLM) having the chemical structure represented by: 【Chemistry 11】 During the ceremony, X １ , X ２ are bond, O, and NR, respectively. Ｙ３ , C.R. Ｙ３ R Ｙ４ , C=O, C=S, SO, and SO ２ are independently selected from the group R Ｙ３ , R Ｙ４ are H, straight or branched chain C １－６ Alkyl (optionally substituted with one or more halo), optionally substituted C １～６ Alkoxyl (e.g., optionally having 0 to 3 R Ｐ substituted with a aryl group; R Ｐ are 0, 1, 2 or 3 groups, each of which is H, halo, —OH, C １－３ alkyl, C=O; W ３ is an optionally substituted -T-N(R １ａ R １ｂ ) X ３ , optionally substituted -T-N(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 S.O., 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 ) S.O. ２ are independently selected from the group consisting of T is optionally substituted alkyl, -(CH ２ ) ｎ - groups, wherein each one of the methylene groups is 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; W ４ teeth, 【Chemistry 12】 R １４ａ、 R １４ｂ are each independently selected from the group: H, haloalkyl, or optionally substituted alkyl; W ５ is selected from the group: phenyl or 5-10 membered heteroaryl; R １５ H, halogen, CN, OH, NO ２ , N.R. １４ａ R １４ｂ , OR １４ａ , C.O.R. １４ａ R １４ｂ , N.R. １４ａ C.O.R. １４ｂ , S.O. ２ N.R. 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; 12. The bifunctional compound of claim 1, wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

13. The ULM is 【Chemistry 13】 and a von Hippel-Lindau (VHL) ligase binding moiety (VLM) having the chemical structure represented by During the ceremony, W ３ is optionally substituted aryl, optionally substituted heteroaryl, or 【Chemistry 14】 is selected from the group R 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 １１ is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, 【Chemistry 15-1】 、 【Chemistry 15-2】 or 【Chemistry 15-3】 is selected from the group R １２ is selected from the group of H or optionally substituted alkyl; R 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 １４ａ、 R １４ｂ are each independently selected from the group: H, haloalkyl, or optionally substituted alkyl; W ５ is selected from the group: phenyl or 5-10 membered heteroaryl; R １５ H, halogen, CN, OH, NO ２ , N.R. １４ａ R １４ｂ , OR １４ａ , C.O.R. １４ａ R １４ｂ , N.R. １４ａ C.O.R. １４ｂ , S.O. ２ N.R. 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 １６ is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R １８ is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and 13. The bifunctional compound of any one of claims 1 to 12, wherein 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 linking at least one PTM or ULM', or both, to a ULM.

14. The ULM is 【Chemistry 16】 having a chemical structure selected from the group During the ceremony, R １ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R １４ａ is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R １５ H, halogen, CN, OH, NO ２、 selected from the group consisting of optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl, each of which is optionally substituted; X is C or C=O; R ３ is a bond or an optionally substituted 5- or 6-membered heteroaryl; 14. The bifunctional compound of any one of claims 1 to 13, wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

15. The ULM is 【Chemistry 17】 and a group according to the chemical structure During the ceremony, R １４ａ is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R ９ is H, R １０ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R １１ teeth 【Chemistry 18-1】 ; optionally substituted heteroaryl; 【Chemistry 18-2】 【Chemistry 18-3】 or 【Chemistry 18-4】 ; p is 0, 1, 2, 3, or 4, and Each R １８ is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R １２ is H, C=O, 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; R １５ is H, halogen, Cl, CN, OH, NO ２、 optionally substituted heteroaryl, optionally substituted aryl, 【Chemistry 19】 is selected from the group consisting of 15. The bifunctional compound of any one of claims 1 to 14, wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

16. the ULM comprises a group according to the following chemical structure: 【Chemistry 20】 During the ceremony, ULM-g R １’ is an optionally substituted C １ -C ６ an alkyl group, optionally substituted -(CH ２ ) ｎ OH, optionally substituted -(CH ２ ) ｎ SH, optionally substituted (CH ２ ) ｎ -O-(C １ -C ６ ) alkyl group, optionally substituted (CH ２ ) ｎ -WCOCW- (C ０ -C ６ ) alkyl groups containing an epoxide moiety, WCOCW, 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)-R １ , optionally substituted -(CH ２ O) ｎ C(O)-NR １ R ２ , -(CH ２ CH ２ O) ｎ H, optionally substituted -(CH ２ CH ２ O) ｎ COOH, optionally substituted -(OCH ２ CH ２ ) ｎ O-(C １ -C ６ alkyl), optionally substituted -(CH ２ CH ２ O) ｎ C(O)-(C １ -C ６ alkyl), optionally substituted - (OCH ２ CH ２ ) ｎ NHC(O)-R １ , optionally 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 N.R. １ R ２ It is based on X and X' in ULM-g are each independently C-O, C-S, -S(O), 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 an alkyl group, optionally substituted -(CH ２ ) ｎ -(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ N.R. １Ｎ R ２Ｎ 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 N.R. 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’ a heterocyclic group; optionally substituted; ULM-g R ３’ is optionally substituted alkyl, optionally substituted —(CH ２ ) ｎ - (O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -alkyl, optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １Ｎ R ２Ｎ , optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １ C(O)R １Ｎ , optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -C(O)NR １ R ２ , optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -aryl, optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heteroaryl, optionally substituted -(CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heterocycle, optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -alkyl, optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １Ｎ R ２Ｎ , optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １ C(O)R １Ｎ , optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -aryl, optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heteroaryl, optionally substituted -NR １ - (CH ２ ) ｎ -C(O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heterocycle, optionally substituted -O-(CH ２ ) n-(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -alkyl, optionally substituted -O-(CH ２ ) n-(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １Ｎ R ２Ｎ , optionally substituted —O—(CH ２ ) n-(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -NR １ C(O)R １Ｎ , optionally substituted —O—(CH ２ ) n-(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -aryl, optionally substituted -O-(CH ２ ) ｎ -(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heteroaryl or optionally substituted -O-(CH ２ ) ｎ -(C=O) ｕ (NR １ ) ｖ (SO ２ ) ｗ -heterocycle; -(CH ２ ) ｎ - (V) ｎ’ - (CH ２ ) ｎ - (V) ｎ’ -alkyl group, optionally substituted -(CH ２ ) ｎ - (V) ｎ’ - (CH ２ ) ｎ - (V) ｎ’ -aryl group, optionally substituted -(CH ２ ) ｎ - (V) ｎ’ - (CH ２ ) ｎ - (V) ｎ’ - Heteroa Aryl group, optionally substituted -(CH ２ ) ｎ - (V) ｎ’ - (CH ２ ) ｎ - (V) ｎ’ -Heterocycle ’ group, optionally substituted -(CH ２ ) ｎ -N(R １’ ) (C=O) ｍ’ - (V) ｎ’ -alkyl group, optionally substituted -(CH ２ ) ｎ -N(R １’ ) (C=O) ｍ’ - (V) ｎ’ -aryl group, 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’ a 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 is a heterocyclic group, V in ULM-g is O, S or NR １ and ULM-g R １ is the same as above, ULM-g R １ and R １’ are each independently H or C １ -C ３ is an alkyl group, ULM-g X Ｒ２’ and X Ｒ３’ are each independently an optionally substituted -(CH ２ ) ｎ -, -(CH ２ ) ｎ -CH(X ｖ )=CH(X ｖ ) - (cis or trans), -(CH ２ ) ｎ -CH≡CH-, -(CH ２ CH ２ O) ｎ - or C ３ -C ６ 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' in ULM-g is independently 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w in ULM-g is independently 0 or 1; and ULM-g R １’ , R ２’ , R ３’ Any one or more of X and X' are optionally modified to 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’ 12. The bifunctional compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein any one or more of X, X, and X' are optionally modified and are covalently bonded to each other directly or through a linker group.

17. 12. The bifunctional compound of any one of claims 1 to 11, wherein the ULM is a cereblon E3 ligase binding moiety (CLM) selected from the group consisting of thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

18. The CLM is 【Chemistry 21-1】 、 【Chemistry 21-2】 、 【Chemistry 21-3】 、 【Chemistry 21-4】 、 【Chemistry 21-5】 、 or 【Chemistry 21-6】 having a chemical structure represented by During the ceremony, W is CH ２ , CHR, C=O, SO ２ , NH and N-alkyl; Each X is O, S, or H. ２ are independently selected from the group consisting of Y is CH ２ , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z is O, S and H. ２ is selected from the group consisting of G and G' 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'; Q １ , Q ２ , Q ３ , and Q ４ represents a carbon C substituted with a group independently selected from R′, N or N-oxide; A is independently selected from the group: H, alkyl (straight chain, branched, optionally substituted), cycloalkyl, Cl, and F; R is -CONR'R", -OR', -NR'R", -SR', -SO ２ R', -SO ２ NR'R", -CR'R"-, -CR'NR'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 Including, R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, heterocyclyl, each of which is optionally substituted; 【Chemical 22】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and R ｎ contains 1 to 4 independently selected functional groups, optionally substituted alkoxyl groups, or atoms; In the formula, n is an integer from 1 to 10 (e.g., 1 to 4), When n is 1, R ｎ is modified to be covalently attached to a linker group (L); and When n is 2, 3, or 4, one R ｎ is modified to be covalently attached to a linker group (L), and any other R ｎ is optionally modified to be covalently attached to a PTM, a CLM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

19. The CLM is 【Chemistry 23】 having a chemical structure represented by During the ceremony, W is CH ２ , C═O, NH and N-alkyl; R is H, methyl, or alkyl (e.g., C １ -C ６ alkyl (straight chain, branched chain, optionally substituted); 【Chemistry 24】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and 19. The bifunctional compound of any one of claims 1 to 11, claim 17 or claim 18, wherein Rn comprises 1 to 4 independently selected functional groups, optionally substituted alkoxyl groups, or atoms, and optionally one of them is modified to be covalently attached to a PTM, a chemical linker group (L), a CLM (or CLM'), or a combination thereof.

20. The CLM is 【Chemistry 25-1】 【Chemistry 25-2】 having a chemical structure represented by During the ceremony, W in formula (h) to formula (ab) is CH ２ , CHR, C=O, SO ２ , NH and N-alkyl; Q in formula (h) to formula (ab) １ , Q ２ , Q ３ , Q ４ , Q ５ represents independently a carbon C substituted with a group independently selected from R′, N, or N-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 formulas (h) to (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy, or halogenated lower alkyl; Formula (h) to (ab) 【Chemistry 26】 is a single bond or a double bond, and The bifunctional compound according to any one of claims 1 to 11, wherein the CLM is covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM') or a combination thereof.

21. 12. The bifunctional compound of any one of claims 1 to 11, wherein the ULM is a (MDM2) linking moiety (MLM) with a chemical moiety selected from the group consisting of substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazolines, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.

22. 12. The bifunctional compound of any one of claims 1 to 11, wherein the ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) comprising the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or non-natural mimetics thereof.

23. 23. The bifunctional compound of any one of claims 1 to 11 or claim 22, wherein the ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) comprising an AVPI tetrapeptide fragment or a derivative thereof.

24. The linker (L) is -(A Ｌ ) ｑ - comprising a chemical structural unit represented by the formula During the ceremony, (A Ｌ ) ｑ is a group attached to a ULM or PTM moiety, q is an integer of 1 or more, Each A Ｌ is bond, CR Ｌ１ R Ｌ２ ,O,S,SO,SO ２ , N.R. Ｌ３ , S.O. ２ N.R. Ｌ３ , SONR Ｌ３ , C.O.R. Ｌ３ , N.R. Ｌ３ C.O.N.R. Ｌ４ , N.R. Ｌ３ SO ２ N.R. Ｌ４ , C.O., C.R. 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 ) N.R. Ｌ４ , 0 to 6 R Ｌ１ Group and / or R Ｌ２ C optionally substituted with a group ３－１１ cycloalkyl, 0 to 6 R Ｌ１ Group and / or R Ｌ２ C optionally substituted with a group ３－１１ heterocyclyl, 0 to 6 R Ｌ１ Group and / or R Ｌ２ aryl optionally substituted with a group; 0 to 6 R Ｌ１ Group and / or R Ｌ２ heteroaryl, optionally substituted with a heteroaryl group, wherein R Ｌ１ Or R Ｌ２ are each independently optionally bonded to other groups, and each independently represent 0 to 4 R Ｌ５ forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group; and R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ and R Ｌ５ are each independently H, halo, C １－８ Alkyl, O.C. １－８ Alkyl, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ Alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, O.C. 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 , S.H., S.O. 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 , C.O.C. １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , C.H.F. ２ , C.H. ２ F. NO ２ , S.F. ５ , S.O. ２ N.H.C. １－８ Alkyl, SO ２ N (C １－８ Alkyl) ２ , SONHC １－８ Alkyl, SON(C １－８ Alkyl) ２ , CONHC １－８ Alkyl, CON(C １－８ Alkyl) ２ , N(C １－８ alkyl)CONH(C １－８ Alkyl), N(C １－８ alkyl)CON(C １－８ Alkyl) ２ , NHCONH(C １－８ alkyl), NHCON(C １－８ Alkyl) ２ , 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 N.H. ２ The bifunctional compound according to any one of claims 1 to 23,

25. The linker (L) is -N(R)-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -OCH ２ -、 -O-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -OCH ２ -、 -O-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O-、 -N(R)-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O-、-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O-、 -(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -OCH ２ -、 【Chemistry 27-1】 【Chemistry 27-2】 【Chemistry 27-3】 、 wherein m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero and there are no N-O or O-O bonds, R is selected from the group of H, methyl, and ethyl, and X is selected from the group of H and F. 【Chemistry 28-1】 【Chemistry 28-2】 【Chemistry 28-3】 【Chemistry 28-4】 【Chemistry 28-5】 【Chemistry 28-6】 【Chemistry 28-7】 【Chemistry 28-8】 25. The bifunctional compound of any one of claims 1 to 24, comprising a group represented by a general structure selected from the group consisting of:

26. The linker (L) is 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 【Chemistry 29-8】 【Chemistry 29-9】 【Chemistry 29-10】 【Chemistry 29-11】 【Chemistry 29-12】 【Chemistry 29-13】 【Chemistry 29-14】 【Chemistry 29-15】 【Chemistry 29-16】 【Chemistry 29-17】 【Chemistry 29-18】 【Chemistry 29-19】 【Chemistry 29-20】 【Chemistry 29-21】 【Chemistry 29-22】 【Chemistry 29-23】 【Chemistry 29-24】 【Chemistry 29-25】 is selected from the group consisting of 25. The bifunctional compound according to any one of claims 1 to 24, wherein m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, or 7.

27. The linker (L) is 【Chemistry 30-1】 【Chemistry 30-2】 【Chemistry 30-3】 【Chemistry 30-4】 wherein each m and n is independently 0, 1, 2, 3, 4, 5, or 6.

28. The linker (L) is 【Chemistry 31-1】 【Chemistry 31-2】 【Chemistry 31-3】 【Chemistry 31-4】 The bifunctional compound according to any one of claims 1 to 24, selected from the group consisting of:

29. The linker (L) is 【Chemistry 32】 containing the chemical structure During the ceremony, W Ｌ１ and W. Ｌ２ are each independently a 4-8 membered ring with 0-4 heteroatoms optionally substituted with RQ, each RQ being 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, optionally substituted), or two RQ groups which together with the atom to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms; 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 bifunctional compound of any one of claims 1 to 23, wherein the dashed lines indicate points of attachment to a PTM or ULM moiety.

30. The linker (L) is 【Chemical Formula 33】 containing the chemical structure During the ceremony, W Ｌ１ and W. Ｌ２ are each independently aryl, heteroaryl, cyclic, heterocyclic, C １－６ alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each of which is optionally R Ｑ and 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 atom to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms Ｑ It is based on Y Ｌ１ each independently represents a bond, NR ＹＬ１ ,O.S.,N.R. 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 and each R Ｑ are independently H, C １～６ Alkyl (straight chain, branched chain, optionally with one or more halo, C １－６ or two R substituted with alkoxyl, ... Ｑ It is based on R ＹＬ１ , R ＹＬ２ are each independently H, OH, or 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 bifunctional compound of any one of claims 1 to 23, wherein the dashed lines indicate points of attachment to a PTM or ULM moiety.

31. The linker (L) is 【Chemistry 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 31. The bifunctional compound of claim 29 or 30, selected from the group consisting of:

32. 25. The bifunctional compound according to any one of claims 1 to 24, wherein said linker (L) is a polyethyleneoxy group optionally substituted with aryl or phenyl containing 1 to 10 ethylene glycol units.

33. The linker is 【Chemistry 35-1】 【Chemistry 35-2】 【Chemistry 35-3】 【Chemistry 35-4】 【Chemistry 35-5】 【Chemistry 35-6】 【Chemistry 35-7】 【Chemistry 35-8】 【Chemistry 35-9】 【Chemistry 35-10】 【Chemistry 35-11】 The bifunctional compound according to any one of claims 1 to 24, selected from the group consisting of:

34. The bifunctional compound according to claim 1, wherein the compound is selected from Tables 1 to 42.

35. The bifunctional compound of any one of claims 1 to 34, wherein the PTM is a small molecule comprising a B-RAF protein targeting moiety.

36. A composition comprising an effective amount of a bifunctional compound according to any one of claims 1 to 35 and a pharma- ceutically acceptable carrier.

37. The compound of claim 30, wherein the composition further comprises at least one of an additional bioactive agent, or another bifunctional compound of any one of claims 1 to 35.

38. 38. The composition of claim 37, wherein the additional bioactive agent is an anti-cancer agent.

39. A composition comprising a pharma- ceutically acceptable carrier and an effective amount of at least one of the compounds according to any one of claims 1 to 35 for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, The composition, wherein the combination is effective to treat or ameliorate at least one symptom of said disease or disorder.

40. 40. The composition of claim 39, wherein the disease or disorder is associated with accumulation and aggregation of BRaf.

41. 41. The composition of claim 39 or 40, wherein the disease or disorder is cancer; cardio-facial-cutaneous syndrome; neurofibromatosis type 1; Costello syndrome; Noonan syndrome; or moles, electrocardiogram abnormalities, ocular segregation, pulmonary valve stenosis, genital abnormalities, growth retardation, and hearing loss associated with RAF accumulation and aggregation (LEOPARD) syndrome.

42. 42. The composition of claim 41, wherein the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; pilocytic astrocytoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma.

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