Modulators of protein degradation and related methods of use

Abstract

The present disclosure relates to bifunctional compounds that find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds that contain, at one end, a von Hippel-Lindau, cereblon, inhibitor of apoptosis protein, or mouse dual minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase, and, at the other end, a moiety that binds to the target protein, thereby positioning the target protein in close proximity to the ubiquitin ligase that affects its degradation (and inhibition). The present disclosure exhibits a wide range of pharmacological activity related to target protein degradation / inhibition. Diseases or disorders resulting from the aggregation, accumulation, and / or hyperactivation of target proteins may be treated or prevented using the compounds and compositions of the present disclosure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to U.S. Provisional Application No. 62 / 652,676, filed April 4, 2018, entitled MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE, the contents of which are incorporated herein by reference in their entirety for all purposes. Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed August 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719, U.S. Patent Application No. 15 / 206,497, filed July 11, 2016, published as U.S. Patent Application Publication No. 2017 / 0008904, U.S. Patent Application No. 15 / 209,648, filed July 13, 2016, published as U.S. Patent Application Publication No. 2017 / 0037004, U.S. Patent Application No. 15 / 730,728, filed October 11, 2017, published as U.S. Patent Application Publication No. 2018 / 0099940, U.S. Patent Application No. U.S. Patent Application No. 14 / 686,640, published as Publication No. 2015 / 0291562; U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application No. 2016 / 0058872; U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application No. 2014 / 0356322; U.S. Patent Application No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application No. 2016 / 0272639; and U.S. Patent Application No. 2018 / 0215731, filed January 31, 2018. U.S. Provisional Patent Application No. 15 / 885,671, published as U.S. Provisional Patent Application No. A1, and International Patent Application No. PCT / US2016 / 023258, filed March 18, 2016, published as International Patent Publication No. WO2016 / 149668, are incorporated herein by reference in their entireties. Additionally, all cited references are incorporated herein by reference in their entireties.

[0002] The present description provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly with respect to Kirsten ras sarcoma proteins (KRas or KRAS), such as mutant or gain-of-function KRas, which are degraded and / or otherwise inhibited by the bifunctional compounds disclosed herein. [Background technology]

[0003] Most small molecule drugs bind to enzymes or receptors in precise, well-defined pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and, in turn, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. 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 have been reported to target E3 ligases, but this field remains underdeveloped. For example, the first small molecule E3 ligase inhibitor, mouse double minute chromosome 2 homolog (MDM2), Since the discovery of Natrin, additional compounds have been reported to target MDM2 (i.e., human double minute 2 or HDM2) E3 ligase (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0004] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate-recognition subunit of the E3 ligase complex VCB, which also consists of 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 vascular endothelial growth factor (VEGF) and the erythropoiesis-inducing cytokine (erythropoietin) in response to low oxygen levels. We generated the first small molecule ligand of VHL to the substrate-recognition subunit of the E3 ligase, obtained its crystal structure, and confirmed that the compound mimics the binding mode of the transcription factor HIF-1α, a primary substrate of VHL.

[0005] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins increases levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 similarly regulates numerous developmental processes, such as limb and otic vesicle formation. The net result is that this ubiquitin ligase complex is critical for limb development in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage-binding protein.

[0006] Inhibitors of apoptosis proteins (IAPs) are a family of proteins involved in the suppression of apoptosis, i.e., cell death. The human IAP family contains eight members, and many other organisms contain IAP homologs. IAPs contain an E3 ligase-specific domain and a baculovirus 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 implement apoptosis (e.g., caspase-3, caspase-7, and caspase-9). Thus, through caspase binding, IAPs inhibit cell death. However, proapoptotic stimuli can trigger the release of the mitochondrial proteins DIABLO (also known as second mitrochondria-derived activator of caspases, or SMAC) and HTRA2 (also known as Omi). Binding of DIABLO and HTRA2 appears to block IAP activity.

[0007] SMAC interacts with essentially all known IAPs, including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin. The first four amino acids of mature SMAC (AVPI) bind to a portion of IAPs that is thought to be essential for blocking the anti-apoptotic effects of IAPs.

[0008] 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. Specifically, these publications describe bifunctional or proteolysis-targeting chimeras (PROTA) that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or alternatively inhibited by the bifunctional compounds. C) Describe the compound.

[0009] The Kirsten rat sarcoma (KRAS) gene is an oncogene that encodes KRas, a small GTPase signaling protein. Ras proteins associate with the plasma membrane and function as switches in the transduction of extracellular signals into intracellular responses, thereby controlling, for example, cell division. Numerous activating or gain-of-function mutations in the KRas gene are known, and KRas is indeed the most frequently mutated gene in cancer. Gain-of-function KRas mutations are found in approximately 30% of all human cancers, including pancreatic cancer (over 80%), colon cancer (approximately 40-50%), lung cancer (approximately 30-50%), non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer. These activating mutations impair the ability of KRas to switch between active and inactive states. The critical role of mutant KRas in the initiation, maintenance, progression, and metastasis of various cancers has been established, and mutations are often correlated with poor prognosis and increased resistance to chemotherapy and biological therapies, including those targeting the epidermal growth factor receptor. However, despite its important role in cancer and high prevalence, there are no effective therapies that directly target this oncogene, leading to its being considered "undruggable."

[0010] Thus, there remains a need in the art for effective treatments for diseases associated with the overexpression, aggregation, and / or hyperactivation (e.g., aggregation of active KRas) of KRas, e.g., gain-of-function KRas mutants (i.e., KRas with gain-of-function mutations). However, nonspecific effects and the inability to target and control mutant Ras remain obstacles to the development of effective treatments. Therefore, small molecule therapeutics that target KRas and exploit or enhance the substrate specificity of VHL, cereblon, MDM2, and IAPs would be highly useful. Summary of the Invention

[0011] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. Specifically, the present disclosure provides bifunctional or proteolysis-targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or alternatively inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they are capable of a wide range of pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein class or family. In addition, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease conditions, such as cancer, for example, pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer.

[0012] Thus, in one aspect, the present disclosure provides bifunctional or PROTAC compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand of 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 targeting a target protein / polypeptide (e.g., Kirsten rat sarcoma protein (KRas or KRAS) and / or KRas G12C In a preferred embodiment, the ULM (ubiquitination ligase modulator) is a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase (VHL) binding moiety (MLM), or an IAPE3 ubiquitin ligase binding moiety (i.e., For example, the structure of a bifunctional compound, which may be an ILM, can be shown as follows:

[0013] [ka]

[0014] The locations of each of the PTM and ULM moieties (e.g., VLM, CLM, MLM, or ILM), as well as their numbers, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and location of each functional moiety can be varied as desired.

[0015] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as follows:

[0016] [ka]

[0017] where PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group, that connects the PTM to ULM, which is an IAP E3 ubiquitin ligase binding moiety (ILM), or a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM).

[0018] For example, the structure of a bifunctional compound can be shown as follows:

[0019] [ka]

[0020] wherein PTM is a protein / polypeptide targeting moiety, "L" is a linker (e.g., a bond or chemical linking group) connecting the PTM to at least one of a VLM, a CLM, an MLM, an ILM, or a combination thereof, a VLM is a von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase, a CLM is a cereblon E3 ubiquitin ligase binding moiety that binds to cereblon, a MLM is an MDM2 E3 ubiquitin ligase binding moiety that binds to MDM2, and an ILM is an IAP binding moiety that binds to an IAP.

[0021] In certain preferred embodiments, the ILM is an AVPI tetrapeptide fragment. Thus, in certain further embodiments, the ILM of the bifunctional compound is selected from the amino acids alanine (A), valine (V), proline (P), and isoleucine (I), respectively. In further embodiments, the amino acids of the AVPI tetrapeptide fragment are joined to one another by amide bonds (ie, -C(O)NH- or -NHC(O)-).

[0022] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0023] In certain embodiments, the ILM comprises a chemical moiety such as those described herein. In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Additionally, other contemplated VLMs are included in U.S. Patent Application Publication No. 2014 / 03022523, which is incorporated herein in its entirety, as discussed above.

[0024] In one embodiment, 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 contemplated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, the entire contents of which are incorporated herein.

[0025] In certain embodiments, the MLM may be a nutlin or a derivative thereof. Additionally, other contemplated MLMs are included in U.S. Patent Application No. 15 / 206,497, filed July 11, 2016, and published as U.S. Patent Application Publication No. 2017 / 0008904, which is incorporated herein in its entirety. In certain further 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.

[0026] In a further embodiment, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as either cis or trans configurations.

[0027] 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. Substitution with halogens such as Cl, F, Br, and I can be included in the linker. Fluorine substitution can include single or multiple fluorines.

[0028] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, in which both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides.

[0029] In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, which may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic ring with a bond as a C-N or C-C bond. Examples of the CLM may be, but are not limited to, pomalidomide, lenalidomide, and thalidomide, and derivatives thereof.

[0030] 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 modulate protein degradation and / or inhibition in a patient or subject, e.g., an animal such as a human, and treat or ameliorate a disease state or condition regulated by the degraded / inhibited protein. In certain embodiments, the therapeutic compositions described herein can be used to cause degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer (e.g., pancreatic cancer, colon cancer, colorectal cancer, lung cancer, or non-small cell lung cancer). In yet another aspect, the disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising an ILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and an MLM, preferably linked via a linker moiety, as described elsewhere herein, wherein the VLM / ILM / CLM / MLM is linked to the PTM via a linker to target the protein that binds to the PTM for degradation. Similarly, a PTM can be attached to a VLM, CLM, MLM, or ILM via a linker to target a protein or polypeptide for degradation. Degradation of the target protein occurs when the target protein is placed in close proximity to an E3 ubiquitin ligase, thus resulting in degradation / 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 disease states or conditions regulated by the target protein by reducing the level of the protein in the patient's cells.

[0031] In yet another aspect, the description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0032] In another aspect, the description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0033] The foregoing general areas of utility are provided by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be understood by those skilled in the art in light of the claims, description, and examples of the present disclosure. For example, the various aspects and embodiments of the present disclosure can be utilized in numerous combinations, all of which are expressly contemplated by this description. These additional aspects and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to illustrate the background of the present disclosure and, in certain cases, to provide further details regarding implementation are incorporated by reference.

[0034] 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 one embodiment of the present disclosure and are not to be construed as limiting the 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]

[0035] [Figure 1A]Diagram of the general principle for PROTAC function. (A) An exemplary PROTAC includes a protein-targeting moiety (PTM; dark rectangle), a ubiquitin ligase-binding moiety (ULM; light triangle), and, optionally, a linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Illustrates the functional use of the PROTACs described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to and recruits the target protein, bringing it into proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (dark circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 1B] Diagram of the general principle for PROTAC function. (A) An exemplary PROTAC includes a protein-targeting moiety (PTM; dark rectangle), a ubiquitin ligase-binding moiety (ULM; light triangle), and, optionally, a linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Illustrates the functional use of the PROTACs described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to and recruits the target protein, bringing it into proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (dark circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 2A]Figure 2A is a Western blot showing exemplary compound 399, a potent degrader. Figure 2B is a Western blot showing exemplary compound 432, a less potent degrader. Both compounds covalently modify KRasG12C, as evidenced by gel shifts. [Figure 2B] Figure 2A is a Western blot showing exemplary compound 399, a potent degrader. Figure 2B is a Western blot showing exemplary compound 432, a less potent degrader. Both compounds covalently modify KRasG12C, as evidenced by gel shifts. DETAILED DESCRIPTION OF THE INVENTION

[0036] The following is a detailed description of the invention, provided to aid those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0037] Compositions and methods are now described that relate to the surprising and unexpected discovery that E3 ubiquitin ligase proteins (e.g., inhibitor of apoptosis protein (IAP), von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon E3 ubiquitin ligase, or mouse double chromosome 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinate target proteins once the two proteins are brought into close proximity via bifunctional or chimeric constructs that link the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such 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 Figure 1). The present disclosure also provides libraries of compositions and uses thereof.

[0038] In certain aspects, the present disclosure provides a method for the preparation of a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), capable of binding to a ubiquitin ligase, such as an IAP, VHL, MDM2, or cereblon. The present invention provides a compound comprising a PTM, ULM, or PROTAC molecule. The compound also comprises a moiety capable of binding to a target protein such that the target protein is placed in proximity to a ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. In addition to the above, small molecule can also mean that the molecule is non-peptidyl, i.e., not generally considered a peptide, and contains, for example, less than 4, 3, or 2 amino acids. According to this description, a PTM, ULM, or PROTAC molecule can be a small molecule.

[0039] 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 in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0040] Where a range of values is provided, it is understood that each intervening value between the upper and lower limits of that range, to the nearest tenth of the lower limit (e.g., in the case of a group containing a number of carbon atoms, each number of carbon atoms falling within the range is provided), and any other stated or intervening value in that stated range, is encompassed within the disclosure, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are subject to any specifically excluded limit in the stated range, and are encompassed within the disclosure. Where 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.

[0041] 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 one of ordinary skill in the art applying the term in the context in which it is used in describing this disclosure.

[0042] As used in this specification and the appended claims, 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 dictates otherwise. By way of example, "an" means one element or more than one element.

[0043] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are sometimes conjunctively present and other times disjunctively present. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0044] 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" should be interpreted as inclusive, i.e., including at least one, but also including more than one, of a number or list of elements, and optionally including additional, unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. Generally, when used herein, "or" refers to a combination of elements, and "or" refers to a combination of elements, but not to a combination of elements. The term "or" when preceded by terms of exclusion, such as "either," "one of," "only one of," or "exactly one of," shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both").

[0045] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like, are understood to be open-ended, i.e., to mean "including, but not limited to." Only the transitional phrases "consisting of" and "consisting essentially of" must be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0046] 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 of the elements in the list of elements, but not necessarily including at least one of every element specifically recited in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer to, in one embodiment, at least one, optionally, two or more A, and no B (and, optionally, including elements other than B); in another embodiment, at least one, optionally, two or more B, and no A (and, optionally, including elements other than A); in yet another embodiment, at least one, optionally, two or more A, and at least one, optionally, two or more B (and, optionally, including other elements).

[0047] It should also be understood that, in certain methods described herein that include more than one step or action, 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 dictates otherwise.

[0048] The terms "co-administration" and "co-administering" or "combination therapy" refer to both co-administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time from the administration of the additional therapeutic agent(s)), as long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents, such as chemotherapy or biological therapy targeting epidermal growth factor receptors (e.g., epidermal growth factor receptor inhibitors, such as at least one of gefitinib, erlotinib, neratinib, lapatinib, cetuximab, vandetanib, necitumab, osimertinib, or a combination thereof). In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0049] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, and, where context requires, to its tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers (including optical isomers (enantiomers) and other stereoisomers (diastereomers)), as well as pharmaceutically acceptable salts and derivatives thereof. Deuterated small molecules include derivatives (including prodrugs and / or deuterated forms thereof, if applicable). Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in the drug molecule have been replaced with deuterium.

[0050] In 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), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of compounds that are modified to facilitate administration and delivery of the compound to the active site. When describing the present compounds, it should be noted that, among other things, numerous substituents and variables associated therewith are described. It is understood by those skilled in the art that the molecules described herein are stable compounds, as outlined herein below. When bonds are shown, both double and single bonds are represented or understood within the context of the compounds shown and the well-known rules of valence interactions.

[0051] 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, IAPs, which are E3 ubiquitin ligase proteins, either alone or in combination with E2 ubiquitin conjugating enzymes, cause ubiquitin to be attached to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, either alone or in combination with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin binds to the first, and a third ubiquitin binds to the second. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead can be modified in their cellular location or function, for example, by binding to other proteins that have domains capable of binding to ubiquitin. A further complication is that different lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin, which is recognized by the proteasome.

[0052] The term "patient" or "subject" is 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 those infections, conditions, or disease states specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or farm animals such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise stated or implied from the context of the use of the term.

[0053] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or ingredient that affects an intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0054] Compounds and Compositions In one aspect, the present description provides an IAP E3 ubiquitin ligase binding moiety ("ILM"), a cereblon E3 ubiquitin ligase binding moiety ("CLM"), a von Hippel-Lindau E3 ubiquitin ligase binding moiety ("CL ...cereblon E3 ubiquitin ligase binding moiety ("CLM"), a cereblon E3 ubiquitin ligase binding moiety ("CLM"), a cereblon E3 ubiquitin ligase binding moiety ("CLM"), a cereblon E3 ubiquitin ligase binding moiety ("CLM"), a

[0003] The present invention provides compounds comprising an E3 ubiquitin ligase binding moiety ("ULM") that is a virion ligase (VHL) binding moiety (VLM), and / or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM). In one exemplary embodiment, the ULM is attached 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 the moieties in the compounds exemplified herein are provided as examples only. As will be understood by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of the respective functional moieties.

[0055] Unless the context indicates otherwise, the terms ULM, ILM, VLM, MLM, and CLM are used in their inclusive sense. For example, the term ULM includes all ULMs, including those that bind to IAPs (i.e., ILMs), those that bind to MDM2 (i.e., MLMs), those that bind to cereblon (i.e., CLMs), and those that bind to VHL (i.e., VLMs). Furthermore, the term ILM includes all possible IAPs. The term MLM includes the E3 ubiquitin ligase binding moiety and all possible MDM2 The term VLM includes all possible VHL binding moieties, and the term CLM includes all possible cereblon binding moieties.

[0056] In another aspect, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for regulating protein activity by inducing target protein degradation. In certain embodiments, the compounds include an ILM or VLM or CLM or MLM attached, for example, covalently, directly, or indirectly, to a moiety that binds to the target protein (i.e., protein targeting moiety or "PTM"). In certain embodiments, the ILM / VLM / CLM / VLM and PTM are joined or coupled 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, and the interaction of each moiety with their target promotes target protein degradation by placing the target protein in close proximity to the ubiquitin ligase protein. Exemplary bifunctional compounds can be represented as follows:

[0057] (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 wherein PTM is a protein / polypeptide targeting moiety, L is a chemical linker, ILM is an IAP E3 ubiquitin ligase binding moiety, CLM is a cereblon E3 ubiquitin ligase binding moiety, VLM is a VHL binding moiety, and MLM is an MDM2 E3 ubiquitin ligase binding moiety.

[0058] In certain embodiments, the ULM (e.g., ILM, CLM, VLM or MLM) is about IC<200 μM 50 exhibit activity against or bind to E3 ubiquitin ligases (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase) at IC 50 can be determined according to any method known in the art, for example, a fluorescence polarization assay.

[0059] 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 It exhibits activity having the following properties:

[0060] In certain embodiments, the compounds described herein include multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that specifically bind to multiple / different E3 ubiquitin ligases, e.g., VHL, IAP, cereblon, and / or MDM2), or combinations thereof. In any of the aspects or embodiments described herein, the PTMs and ULMs (e.g., ILM, VLM, CLM, and / or MLM) may be linked directly, via one or more chemical linkers, or combinations thereof. In further embodiments in which the compound has multiple ULMs, the ULMs may be for the same E3 ubiquitin ligase, or each ULM may specifically bind to a different E3 ubiquitin ligase. In still further embodiments in which the compound has multiple PTMs, the PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

[0061] In certain embodiments, 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 attached to a ULM directly or 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, where the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0062] 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 attached to the ULM or ULM' directly, via a chemical linker, or both. In any of the embodiments described herein, a compound comprising at least two different ULMs 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 further embodiments, the PTM itself is a ULM (or ULM'), such as an ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

[0063] In additional embodiments, the present description provides the compounds described herein, including their pharmaceutically acceptable salt forms, e.g., acid and base salt forms, including their enantiomers, diastereomers, solvates, and polymorphs.

[0064] Exemplary ILM AVPI tetrapeptide fragment In any of the compounds described herein, the ILM may comprise an alanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment or a non-natural mimetic thereof. In certain embodiments, the ILM is represented by Formulas (I), (II), (III), (IV), and (V):

[0065] [ka]

[0066] wherein: R in formulas (I), (II), (III), (IV) and (V) 1is 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 in formulas (I), (II), (III), (IV) and (V) 5 and R 6 is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably, R 5 and R 6 together form a pyrrolidine or piperidine ring, optionally fused to one to two cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings, each of which may be further fused to another cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R in formulas (I), (II), (III), (IV) and (V) 3 and R 5 may be taken together to form a 5-8 membered ring which is optionally further fused to 1-2 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R in formulas (I), (II), (III), (IV) and (V) 7 is cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C(O)-R 4 , arylalkyl, heteroaryl, heteroaryl-C(O)-R 4 , heteroaryl-R 4 , heteroaryl-naphthalene, heteroarylalkyl or -C(O)NH-R 4 wherein each one is selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl, aryl, (hetero)aryl, —C(O)NH—R 4 or -C(O)-R 4is optionally further substituted with 1 to 3 substituents selected from R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or bicyclic aryl, arylalkyl, heteroaryl or bicyclic heteroaryl, heteroarylalkyl, optionally further substituted with 1 to 3 substituents as described above.

[0067] As shown 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, each of formulas (I) and (III)-(V) has moieties that correlate to A, V, P, and I, respectively, of an AVPI tetrapeptide fragment or non-natural mimetic thereof.

[0068] Any of the compounds described herein can have the structure of formula (VI), which is a derivative of the IAP antagonists described in WO 2008 / 014236, or a non-naturally occurring mimetic thereof:

[0069] [ka]

[0070] During the ceremony, R1 in formula (VI) is independently unsubstituted or substituted, H, C 1- C 4- Alkyl, C 1- C 4- Alkenyl, C 1- C 4- Alkynyl, or C 3- C 10- cycloalkyl; R2 in formula (VI) is independently unsubstituted or substituted, H, C 1- C 4- Alkyl, C 1- C 4- Alkenyl, C 1- C 4-Alkynyl, or C 3- C 10- cycloalkyl; R in formula (VI) 3 are independently H, -CF3, -C2H5, C 1- C 4- Alkyl, C 1- C 4- Alkenyl, C 1- C 4- Alkynyl, -CH 2- Z, or any of R2 and R3 taken together form a heterocycle; each Z in formula (VI) is independently selected from H, —OH, F, Cl, —CH, —CF, —CHCl, —CHF, or —CHOH; R4 in formula (VI) is independently C 1- C 16 Straight or branched chain alkyl, C 1- C 16- Alkenyl, C 1- C 16- Alkynyl, C 3- C 10- Cycloalkyl, -(CH2) 0-6 -Z1, -(CH2) 0-6 -aryl, and -(CH2) 0-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; R5 in formula (VI) is independently 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 -C(O)-phenyl, -(CH2) 0-6 -het, -C(O)-(CH2) 1-6 -het, or R5 is selected from the residue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted; Z1 in formula (VI) is independently —N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 10 )-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)-(CH) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; het in formula (VI) is independently selected from a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S, or an 8- to 12-membered fused ring system containing at least one 5- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heterocycle or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom; R in formula (VI) 10 is selected from H, —CH3, —CF3, —CH2OH, or —CH2Cl; R in formula (VI) 11 and R 12 are independently H, C 1-4 -Alkyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloakyl, (CH2) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R 11 and R 12 combines with nitrogen to form het, U in formula (VI) can independently be, as shown in formula (VIII):

[0071] [ka]

[0072] or a pharmaceutically acceptable salt or hydrate thereof, wherein: each n in formula (VII) is independently selected from 0 to 5; X in formula (VII) is selected from the group of -CH and N; R in formula (VII) a and R b are independently an O, S or N atom or C 0-8 - 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 each alkyl is independently either unsubstituted or substituted; R in formula (VII) d But Re-Q-(R f ) p (R g ) q and Ar1-D-Ar2, R in formula (VII) c is selected from the group H or any R c and R d together form a cycloalkyl or het, and R c and R d forms a cycloalkyl or het, R5 is attached to the formed ring via a C atom or an N atom, p and q in formula (VII) are independently selected from 0 or 1; R in formula (VII) e But 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 consisting of substituted or unsubstituted aryl and het; R in formula (VII) f and R g are independently H, -C 1-10 -Alkyl, C 1-10 -Alkylaryl, -OH, -OC 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH2) 1-6 -het, -O-(CH2) 1-6 -het, -OR 13 , -C(0)-R 13 , -C(O)-N(R 13)(R 14 ), -N(R 13 )(R 14 ), -SR 13 , -S(O)-R 13 , -S(O)2-R 13 , -S(O)2-NR 13 R 14 , -NR 13 -S(O)2-R 14 , -SC t-10 -Alkyl, Aryl-C 1-4 -Alkyl or het-C 1-4 -alkyl (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 (wherein r is 0 to 2), 1,3-dioxalane, or C 1-7 -alkyl-OH, where alkyl, alkylene, or arylene is unsubstituted or is selected from the group consisting of one or more halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -alkyl or -CF3, or each D is independently N(R h ) and R h 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 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 14 wherein each alkyl, cycloalkyl, and aryl is unsubstituted or substituted, and any of R6, R7, R8, and R9 optionally taken together form a ring system; R in formula (VII) 13 and R 14 are independently H, C 1-10 -Alkyl, -(CH2) 0-6 -C 3-7 -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, R in formula (VII) 13 and R 14 The alkyl substituents in may be unsubstituted or substituted, and when substituted, may be C 1-10 -Alkyl, halogen, OH, -OC 1-6 -Alkyl, -SC 1-6 -substituted by one or more substituents selected from -alkyl and -CF3; 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, or a non-natural mimetic thereof, linked to the ILM of Formula (VI) via at least one additional independently selected linker group. In certain embodiments, the second ILM is a derivative of Formula (VI) or a non-natural mimetic thereof. In certain embodiments, the at least one additional independently selected linker group comprises two additional independently selected linker groups chemically linking the ILM and the second ILM. In one embodiment, the at least one additional linker group for 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, at least one further independently selected linker group L and the second ILM are selected from the following:

[0076] [ka]

[0077] [ka]

[0078] and is a derivative of the IAP antagonists described in WO 2008 / 014236.

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

[0080] [ka]

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

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

[0083] In certain embodiments, the ILM comprises:

[0084] [ka]

[0085] is selected from the group consisting of: In any of the compounds described herein, the ILM has the structure of formula (IX) (which is described in Mannhold, R. et al., IAP antagonists: promising 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 have the structure of formula (X) (which is 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:

[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) 2 teeth,

[0091] [ka]

[0092] is selected from R in formula (X) 3 and R 4 is independently selected from H or Me.

[0093] In any of the compounds described herein, the ILM has the structure of formula (XI) (which is described in Mannhold, R. et al., IAP antagonists: promising 15(5-6), 210-9 (2010)) or a non-natural mimetic thereof,

[0094] [ka]

[0095] In the formula, R in formula (XI) 1 is selected from H or Me, and R of formula (XI) 2 But H or

[0096] [ka]

[0097] is selected from. In any of the compounds described herein, the ILM may have the structure of formula (XII) (which is 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:

[0098] [ka]

[0099] During the ceremony, R in formula (XII) 1 but,

[0100] [ka]

[0101] is selected from R in formula (XII) 2 but,

[0102] [ka]

[0103] is selected from. In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is

[0104] [ka]

[0105] [ka]

[0106] is selected from the group consisting of: In any of the compounds described herein, the ILM has the structure of formula (XIII) (which is described by Flygare, JA et al., Small-molecule pan-IAP antagonists: derived from IAP ligands summarized in a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010)), or a non-natural mimetic thereof;

[0107] [ka]

[0108] During the ceremony, Z in formula (XIII) is absent or O; R in formula (XIII) 1 but,

[0109] [ka]

[0110] is selected from

[0111] [ka]

[0112] R 10 is selected from H, alkyl or aryl; X is selected from CH2 and O;

[0113] [ka]

[0114] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM has the structure of formula (XIV) (which is described 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;

[0115] [ka]

[0116] During the ceremony, Z in formula (XIV) is absent or O; R in formula (XIV) 3 and R 4 is independently selected from H or Me; R in formula (XIV) 1 but,

[0117] [ka]

[0118] is selected from

[0119] [ka]

[0120] R 10 is selected from H, alkyl or aryl;

[0121] [ka]

[0122] X is selected from CH2 and O;

[0123] [ka]

[0124] of

[0125] [ka]

[0126] is a nitrogen-containing heteroaryl. In any of the compounds described herein, the ILM may be

[0127] [ka]

[0128] which are derivatives of the ligands disclosed in US Patent Publication No. 2008 / 0269140 and US Patent No. 7,244,851.

[0129] In any of the compounds described herein, the ILM may have the structure of formula (XV), which was the IAP ligand described in WO 2008 / 128171, or a non-natural mimetic thereof:

[0130] [ka]

[0131] During the ceremony, Z in formula (XV) is absent or O; R in formula (XV) 1 but,

[0132] [ka]

[0133] is selected from

[0134] [ka]

[0135] R 10 is selected from H, alkyl or aryl;

[0136] [ka]

[0137] X is selected from CH2 and O;

[0138] [ka]

[0139] of

[0140] [ka]

[0141] is a nitrogen-containing heteroaryl; R in formula (XV) 2 is selected from H, alkyl or acyl.

[0142] In certain embodiments, the ILM has the following structure:

[0143] [ka]

[0144] In any of the compounds described herein, the ILM may have the structure of formula (XVI), which is based on the IAP ligands described in WO 2006 / 069063, or a non-natural mimetic thereof:

[0145] [ka]

[0146] 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)

[0147] [ka]

[0148] is a 5- or 6-membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl, most preferably a thiazole; In formula (XVI), Ar is aryl or heteroaryl.

[0149] In any of the compounds described herein, the ILM may have the structure of formula (XVII) (which is derived from 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:

[0150] [ka]

[0151] During the ceremony, R in formula (XVII) 1 but halogen (e.g., fluorine), cyano,

[0152] [ka]

[0153] is selected from the group X in formula (XVII) is selected from the group of O or CH2.

[0154] In any of the compounds described herein, the ILM may have the structure of formula (XVIII) (which is described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, derived from IAP ligands described in Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or non-natural mimetics thereof;

[0155] [ka]

[0156] wherein R in formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or halogen (at variable substitution positions).

[0157] In any of the compounds described herein, the ILM may have the structure of formula (XIX) (which is derived from 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:

[0158] [ka]

[0159] During the ceremony,

[0160] [ka]

[0161] is a six-membered nitrogen heteroaryl. In certain embodiments, the ILM of the composition comprises:

[0162] [ka]

[0163] is selected from the group consisting of: In certain embodiments, the ILM of the composition comprises:

[0164] [ka]

[0165] is selected from the group consisting of: In any of the compounds described herein, the ILM may have the structure of formula (XX), which is based on the IAP ligands described in WO 2007 / 101347, or a non-natural mimetic thereof:

[0166] [ka]

[0167] wherein X in formula (XX) is selected from CH2, O, NH or S. In any of the compounds described herein, the ILM may have the structure of formula (XXI), which is based on the IAP ligands described in U.S. Pat. Nos. 7,345,081 and 7,419,975, or a non-natural mimetic thereof:

[0168] [ka]

[0169] During the ceremony, R in formula (XXI) 2 but,

[0170] [ka]

[0171] is selected from R in formula (XXI) 5 but,

[0172] [ka]

[0173] is selected from W in formula (XXI) is selected from CH or N;

[0174] [ka]

[0175] R 6 is independently a monocyclic or bicyclic fused aryl or heteroaryl.

[0176] In certain embodiments, the ILM of the compound is

[0177] [ka]

[0178] is selected from the group consisting of: In certain embodiments, the ILM of the compound is

[0179] [ka]

[0180] [ka]

[0181] and / or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; These are described in WO 2009 / 060292, U.S. Pat. No. 7,517,906, WO 2008 / 134679, WO 2007 / 130626, and WO 2008 / 128121.

[0182] In any of the compounds described herein, the ILM may have the structure of formula (XXII) or (XXIII) (which is derived from the IAP ligands described in WO 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015)), or a non-natural mimetic thereof:

[0183] [ka]

[0184] [ka]

[0185] During the ceremony, R of formula (XXII) or (XXIII) 1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl and R of formula (XXII) or (XXIII) 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; Alternatively, R of formula (XXII) or (XXIII) 1 and R 2 are independently optionally substituted thioalkyl, where the substituent attached to the S atom of the thioalkyl is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH) v COR20 , -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 However, independently, OH, NR 24 R 25 OR 26 is selected from -CH2CHR 21 COR 2 R 21 But NR 24 R 25 is selected from the group -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 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, the optional substituents being OH, halogen, or NH; m is an integer from 1 to 8; R of formula (XXII) or (XXIII) 3 and R 4is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXII) or (XXIII) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; X is selected from a bond or a chemical linker group.

[0186] In certain embodiments, X is a bond or:

[0187] [ka]

[0188] wherein the formula is selected from the group consisting of: * " is the connection point of PTM, L or ULM, for example, ILM.

[0189] In any of the compounds described herein, the ILM may have the structure of formula (XXIV) or (XXVI) (which is derived from the IAP ligands described in WO 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015)), or a non-natural mimetic thereof, and / or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and may be linked via a chemical linker to the linker group L, as shown below:

[0190] [ka]

[0191] During the ceremony, R of formula (XXIV), (XXV) or (XXVI) 1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXIV), (XXV) or (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), (XXV) or (XXVI) 1 and R 2 is independently selected from optionally substituted thioalkyl, where the substituents attached to the S atom of the thioalkyl are 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 However, independently, OH, NR 24 R 25 OR 26 is selected from -CH2CHR 21 COR 2 R 21But 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 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, the optional substituents being OH, halogen, or NH; m is an integer from 1 to 8; R of formula (XXIV), (XXV) or (XXVI) 3 and R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXIV), (XXV) or (XXVI) 5 , R 6 , R 7 and R 8 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0192] In certain embodiments, the ILM of formula (XXII)-(XXVI) is R 7 and R 8 is selected from H or Me; R 5 and R 6 but,

[0193] [ka]

[0194] and selected from the group comprising: R 3 and R 4 but,

[0195] [ka]

[0196] is selected from the group comprising: In any of the compounds described herein, the ILM may have the structure of formula (XXVII) or (XXVII), which is described in WO 2014 / 055461 and Kim, K S, derived from the IAP ligands described in "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 a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

[0197] [ka]

[0198] [ka]

[0199] During the ceremony, R 35is 1 to 2 substituents selected from alkyl, halogen, alkoxy, cyano, and haloalkoxy; R of formula (XXVII) and (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 (XXVIII) 2 is selected from H, or optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; Or, alternatively, R of formula (XXVII) and (XXVIII) 1 and R 2 are independently and arbitrarily substituted Thioalkyl-CR 60 R 61 SR 70 wherein R 60 and R 61 is selected from H or methyl, and R 70 is optionally substituted alkyl, optionally substituted branched alkyl, 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 -CHCHR 21 COR 22 R 20 and R 22 However, independently, OH, NR 24 R 25 OR 26 is selected from -CH2CHR21 COR 22 R 21 But 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 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 polyamine chain -[CH2CH2(CH2) δ NH] Ψ CH2CH2(CH2)

[0200] [ka]

[0201] NH2, for example, selected from spermine or spermidine; In the formula, δ=0~2, Ψ=1~3,

[0202] [ka]

[0203] =0 to 2, OR 26 R 26 is selected from optionally substituted alkyl, the optional substituents being OH, halogen, or NH; m is an integer from 1 to 8; R of formula (XXVII) and (XXVIII) 3 and R 4is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXVII) and (XXVIII) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R of formula (XXVII) and (XXVIII) 31 is selected from alkyl, aryl, arylalkyl, heteroaryl, or optionally further substituted heteroarylalkyl, preferably

[0204] [ka]

[0205] is selected from the group consisting of X in formula (XXVII) and (XXVIII) is -(CR 81 R 82 ) m -, optionally substituted heteroaryl or heterocyclyl,

[0206] [ka]

[0207] 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 82are independently selected from hydrogen, halogen, alkyl, or cycloalkyl, or R 81 and R 82 can be taken together to form a carbocyclic ring,

[0208] [ka]

[0209] R 10 and R 11 are independently selected from hydrogen, halogen, or alkyl;

[0210] [ka]

[0211] R 12 , R 13 , R 14 , R 15 and R 16 are independently hydrogen, halogen, or optionally substituted alkyl, or OR 17 is selected from R 17 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 21 R 22 ) m - and

[0212] [ka]

[0213] m and n are independently 0, 1, 2, 3, or 4;

[0214] [ka]

[0215] o and p are independently 0, 1, 2, or 3;

[0216] [ka]

[0217] q and t are independently 0, 1, 2, 3, or 4;

[0218] [ka]

[0219] r is 0 or 1. In any of the compounds described herein, the ILM may have the structure of formula (XXIX), (XXX), (XXXI) or (XXXII) (which is derived from the IAP ligands described in 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 a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and may be linked via a chemical linker to the linker group L, as shown below:

[0220] [ka]

[0221] During the ceremony, R of formulas (XXIX) to (XXXII) 2 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted aryl; Or, alternatively, R of formula (XXVII) and (XXVIII) 1 and R 2 are independently H, optionally substituted thioalkyl-CR 60 R 61 SR 70 wherein R 60 and R 61 is selected from H or methyl, and R 70 is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 and During the ceremony, v is an integer from 1 to 3, -(CH2) v COR 20 and -CHCHR 21 COR 22 R 20 and R 22 However, independently, OH, NR 24 R 25 OR 26 is selected from -CH2CHR 21 COR 22 R 21 But 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 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 polyamine chain -[CH2CH2(CH2) δ NH] Ψ CH2CH2(CH2)

[0222] [ka]

[0223] r NH2, for example, selected from spermine or spermidine; In the formula, δ=0~2, Ψ=1~3,

[0224] [ka]

[0225] =0 to 2, OR 26 R 26 is selected from optionally substituted alkyl, the optional substituents being OH, halogen, or NH; m is an integer from 1 to 8; R of formulas (XXIX) to (XXXII) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R of formulas (XXIX) to (XXXII) 31 is selected from alkyl, aryl, arylalkyl, heteroaryl, or optionally further substituted heteroarylalkyl, preferably

[0226] [ka]

[0227] is selected from the group consisting of: In certain embodiments, the ILM of the compound is

[0228] [ka]

[0229] is. In any of the compounds described herein, the ILM may have the structure of formula (XXXIII), which is derived from the IAP ligands described in WO 2014 / 074658 and WO 2013 / 071035, or a non-natural mimetic thereof:

[0230] [ka]

[0231] 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; R in formula (XXXIII) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; R in formula (XXXIII) 32 (C1-C4 alkylene)-R 33 wherein R 33 is selected from hydrogen, aryl, heteroaryl, or optionally further substituted cycloalkyl; X in formula (XXXIII) is

[0232] [ka]

[0233] is selected from Z and Z′ in formula (XXXIII) are independently

[0234] [ka]

[0235] wherein each

[0236] [ka]

[0237] represents a point of attachment to the compound, and Z and Z' are both

[0238] [ka]

[0239] It cannot be, Y in formula (XXXIII) is

[0240] [ka]

[0241] wherein Z and Z' in formula (XXXIII) are the same, and Z is

[0242] [ka]

[0243] and each

[0244] [ka]

[0245] represents the connection point for the compound, and X represents

[0246] [ka]

[0247] is selected from Y in formula (XXXIII) is independently

[0248] [ka]

[0249] [ka]

[0250] is selected from During the ceremony,

[0251] [ka]

[0252] represents the point of attachment to the -C=O portion of the compound;

[0253] [ka]

[0254] represents the point of attachment to the -NH moiety of the compound;

[0255] [ka]

[0256] represents the first connection point to Z,

[0257] [ka]

[0258] represents the second connection point to Z, m is an integer from 0 to 3, n is an integer from 1 to 3, p is an integer from 0 to 4, A is -C(O)R 3 and R 3 But -C(O)R 3 selected from OH, NHCN, NHSOR 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 independently selected from hydrogen, —C1-C4 alkyl, —(C1-C4) alkylene)-NH—(C1-C4 alkyl), and —(C1-C4 alkylene)-O—(C1-C4 hydroxyalkyl), or R 12 and R 13 taken together with the nitrogen atom to which they are commonly attached form a saturated heterocyclyl optionally containing one further heteroatom selected from N, O and S, the saturated heterocycle being optionally substituted with methyl.

[0259] In any of the compounds described herein, the ILM may have the structure of formula (XXXIV) or (XXXV), which is derived from the IAP ligands described in WO 2014 / 047024, or a non-natural mimetic thereof, and / or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0260] [ka]

[0261] [ka]

[0262] During the ceremony, In the formula (XXXIV) or (XXXV), X is absent or -(CR 10 R 11 ) m -, optionally substituted heteroaryl, or optionally substituted heterocyclyl,

[0263] [ka]

[0264] is a group selected from Y and Z in formula (XXXIV) or (XXXV) are independently C=0, -0-, -NR 9 -, -CONH-, -NHCO- or may be absent; R of formula (XXXIV) or (XXXV) 1 and R 2 are independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted aryl; or R of formula (XXXIV) or (XXXV) 1 and R 2 is independently selected from optionally substituted thioalkyl, where the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH) v COR 20 , -CH2CHR 21 COR 22 or -CH2R 23 where: v is an integer from 1 to 3, -(CH2) v COR 20 and -CHCHR 21 COR 22 R 20 and R 22 However, independently, OH, NR24 R 25 OR 26 is selected from -CH2CHR 21 COR 22 R 21 But 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 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 substituents are OH, halogen, or NH; -(CR 10 R 11 ) m - m is an integer from 1 to 8, R of formula (XXXIV) or (XXXV) 3 and R 4 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen, or OH; R of formula (XXXIV) or (XXXV) 5 , R 6 , R 7 and R8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 10 R 11 ) m -R 10 and R 11 is independently selected from hydrogen, halogen, or optionally substituted alkyl;

[0265] [ka]

[0266] R 12 and R 13 are independently selected from hydrogen, halogen, or optionally substituted alkyl, or R 12 and R 13 can be taken together to form a carbocyclic ring,

[0267] [ka]

[0268] R 14 , R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, optionally substituted alkyl, or OR 19 is 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 are independently 0, 1, 2, 3, or 4; -(CR 10 R 11 ) m - o and p are independently 0, 1, 2, or 3; -(CR10 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.

[0269] In any of the compounds described herein, the ILM may have the structure of formula (XXXVI), which is 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:

[0270] [ka]

[0271] During the ceremony, A in formula (XXXVI) is

[0272] [ka]

[0273] where the dotted line represents an optional double bond; X in formula (XXXVI) is -(CR 21 R 22 ) m -,

[0274] [ka]

[0275] is selected from In formula (XXXVI), Y and Z are independently -0-, -NR 6 - 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), (XXV) or (XXVI) 5 , R 6 , R 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, or is preferably methyl;

[0276] [ka]

[0277] R 9 and R 10 are independently selected from hydrogen, halogen, or optionally substituted alkyl, or R 9 and R 10 can come together to form a ring,

[0278] [ka]

[0279] R 11 , R 12 , R 13 and R 14are independently hydrogen, halogen, optionally substituted alkyl, or OR 15 is selected from OR 15 R 15 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 21 R 22 ) m - and

[0280] [ka]

[0281] m and n are independently selected from 0, 1, 2, 3, or 4;

[0282] [ka]

[0283] o and p are independently selected from 0, 1, 2, or 3;

[0284] [ka]

[0285] q is selected from 0, 1, 2, 3, or 4;

[0286] [ka]

[0287] r is selected from 0 or 1. In any of the compounds described herein, the ILM may have the structure of formula (XXXVII) or (XXXVIII), which is derived from the IAP ligands described in WO 2014 / 011712, or a non-natural mimetic thereof, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0288] [ka]

[0289] During the ceremony, X in formula (XXXVII) and (XXXVIII) is -(CR 16 R 17 ) m -,

[0290] [ka]

[0291] or does not exist, Y and Z in formula (XXXVII) and (XXVIII) are independently -0-, C=0, NR 6 or absent, R of formula (XXXVII) and (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 (XXXVIII) 3 and R 4 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl; R of formula (XXXVII) and (XXXVIII) 5 and R 6 is independently selected from optionally substituted alkyl, or optionally substituted cycloalkyl; R of formula (XXXVII) and (XXXVIII) 7 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, or is preferably methyl;

[0292] [ka]

[0293] R 9 and R 10 is independently selected from hydrogen, optionally substituted alkyl, or R 9 and R 10 may be taken together to form a ring,

[0294] [ka]

[0295] R 11 ~R 14 are independently hydrogen, halogen, optionally substituted alkyl, or OR 15 is selected from OR 15 R 15 is selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; -(CR 16 R 17 ) m -R 16 and R 17 is independently selected from hydrogen, halogen, or optionally substituted alkyl; R of formula (XXXVII) and (XXXVIII) 50 and R 51 is independently selected from optionally substituted alkyl, or R 50 and R 51 together to form a ring, -(CR 16 R 17 ) m - and

[0296] [ka]

[0297] m and n are independently an integer of 0 to 4,

[0298] [ka]

[0299] o and p are independently an integer of 0 to 3;

[0300] [ka]

[0301] q is an integer of 0 to 4,

[0302] [ka]

[0303] r is an integer of 0 to 1. In one embodiment, R of the ILM of formula (XXXVII) or (XXVIII) 1 and R 2 is t-butyl, and R of the ILM of formula (XXXVII) or (XXXVIII) 3 and R 4 is tetrahydronaphthalene.

[0304] In any of the compounds described herein, the ILM may have the structure of formula (XXXIX) or (XL), which is derived from the IAP ligands described in WO 2014 / 071039, or a non-natural mimetic thereof:

[0305] [ka]

[0306] During the ceremony, R of formula (XXXXIX) and (XL) 43 and R 44are independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and optionally substituted cycloalkylalkyl; R in formula (XXXIX) and (XL) 6 and R 8 is independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0307] Each X in formulas (XXXIX) and (XL) is independently

[0308] [ka]

[0309] [ka]

[0310] is selected from Each Z in formula (XXXIX) and (XL) is

[0311] [ka]

[0312] Each is selected from

[0313] [ka]

[0314] represents the connection point for the compound, Each Y is

[0315] [ka]

[0316] [ka]

[0317] is selected from During the ceremony,

[0318] [ka]

[0319] represents the point of attachment to the -C=O portion of the compound;

[0320] [ka]

[0321] represents the point of attachment to the amino moiety of the compound;

[0322] [ka]

[0323] represents the first connection point to Z,

[0324] [ka]

[0325] represents the second connection point to Z, A is -C(O)R 3 ,or

[0326] [ka]

[0327] or a tautomeric form as defined above, -C(O)R 3 R 3 OH, NHCN, NHSOR 10 , NHOR 11or N(R 12 )(R 13 ) and NHSO2R 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 are independently 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 taken together with the nitrogen atom to which they are commonly attached form a saturated heterocyclyl optionally containing one further heteroatom selected from N, O and S, the saturated heterocycle being optionally substituted with methyl.

[0328] In any of the compounds described herein, the ILM may have the structure of formula (XLI), which is derived from the IAP ligands described in WO 2013 / 071039, or a non-natural mimetic thereof:

[0329] [ka]

[0330] During the ceremony, W in formula (XLI) 1 But O, S, NR A , or C(R 8a )(R 8b ) R, W in formula (XLI) 2 But 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, C-C alkyl, C-C cycloalkyl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); X 1 But, O, NR A , S, S(O) or S(O)2, X 2 But C(R 2a R 2b ) and or X in formula (XLI) 1 But, CR 2c R 2d Selected from X 2 But, CR 2a R 2b and R 2c and R 2a together form a bond, or X in formula (XLI) 1 and X 2 are independently selected from C and N and are members 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 However, C=0, C=C(RC )2 or C=NR C and each R C is 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, C-C alkyl, —C(═O)C-C alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d and CR 2a R 2b R 2a , R 2b , R 2c , R 2d are independently H, substituted or unsubstituted C1-C6 alkyl, 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) B is 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 are independently 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 C2-C5 heterocycloalkyl), -C1-C6 alkyl -C1-C6 alkyl-(substituted or unsubstituted aryl), or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl); m in formula (XLI) is selected from 0, 1 or 2; -U- in formula (XLI) is 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 But, -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, together with the atoms to which they are attached, a substituted or unsubstituted 5- to 7-membered ring, or R in formula (XLI) 3 is bonded to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLI) 6 But -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 are independently 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 -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); pR 7 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 8dare independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl; R, or R 8a and R 8d is as defined above, and R 8b and R 8c come together to form a bond, 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 selected from 1 to 3 R 9is 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 is unsubstituted or substituted with halogen, —OH, or C1-C3 alkyl.

[0331] In any of the compounds described herein, the ILM may have the structure of formula (XLII), which is derived from the IAP ligands described in WO 2013 / 071039, or a non-natural mimetic thereof:

[0332] [ka]

[0333] During the ceremony, W in formula (XLII) 1 But O, S, NR A or C(R 8a )(R 8b ) and W in formula (XLII) 2 But O, S, NR A or C(R 8c )(R 8d ), where W 1 and W 2are not both O or both S, R in formula (XLII) 1 is selected from H, C-C alkyl, C-C cycloalkyl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLII) 1 NR A If X 2 C=O or CR 2c R 2d and X 3 But, CR 2a R 2b and or X in formula (XLII) 1 is selected from S, S(O) or S(O)2, then X 2 But, CR 2c R 2d and X 3 But, CR 2a R 2b and or X in formula (XLII) 1 If is O, then X 2 But, CR 2c R 2d and N.R. A and X 3 But, CR 2a R 2b and or X in formula (XLII) 1 If CH3, then X 2 But, O, NR A , S, S(O) or S(O)2, and X 3 But, CR 2a R 2b and X in formula (XLII) 1 is CR 2e R 2f and X 2 is CR 2cR 2d If R 2e and R 2c together form a bond, and X in formula (VLII) 3 But, CR 2a R 2b If or X in formula (XLII) 1 and X 3 are both CH2, and X in formula (XLII) 2 However, C=0, C=C(R C )2 or C=NR C and each R C is 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); or X in formula (XLII) 1 and X 2 is independently selected from C and N and is a member 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 But, CR 2a R 2b and or X in formula (XLII) 2 and X 3are independently selected from C and N and are members 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 of formula (VLII) 1 But, CR 2e R 2f and NR A R A is selected from H, C-C alkyl, —C(═O)C-C alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b and CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2f are independently H, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O) B is 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 independently selected from H, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), —C-C alkyl-(substituted or unsubstituted C-C heterocycloalkyl), —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); m in formula (XLII) is selected from 0, 1 or 2; -U- in formula (XLII) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)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 But, -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, together with the atoms to which they are attached, a substituted or unsubstituted 5- to 7-membered ring, or R in formula (XLII) 3 is bonded to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLII) 6 But -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 are independently 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 -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 8dis 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 come together to form a bond, 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 selected from 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, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 alkyl)2, -C(=O)OH, -C(=O)NH2, -C(=O)C1-C3 alkyl, -S(=O)2CH3, -NH(C1-C4 alkyl)-OH, -NH(C1-C4 alkyl)-O-(C-C4 alkyl), -O(C1-C4 alkyl)-NH2, -O(C1-C4 alkyl)-NH-(C1-C4 alkyl) and -O (C1-C4 alkyl)-N-(C1-C4 alkyl)2, or two R 9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring which is unsubstituted or substituted with halogen, —OH, or C1-C3 alkyl.

[0334] In any of the compounds described herein, the ILM may have the structure of formula (XLIII), which is derived from the IAP ligands described in WO 2013 / 071039, or a non-natural mimetic thereof:

[0335] [ka]

[0336] During the ceremony, W in formula (XLIII) 1 But O, S, NR A , or C(R 8a )(R 8b ) and W in formula (XLIII) 2 But O, S, NR A or C(R 8c )(R 8d ), where W 1and W 2 are not both O or both S, R in formula (XLIII) 1 is selected from H, C-C alkyl, C-C cycloalkyl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIII) 1 But NR A , S, S(O) or S(O)2, X in formula (XLIII) 2 But, CR 2c R 2d and X in formula (XLIII) 3 But, CR 2a R 2b and or X in formula (XLIII) 1 is O, then X in formula (XLIII) 2 But, O, NR A , S, S(O) or S(O)2, and X of formula (XLIII) 3 But, 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 to form a bond, and X in formula (XLIII) 3 But, CR 2a R 2b and or X in formula (XLIII) 1 and X 2is independently selected from C and N and is a member 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 of formula (XLIII) 3 But, CR 2a R 2b and or X in formula (XLIII) 2 and X 3 are independently selected from C and N, and are fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered cycloalkyl rings, fused substituted or unsubstituted saturated or partially saturated 3- to 10-membered heterocycloalkyl rings, a fused substituted or unsubstituted 5- to 10-membered aryl ring, a fused substituted or unsubstituted 5- to 10-membered heteroaryl ring, and X of formula (VLII) 1 But, 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 CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2fare independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O) B is 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 independently selected from H, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), —C-C alkyl-(substituted or unsubstituted C-C heterocycloalkyl), —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); In formula (XLIII), m is 0, 1 or 2; -U- in formula (XLIII) is -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O)2NH-; R in formula (XLIII) 3 is C1-C3 alkyl or C1-C3 fluoroalkyl; R in formula (XLIII) 4 But, -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, together with the atoms to which they are attached, a substituted or unsubstituted 5- to 7-membered ring, or R in formula (XLIII) 3 is bonded to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLIII) 6 But -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 are independently 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-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 is 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 come together to form a bond, 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 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 selected from 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 is unsubstituted or substituted with halogen, —OH, or C1-C3 alkyl.

[0337] In any of the compounds described herein, the ILM may have the structure of formula (XLIV), which is derived from the IAP ligands described in WO 2013 / 071039, or a non-natural mimetic thereof:

[0338] [ka]

[0339] During the ceremony, W in formula (XLIV) 1 But O, S, NR A , or C(R 8a )(R 8b ) and W in formula (XLIV) 2 But 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 But 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 selected from H, C-C alkyl, C-C cycloalkyl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); X in formula (XLIV) 1 When is O, X in formula (XLIV) 2 But, CR 2c R 2d and N.R. AX of formula (XLIV) is selected from 3 But, CR 2a R 2b and or X in formula (XLIV) 1 is CH2, X in formula (XLIV) 2 But, O, NR A , S, S(O) or S(O)2, and X of formula (XLIV) 3 But, CR 2a R 2b and or X in formula (XLIV) 1 is CR 2e R 2f and X in formula (XLIV) 2 is CR 2c R 2d If R 2e and R 2c together to form a bond, and X in formula (XLIV) 3 But, CR 2a R 2b and or X in formula (XLIV) 1 and X 3 are both CH2, and X in formula (XLII) 2 but , C=O, C=C(R C )2 or C=NR C and each R C is 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); or X in formula (XLIV) 1 and X 2are independently selected from C and N and are members 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 of formula (XLIV) 3 But, CR 2a R 2b and or X in formula (XLIV) 2 and X 3 are independently selected from C and N and are members 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 of formula (VLIV) 1 But, CR 2e R 2f and NR A R A is selected from H, C-C alkyl, —C(═O)C-C alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; CR 2c R 2d , C.R. 2a R 2b and CR 2e R 2f R 2a , R 2b , R 2c , R 2d , R 2e and R 2fare independently H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), and -C(=O) B is 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 independently selected from H, substituted or unsubstituted C-C alkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C-C alkyl-(substituted or unsubstituted C-C cycloalkyl), —C-C alkyl-(substituted or unsubstituted C-C heterocycloalkyl), —C-C alkyl-(substituted or unsubstituted aryl), or —C-C alkyl-(substituted or unsubstituted heteroaryl); m in formula (XLIV) is selected from 0, 1 or 2; -U- in formula (XLIV) is -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, - selected from -O(C=O)NH- or -NHS(=O)NH-; R in formula (XLIV) 3 is selected from C1-C3 alkyl or C1-C3 fluoroalkyl; R in formula (XLIV) 4 But, -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 (XLIV) 3 and R 5 form, together with the atoms to which they are attached, a substituted or unsubstituted 5- to 7-membered ring, or R in formula (XLIII) 3 is bonded to the nitrogen atom of U to form a substituted or unsubstituted 5- to 7-membered ring, R in formula (XLIII) 6 But -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 are independently 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-CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl); R 7 p is selected from 0, 1 or 2; C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is 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 come together to form a bond, or C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8b , R 8d and R 8f is as defined above, and R 8cand R 8e come together to form a bond, or C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f )R 8a , R 8d , R 8e and R 8f is as defined above, 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 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 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 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 , R 8b , R 8e and R 8f is as described above, and R 8c and R 8d together with the atom to which they are attached form a substituted or unsubstituted saturated or partially saturated 3- to 7-membered spiro or heterospiro ring containing 1 to 3 heteroatoms selected from S, O, and N; or C(R 8a )(R 8b ) and C(R 8c )(R 8d )R 8a , R 8b , R 8c and R 8d is as defined above, and R 8e and R 8f together with the 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 selected from 1 to 3 R 9 is replaced by R 8a , R 8b , R 8c , R 8d , R 8e and R 8f Each R9 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 halogens, -OH or or C1-C3 alkyl, or a methylenedioxy or ethylenedioxy ring, which may be unsubstituted.

[0340] In any of the compounds described herein, the ILM may have the structure of formula (XLV), (XLVI) or (XLVII) (which is derived from the IAP ligands described in Vamos, M. et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013)), or a non-natural mimetic thereof:

[0341] [ka]

[0342] [ka]

[0343] During the ceremony, R in formula (XLV) 2 , R3 and R 4 are independently selected from H or ME; X in formula (XLV) is independently selected from O or S; R in formula (XLV) 1 but,

[0344] [ka]

[0345] is selected from. In certain embodiments, the ILM has the structure of formula (XLVIII):

[0346] [ka]

[0347] wherein R in formula (XLVIII) 3 and R 4 is independently selected from H or Me;

[0348] [ka]

[0349] but,

[0350] [ka]

[0351] is a five-membered heterocycle selected from In certain embodiments, the compound of formula XLVIII)

[0352] [ka]

[0353] but,

[0354] [ka]

[0355] is. In certain embodiments, the ILM has the structure shown below and is connected to a linker group, L:

[0356] [ka]

[0357] In certain embodiments, the ILM has the structure of formula (XLIX), (L) or (LI):

[0358] [ka]

[0359] During the ceremony, R of formula (XLIX), (L) or (LI) 3 are independently selected from H or ME;

[0360] [ka]

[0361] but,

[0362] [ka]

[0363] is a 5-membered heterocycle selected from In formula (XLIX), (L) or (LI), L is

[0364] [ka]

[0365] is selected from. In certain embodiments, L in formula (XLIX), (L) or (LI) is

[0366] [ka]

[0367] is. In certain embodiments, the ILM has the structure of formula (LII):

[0368] [ka]

[0369] In certain embodiments, the ILM of formula (LII) is

[0370] [ka]

[0371] Within the region indicated by is chemically linked to a linker group L as shown below.

[0372] [ka]

[0373] In any of the compounds described herein, the ILM may have the structure of formula (LIII) or (LIV) (which is derived from 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:

[0374] [ka]

[0375] [ka]

[0376] During the ceremony, R in formula (LIII) and (LIV) 1 but,

[0377] [ka]

[0378] is selected from R in formula (LIII) and (LIV) 2 is selected from H or Me; R in formula (LIII) and (LIV) 3 but,

[0379] [ka]

[0380] is selected from The X is selected from H, halogen, methyl, methoxy, hydroxy, nitro or trifluoromethyl.

[0381] In any of the compounds described herein, the ILM may have the structure of formula (LV) or (LVI), may be chemically linked to a linker shown in formula (LV) or (LVI), or may have the structure of a non-natural mimetic thereof:

[0382] [ka]

[0383] In any of the compounds described herein, the ILM may have the structure of formula (LVII) (which is derived from 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:

[0384] [ka]

[0385] During the ceremony, R in formula (LVII) 1 but,

[0386] [ka]

[0387] is selected from

[0388] [ka]

[0389] wherein X is selected from H, fluoro, methyl or methoxy. In certain embodiments, the ILM is represented by the following structure:

[0390] [ka]

[0391] In certain embodiments, the ILM is selected from the group consisting of:

[0392] [ka]

[0393] In any of the compounds described herein, the ILM is selected from the group consisting of the following structures (which are derived from the IAP ligands described in Asano, M et al., Design, sterioselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitors of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18):5725-37 (2013)), or the structure of a non-natural mimetic thereof:

[0394] [ka]

[0395] In certain embodiments, the ILM is selected from the group consisting of:

[0396] [ka]

[0397] In any of the compounds described herein, the ILM may have the structure of formula (LVIII) (which is derived from the IAP ligand 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 a non-natural mimetic thereof.

[0398] [ka]

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

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

[0401] [ka]

[0402] 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.

[0403] In any of the compounds described herein, the ILM may have the structure of formula (LXI) (which is 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 the structure of a non-natural mimetic thereof.

[0404] [ka]

[0405] During the ceremony, Formula (LXI)

[0406] [ka]

[0407] is a natural or unnatural amino acid, R in formula (LXI) 2 but,

[0408] [ka]

[0409] is selected from. In any of the compounds described herein, the ILM may have the structure of formula (LXII) or (LLXIII) and may be chemically linked to a linker group L shown in formula (LXII) or (LLXIII), or may have the structure of a non-natural mimetic thereof:

[0410] [ka]

[0411] Formula (LXI)

[0412] [ka]

[0413] is a natural or unnatural amino acid, L in formula (LXI) is a linker group as described herein.

[0414] In any of the compounds described herein, the ILM may have a structure selected from the group consisting of the following (which is derived from an IAP ligand described in Wang, J et al., Discovery of novel second mitochondrial-derived activator of caspase mimetics as selective inhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther., 349(2):319-29 (2014)), or the structure of a non-natural mimetic thereof:

[0415] [ka]

[0416] In any of the compounds described herein, the ILM may have the structure of formula (LXIX) (which is described in Hird, AW et al., Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, derived from IAP ligands described in Bioorg. Med. Chem. Lett., 24(7):1820-4(2014), or a non-natural mimetic thereof.

[0417] [ka]

[0418] wherein R in formula LIX is:

[0419] [ka]

[0420] is selected from the group consisting of

[0421] [ka]

[0422] R 1 is selected from H or Me;

[0423] [ka]

[0424] R 2 is selected from alkyl or cycloalkyl;

[0425] [ka]

[0426] X is independently 1 to 2 substituents selected from halogen, hydroxy, methoxy, nitro and trifluoromethyl.

[0427] [ka]

[0428] Z is O or NH;

[0429] [ka]

[0430] HET is a monocyclic or fused bicyclic heteroaryl; In formula (LIX), --- represents an optional double bond.

[0431] In certain embodiments, the ILM of the compound has a chemical structure represented by:

[0432] [ka]

[0433] In certain embodiments, the ILM of the compound is

[0434] [ka]

[0435] [ka]

[0436] or has a chemical structure selected from the group consisting of: The term "independently" is used herein to indicate that the variable, as applied independently, varies independently from application to application.

[0437] The term "alkyl" refers, within its context, to a straight chain, branched chain, or cyclic alkyl group that may be optionally substituted. fully saturated hydrocarbon radicals or alkyl groups, preferably C1-C 10 , more preferably C1-C6, or C1-C3 alkyl groups. Examples of alkyl groups are, among others, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl group is terminally protected with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds of the present disclosure can be used to covalently bind to dehalogenase enzymes. These compounds generally contain side chains (often linked via a polyethylene glycol group) that terminate in an alkyl group with a halogen substituent (often chlorine or bromine) at the distal end, resulting in covalent attachment of the compound containing such a moiety to a protein.

[0438] 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.

[0439] 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.

[0440] The term "alkylene," when used, refers to an optionally substituted -(CH) n -group (n is generally an integer from 0 to 6). When substituted, the alkylene group is preferably substituted at one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl or t-butyl group), but may also be substituted with one or more halo groups (preferably 1 to 3 halo groups), or one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain, as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which in turn is further substituted with a polyethylene glycol chain (of 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively, at the distal end of the polyethylene glycol chain) an alkyl chain substituted with one halogen, preferably a chlorine, group. In still other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, e.g., the side chain group of a natural or unnatural amino acid, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0441] 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 that is C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, an H is present in place of the carbon.

[0442] The terms "substituted" or "optionally substituted" are intended to mean, independently (i.e., when a substituent occurs more than once, each substituent is independent of another substituent) one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, and most often 1 or 2 substituents) on a moiety in a compound of the present disclosure, which may themselves include substituents which may be further substituted at a carbon (or nitrogen) anywhere on a molecule herein, including hydroxyl, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably 1, 2, or 3 halogens, particularly alkyl, especially halogen on a methyl group such as trifluoromethyl), and the like. alkyl groups (preferably C1-C 10, more preferably C1-C6), 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 (such that the connection is on the alkylene group rather than the ester function, which is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amines (including 5- or 6-membered cyclic alkyleneamines). and further including C1-C6 alkylamines or C1-C6 dialkylamines, where the alkyl group may be substituted with one or two hydroxyl groups, or an optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) group (optionally substituted with a polyethylene glycol chain to which is further attached an alkyl group containing a single halogen, preferably chlorine, substituent); hydrazine; amide, preferably substituted with one or two C1-C6 alkyl groups (including carboxamide 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 of the present disclosure may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as otherwise described herein, and R3 is H or a C1-C6 alkyl group, preferably R1, R2, R3 in this context are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly linked to the substituted moiety, or the substituent may be an optionally substituted -(CH2) m - or optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) mThe alkylene group -(CH) may be linked via a - group to a substituted moiety (preferably in an aryl or heteroaryl moiety), which may be substituted with any one or more of the substituents described above. m -or-(CH2) n -groups, or other chains such as ethylene glycol chains as identified above, may be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which may be 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 described elsewhere herein, and optionally substituted amide (preferably carboxamido substituted as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids described elsewhere herein. In the present disclosure, moieties in a molecule may be optionally substituted with up to 5 substituents, preferably up to 3. Most often, in the present disclosure, substituted moieties are substituted with 1 or 2 substituents.

[0443] The term "substituted" (each substituent independent of any other substituent) is also intended to mean, within the context of its use, C-C alkyl, C-C alkoxy, halogen, amido, carboxamide, sulfone (including sulfonamide), keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane-OC(O)-NR1R2, or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C-C alkylene-NR1R2, including mono- or di-C-C alkyl-substituted amines optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms unless the context indicates otherwise. In certain embodiments, preferred substituents, depending on the context of the substituent's use, include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m -( where m and n are 1, 2, 3, 4, 5 or 6, in the context), -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 The alkylene groups may also be substituted with an optionally substituted C-C alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl being preferred, thus providing a chiral center), the side chain of an amino acid group as described elsewhere herein, an amide group as described herein above, or a urethane group O-C(O)-NR-R group, where R and R are as described elsewhere herein, although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with more than two substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds at certain positions in the molecule, where substitution is required (primarily due to valence) but no substitution is indicated, that substituent is interpreted or understood to be H, unless the context of the substitution suggests otherwise.

[0444] The term "aryl" or "aromatic," in context, refers to a substituted (as described elsewhere 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 of the present disclosure at any available stable position on the ring or as otherwise shown in the chemical structure provided. Other examples of aryl groups, in context, may include heterocyclic aromatic ring systems, "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a (single) ring, such as imidazole, furyl, pyrrole, furanyl, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be optionally substituted as described above. Heteroaryl groups which may be mentioned in particular 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, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclohexane-17, cyclohexane-18, cyclohexane-19, cyclohexane-20, cyclohexane-21, cyclohexane-22, cyclohexane-23, cyclohexane-24, cyclohexane-25, cyclohexane-26, cyclohexane-27, cyclohexane-28, cyclohexane-29, cyclohexane-30, cyclohexane-31, cyclohexane-32, cyclohexane-33, cyclohexane-34, cyclohexane-35, cyclohexane-46, cyclohexane-47, cyclohexane-48, cyclohexane-49, cyclohexane-51, cyclohexane-52, cyclohexane-15, cyclohexane-16, cyclohexane-17, aromatic heterocycles containing nitrogen, sulfur, and benzothiophene; aromatic heterocycles containing oxygen, such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; aromatic heterocycles containing nitrogen, sulfur, and benzophenone ... Aromatic heterocycles containing two or more heteroatoms selected from oxygen include, for example, thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoleoxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0445] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or multiple fused rings, at least one of which is aromatic, and the ring is substituted with one or more substituents. For example, an aryl group can be -(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) nand optionally substituted phenyl groups, each of which may be substituted at the ortho, meta and / or para positions of the phenyl ring, preferably at the para position; and / or 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 the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, methyl-substituted oxazoline, methyl-substituted oxazolyl ... optionally substituted oxazoles 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 thiazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl substituted pyridine or oxapyridine groups (the pyridine group is linked 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.

[0446] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where these generic substituents have the same meaning as the corresponding groups defined herein.

[0447] The terms "heteroaryl" or "hetaryl" include, but are not limited in any manner to, optionally substituted quinoline (which may be attached to a 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 benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzodiazole, optionally substituted benzodiazole, optionally substituted oxazole (preferably methyl substituted), ... Substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl and / or thiol substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably methyl groups, triisopropylsilyl groups, 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:

[0448] [ka]

[0449] During the ceremony, S c But CHR SS , N.R. URE or O, RHET 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 where R a is H or a C1-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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; Y C But N or CR YC where R YC is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0450] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both aryl and / or heteroaryl, respectively, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems as defined above.

[0451] The term "arylalkyl," as used herein, refers to an aryl group, as defined above, appended to an alkyl group, as defined above. An arylalkyl group is connected to the parent moiety through an alkyl group, and the alkyl group is 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as defined above.

[0452] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and can be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included in the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described above.

[0453] 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, isothiazolyl, and isothiazolyl. Examples include azolidinyl, isothiazolyl, 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 thirane.

[0454] Heterocyclic groups may be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, 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 may have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include 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, imidazoline, and the like. Examples of heterocyclic rings include, but are not limited to, lysine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, and N-alkoxy-nitrogen-containing heterocycles. The term "heterocycle" also includes bicyclic groups in which either of the heterocycles is fused to a benzene ring or a cyclohexane ring or to another heterocycle (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and the like).

[0455] The term "cycloalkyl" can refer to, but is not limited in any manner to, a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, for example, a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can refer to, but is not limited to, a monocyclic or polycyclic alkyl group, which can be substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, with these generic substituents having the same meaning as the corresponding group defined in this Legend.

[0456] "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 contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these common substituents have the same meaning as the definition of the corresponding group defined in this Legend.

[0457] The term "hydrocarbyl" is intended to mean compounds that contain carbon and hydrogen and that may be fully saturated, partially unsaturated or aromatic, and that include aryl, alkyl, alkenyl and alkynyl groups.

[0458] The term "independently" is used herein to indicate that the variable, as applied independently, varies independently from application to application.

[0459] The term "lower alkyl" refers to methyl, ethyl or propyl. The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0460] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A and Rn can independently be covalently linked to a linker and / or a linker connected to one or more PTM, ULM, ILM or ILM' groups.

[0461] Exemplary MLM In certain further embodiments, the MLM of the bifunctional compound comprises 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.

[0462] In a further embodiment, the MLM comprises the core structure described above with adjacent bis-aryl substitutions positioned as either cis or trans configurations.

[0463] In still further embodiments, the MLM is RG7112, RG7388, SAR4058 38, AMG-232, AM-7209, DS-5272, MK-8242 and NVP-CGM-097, as well as analogs or derivatives thereof.

[0464] In certain preferred embodiments, the MLM is a derivative of a substituted imidazoline of formula (A-1), or a thiazoloimidazoline of formula (A-2), or a spiroindolinone of formula (A-3), or a pyrrolidine of formula (A-4), or a piperidinone / morphulinone of formula (A-5), or an isoquinolinone of formula (A-6), or a pyrrolopyrimidine / imidazolopyridine of formula (A-7), or a pyrrolopyrrolidinone / imidazolopyrrolidinone of formula (A-8).

[0465] [ka]

[0466] From the above equation (A-1) to equation (A-8), X in formulas (A-1) to (A-8) is carbon, oxygen, sulfur, sulfoxide, sulfone, or Yo 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 formulas (A-1) to (A-8) may also be independently one or two atoms selected from C, N, O or S forming a fused bicyclic ring, or 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 an aryl or heteroaryl group, and a heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, and the aryl or heteroaryl group may be monocyclic or bicyclic, may be unsubstituted, or may be substituted with 1 to 3 substituents independently selected from the group consisting of: Halogen, -CN, a C1-C6 alkyl group, a C3-C6 cycloalkyl, -OH, an alkoxy having 1 to 6 carbons, a fluorine-substituted alkoxy having 1 to 6 carbons, a sulfoxide having 1 to 6 carbons, a sulfone having 1 to 6 carbons, a ketone having 2 to 6 carbons, an amide having 2 to 6 carbons, and a dialkylamine having 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 or heteroaryl group, and a heteroaryl group having 1 or 2 heteroatoms independently selected from sulfur or nitrogen, and the aryl or heteroaryl group may be monocyclic or bicyclic, may be unsubstituted, or may be substituted with 1 to 3 substituents independently selected from the group consisting of: Halogen, -CN, C1-C6 alkyl group, C3-C6 cycloalkyl, -OH, alkoxy having 1-6 carbons, fluorine-substituted alkoxy having 1-6 carbons, sulfoxide having 1-6 carbons, sulfone having 1-6 carbons, ketone having 2-6 carbons, amide having 2-6 carbons, dialkylamine having 2-6 carbons, alkyl ether (C2-C6), alkyl ketone (C3-C6), morpholinyl, alkyl ester (C3-C6), alkyl cyanide (C3-C6), R6 in formula (A-1) to formula (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) dis selected from the group consisting of alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R in formulas (A-1) to (A-8) 7 is selected from the group consisting of H, C1-C6 alkyl, cyclic alkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, and substituted 5- or 6-membered heteroaryl or aryl; R in formulas (A-1) to (A-8) 8 But -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 alkylene having 1 to 6 carbon atoms, is 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 of formula (A-3), wherein the substituents are independently selected from the group consisting of halogen, alkene, alkyne, alkyl, unsubstituted or substituted with Cl or F; R in formulas (A-1) to (A-8) 10is selected from the group consisting of aryl or heteroaryl groups, the heteroaryl group can contain one or two heteroatoms as sulfur or nitrogen, the aryl or heteroaryl group can be monocyclic or bicyclic, the aryl or heteroaryl group can 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 having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons; R in formulas (A-1) to (A-8) 11 But -C(O)-N(R h )(R i ) where R h and R i is selected from the group consisting of: H, optionally substituted straight or branched chain C1-C6 alkyl, alkoxy-substituted alkyl, monohydroxy- and dihydroxy-substituted alkyl (e.g., C3-C6), sulfone-substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, mono-, di-, or tri-substituted aryl or heteroaryl, phenyl-4-carboxylic acid, substituted phenyl-4-carboxylic acid, alkylcarboxylic acid, optionally substituted heteroarylcarboxylic acid, alkylcarboxylic acid, fluorine-substituted alkylcarboxylic acid, optionally substituted cycloalkyl, 3-hydroxycyclobutane, 4-hydroxycyclohexane, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl, or R h and R i together to form a ring, R in formulas (A-1) to (A-8) 12 and R 13is 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 ring aryl, and heteroaryl; R 12 and R 13 can be connected to form 5- and 6-membered rings, with or without substitution on the ring; 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, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl; R in formulas (A-1) to (A-8) 15 But it is CN, R in formulas (A-1) to (A-8) 16 However, one or more hydrogen atoms are replaced by fluorine atoms. 1-6 Alkyl, C 1-6 Cycloalkyl, C 2-6 Alkenyl, C 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 the 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), C in which a hydrogen is replaced by a hydroxyl group 1-6 and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is selected from the group consisting of alkylalkyl-cycloalkyl, 3-7 membered cycloalkyl or heterocycloalkyl, optionally containing a -(C=O)- group, or 5-6 membered aryl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group may contain 1-3 heteroatoms independently selected from O, N, and S, and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is selected from the group consisting of Unsubstituted or halogen, C 1-6 Alkyl groups, hydroxylated C 1-6 Alkyl, C 1-6 optionally substituted with 1 to 3 substituents independently selected from alkyl-containing thioether, ether, sulfone, sulfoxide, fluorine-substituted ether, or cyano group; R in formulas (A-1) to (A-8) 17 But (CH2) n C(O)NR k R l wherein R k and R l However, independently, H, C 1-6 Alkyl, Hydroxylated C 1-6 Alkyl, C 1-6 Alkoxyalkyl, C in which one or more hydrogens are replaced by fluorine 1-6 Alkyl, one carbon replaced by S(O), S(O)(O) 1-6 Alkyl, C in which one or more hydrogens are replaced by fluorine 1-6 Alkoxyalkyl, C in which hydrogen is replaced by a cyano group 1-6 selected from alkyl, 5-6 membered aryl or heteroaryl, alkylaryl in which the alkyl group contains 1-6 carbons, and alkylheteroaryl in which the alkyl group contains 1-6 carbons, and the aryl or heteroaryl group may 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)-(heterocycle-substituted)-cycloalkyl]; R in formulas (A-1) to (A-8) 19 is selected from the group consisting of aryl, heteroaryl, bicyclic heteroaryl, and the aryl or heteroaryl group is selected from the group consisting of halogen, C 1-6Alkyl, C 1-6 It may be substituted with cycloalkyl, CF, F, CN, alkyne, alkylsulfone, and the halogen substitution may be mono-, di-, or tri-substituted; R in formulas (A-1) to (A-8) 20 and R 21 But independently, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-6 Alkoxy, Hydroxylated C 1-6 Alkoxy and Fluorine Substituted C 1-6 alkoxy, wherein R 20 and R 21 can be further connected to form 5-, 6-, and 7-membered cyclic or heterocyclic rings, which can be further substituted; R in formulas (A-1) to (A-8) 22 But H, C 1-6 Alkyl, C 1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea, nitrogen-containing five-membered heterocycle, wherein the five-membered heterocycle is selected from the group consisting of C 1-6 may be further substituted with 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, -N(alkyl)-heteroaryl, and the aryl or heteroaryl group is selected from halogen, C 1-6 Alkyl, Hydroxylated C 1-6 Alkyl, cycloalkyl, fluorine-substituted C 1-6 optionally substituted with alkyl, CN, alkoxy, alkylsulfone, amide, and sulfonamide; R in formulas (A-1) to (A-8) 24 But -CH2-(C 1-6-alkyl), -CH-cycloalkyl, -CH-aryl, CH-heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloaryl, and substituted cycloalkyl; R in formulas (A-1) to (A-8) 25 But C 1-6 Alkyl, C 1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-, 6- and 7-membered nitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocycles, wherein these saturated heterocycles are selected from the group consisting of C 1-6 Alkyl, Fluorine-substituted C 1-6 Alkyl, alkoxy and optionally substituted with aryl, aryl, and heteroaryl groups; R in formulas (A-1) to (A-8) 26 is C 1-6 Alkyl, C 3-6 cycloalkyl, wherein 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, bicyclic heteroaryl, and the aryl or heteroaryl group is C 1-6 may be substituted with alkyl, alkoxy, NH, NH-alkyl, halogen, or -CN, and the substitution may be mono-, di-, or tri-substituted; R in formulas (A-1) to (A-8) 28is selected from the group consisting of aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle, such as piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl, saturated heterocycle, aryl, or heteroaryl may be further substituted with -OH, alkoxy, and may be further substituted with mono-, di-, or tri-substituted groups including halogen, -CN, alkylsulfone, and fluorine-substituted alkyl groups; R in formulas (A-1) to (A-8) 1” is selected from the group consisting of H, alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0467] 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.

[0468] More specifically, non-limiting examples of MLMs include those shown below, as well as "hybrid" molecules resulting from combining one or more of the different features shown in the molecules below.

[0469] Using the MLMs of Formulas A-1 through A-8, the following PROTACs can be prepared to target specific proteins for degradation, where "L" is a connector (i.e., a linker group) and "PTM" is a ligand bond to the target protein.

[0470] In certain embodiments, the present description

[0471] [ka]

[0472] providing a bifunctional molecule comprising a structure selected from Formula X, R a , Y, Z, A, A', A"', R1, R2, R3, R4, R5, R6, R b , R c , R d , R7, R e , R f , R g , R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R k , R l , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 and R 1” as described herein with respect to Formulas (A-1) through (A-8).

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

[0474] [ka]

[0475] During the ceremony, R in formulas A-1-1 to A-1-4 (i.e., A-1-1, A-1-2, A-1-3 and A-1-4) 1’ and R 2’are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF3, and NO2; R 3’ is selected from the group consisting of -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3 and -OCH(CH3)2; R in formulas A-1-1 to A-1-4 4’ is selected from the group consisting of 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)2CH2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C(CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O2)CH2CH3, -NHC(CH3)3, -N(CH3)2, pyrrolidinyl and 4-morpholinyl; R in formulas A-1-1 to A-1-4 5’ 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; R in formulas A-1-1 to A-1-4 6’ is selected from the structures shown below, wherein the linker attachment points are * " is shown.

[0476] R as a linker attachment point 6’ In addition, R 4’ can also function as a linker attachment point. 4’ is the linker attachment site, the linker is 4’ It is connected to the terminal atom of the group.

[0477] In certain embodiments, the linker attachment position of Formulas A-1-1 to A-1-4 is R 4’ or R 6’At least one of these, or both.

[0478] In certain embodiments, R of formulas A-1-1 to A-1-4 6’ But independently, H,

[0479] [ka]

[0480] [ka]

[0481] wherein the formula is selected from the group consisting of: * " indicates a linker connection point. In certain embodiments, the linker of formulas A-4-1 to A-4-6 is R 1’ , R 2’ , R3 ’ , R 4’ , R 5’ , R 6’ or a combination thereof.

[0482] In certain embodiments, the present description provides bifunctional or chimeric moieties having the following structure: PTM-L-MLM, where PTM is a protein target binding moiety linked to MLM by L, and L is a bond (i.e., absent) or a chemical linker. In certain embodiments, MLM has a structure selected from the group consisting of A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6,

[0483] [ka]

[0484] During the ceremony, R in formulas 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)7’ is one or more (e.g., 1, 2, 3, 4) halogens; R in Equations A-4-1 to A-4-6 8’ -H, -F, -Cl, -Br, -I, -CN, -NO2, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C 1-6 Alkyl, other C 1-6 Alkenyl and C 1-6 one or more groups (e.g., 1, 2, 3, or 4 groups) selected from the group consisting of alkynyl, mono-, di-, or tri-substituted; R in Equations A-4-1 to A-4-6 9’ 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 of formulae A-4-1 to A-4-6 is selected from the group consisting of H, —OCH 3 , —OCH 2 CH 3 and halogen; R in Equations A-4-1 to A-4-6 10’ and R 11’ are each independently H, (CH2) n -R', (CH2) n -NR'R”, (CH2) n -NR'COR”, (CH2) n -NR'SO2R”, (CH2) n -COOH, (CH2) n -COOR', (CH) n -CONR'R”, (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”, (CH2CH2O) m -(CH2)n -R'、(CH2CH2O) m -(CH2) n -OH、(CH2CH2O) m -(CH2) n -OR'、(CH2CH2O) m -(CH2) n -NR'R”、(CH2CH2O) m -(CH2) n -NR'COR”、(CH2CH2O) m (CH2) n -NR'SO2R”、(CH2CH2O) m (CH2) n -COOH、(CH2CH2O) m (CH2) n -COOR'、(CH2CH2O) m -(CH2) n -CONR'R”、(CH2CH2O) m -(CH2) n -SO2R'、(CH2CH2O) m -(CH2) n -COR'、(CH2CH2O) m -(CH2) n -SONR'R”、(CH2CH2O) m -(CH2) n -SO2NR'R”、(CH2) p -(CH2CH2O) m -(CH2) n R'、(CH2) p -(CH2CH2O) m -(CH2) n -OH、(CH2) p -(CH2CH2O) m -(CH2) n -OR',(CH2) p -(CH2CH2O) m -(CH2) n -NR'R”、(CH2) p -(CH2CH2O) m -(CH2) n -NR'COR”、(CH2) p -(CH2CH2O) m -(CH2) n -NR'SO2R”、(CH2)p -(CH2CH2O) m -(CH2) n -COOH, (CH2) p -(CH2CH2O) m -(CH2) n -COOR', (CH2) p -(CH2CH2O) m -(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 -SO2NR'R", aryl-(CH2) n -COOH and heteroaryl-alkyl-CO-alkyl-NR'R"m, wherein the alkyl is optionally substituted with OR', and heteroaryl-(CH2) n -heterocycles, said heterocycles being optionally substituted with alkyl, hydroxyl, COOR' and COR', wherein R' and R" are selected from H, alkyl, halogen, hydroxyl, NH, NH(alkyl), N(alkyl), oxo, carboxy, alkyl substituted with cycloalkyl and heteroaryl; m, n, and p are independently 0 to 6; R in Equations A-4-1 to A-4-6 12’ 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); R in Equations A-4-1 to A-4-6 1” is selected from the group consisting of H, alkyl, aryl-substituted alkyl, aroxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0485] In any of the aspects or embodiments described herein, alkyl, alkoxy, etc. may be lower alkyl or lower alkoxy.

[0486] In certain embodiments, the linker attachment positions of formulas A-4-1 to A-4-6 are Z, R 8’ , R 9’ , R 10’ , R 11” , R 12” or R 1” At least one of the following is true:

[0487] The methods used to design the chimeric molecules shown in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLMs having formulas A-2, A-3, A-5, A-6, A-7, and A-8, and the solvent-exposed regions in the MLMs can be connected to linkers "L" that bind to target protein ligands "PTMs" to construct PROTACs.

[0488] In any aspect or embodiment described herein, the MLM comprises:

[0489] [ka]

[0490] is selected from. Exemplary MDM2 binding moieties include, but are not limited to, the following:

[0491] 1. 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 HDM2 / MDM2 inhibitors as identified in "Protein degradation induced by a small molecule: An route to chemical proteomics," Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or alternatively including) the (derivatized) compounds Nutlin-3, Nutlin-2 and Nutlin-1 as described below, and all derivatives and analogues thereof,

[0492] [ka]

[0493] (The linker group L or -(L-MLM) group is derivatized when attached, for example, with a methoxy group or as a hydroxyl group.)

[0494] [ka]

[0495] (The linker group L or -(L-MLM) group is derivatized when attached, for example, by a methoxy or hydroxyl group.)

[0496] [ka]

[0497] (derivatized when the linker group L or -(L-MLM) group is attached, for example, via a methoxy group or as a hydroxyl group), and 2. trans-4-iodo-4'-boranyl chalcone

[0498] [ka]

[0499] (The linker group L or the linker group L or -(L-MLM) group is derivatized when attached, for example, via a hydroxy group).

[0500] Exemplary CLM Neoimide Compounds In one aspect, the present description provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compounds have the following chemical structure:

[0501] [ka]

[0502] [ka]

[0503] wherein: W in formulas (a) through (f) is independently selected from the group of CH, CHR, C=O, SO, NH, and N-alkyl; X in formulas (a) through (f) is independently selected from the group of O, S, and H2; Y in formulas (a) through (f) is independently selected from the group: CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a) through (f) is independently selected from the group of O, S, or H2, with the proviso that X and Z cannot both be H2; G and G' of formulas (a) to (f) are independently selected from the group consisting of H, optionally substituted straight or branched chain alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) represent a carbon C substituted with a group independently selected from R', N, or N-oxide; Formula A of formulas (a) through (f) is independently selected from the group consisting of H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; R in formulas (a) to (f) includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n 'R", -aryl, -hetaryl, optionally substituted straight or branched chain alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'C OR”, -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 (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, —C(═O)R, and heterocyclyl, each of which is optionally substituted; n' in formulas (a) through (f) is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); Equations (a) to (f)

[0504] [ka]

[0505] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R in equations (a) to (f) ncontains 1 to 4 independently selected functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy.

[0506] Exemplary CLM In any of the compounds described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0507] [ka]

[0508] [ka]

[0509] During the ceremony, W in formulas (a) through (f) is independently selected from the group of CH, CHR, C=O, SO, NH, and N-alkyl; X in formulas (a) through (f) is independently selected from the group of O, S, and H2; Y in formulas (a) through (f) is independently selected from the group: CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a) through (f) is independently selected from the group of O, S, or H2, with the proviso that X and Z cannot both be H2; G and G' of formulas (a) to (f) are independently selected from the group consisting of H, optionally substituted straight or branched chain alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A in formulas (a) through (f) is independently selected from the group consisting of H, alkyl (straight chain, branched chain, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) to (f) includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP (O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR' C(=N-CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3, R′ and R″ of formulas (a) through (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, —C(═O)R, and heterocyclyl, each of which is optionally substituted; n in formulas (a) through (f) is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); Equations (a) to (f)

[0510] [ka]

[0511] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R in equations (a) to (f) ncomprises 1 to 4 independently selected functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0512] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of:

[0513] [ka]

[0514] During the ceremony, W of formula (g) is independently selected from the group of CH2, C=O, NH and N-alkyl; R of formula (g) is independently selected from H, methyl, or optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl); In equation (g),

[0515] [ka]

[0516] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; R in formula (g) ncomprises 1 to 4 independently selected functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0517] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A and R of formulas (a) through (g) n can be independently covalently attached to a linker and / or a linker connected to one or more PTM, ULM, CLM, or CLM′ groups.

[0518] In any of the aspects or embodiments described herein, R n comprises 1 to 4 independently selected functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0519] In any of the aspects or embodiments described herein, R n contains 1 to 4 functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, amine, amide, or carboxy, optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0520] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules resulting from combining one or more of the different features shown in the molecules below.

[0521] [ka]

[0522] [ka]

[0523] [ka]

[0524] [ka]

[0525] [ka]

[0526] [ka]

[0527] [ka]

[0528] [ka]

[0529] [ka]

[0530] [ka]

[0531] In any of the compounds described herein, the CLM may be selected from the following groups:

[0532] [ka]

[0533] [ka]

[0534] [ka]

[0535] [ka]

[0536] wherein: W is independently selected from CH, CHR, C=O, SO, NH, and N-alkyl; Q1, Q2, Q3, Q4 and Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N or N-oxide; R 1 is absent or selected from H, OH, CN, C1-C3 alkyl, and C=O; R 2 is absent or selected from the group H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2; R 3 is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently H, halogen, C(=O)R', CN, OH, or CF; X is C, CH, C═O or N; X1 is C=O, N, CH or CH2; R' is H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl; n is 0 to 4,

[0537] [ka]

[0538] is a single bond or a double bond, The CLM is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0539] In any aspect or embodiment described herein, the CLM or CLM′ may be an R group (e.g., R, R 1 , R 2 , R 3 , R 4 or R′), W, X or Q group (e.g., Q1, Q2, Q3, Q4 or Q5) to a PTM, chemical linker group (L), ULM, CLM, CLM′, or combination thereof.

[0540] In any of the embodiments described herein, CLM or CLM′ is selected from the group consisting of W, X, R , R 1 , R 2 , R 3 , R4 , 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.

[0541] In any of the embodiments described herein, W, X, R 1 , R 2 , R 3 , R 4 , R', Q1, Q2, Q3, Q4 and Q5 can independently be covalently attached to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0542] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds that result from combining features of one or more of the following compounds:

[0543] [ka]

[0544] [ka]

[0545] [ka]

[0546] During the ceremony, W is independently selected from the group: CH, CHR, C=O, SO, NH, and N-alkyl; R 1 is absent or selected from the group H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl; R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R 4 is methyl or ethyl, R 5 is H or halo, R 6 is H or halo, R of CLM is H, R' is H or the attachment point of a PTM, PTM', chemical linker group (L), ULM, CLM, CLM'; Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;

[0547] [ka]

[0548] is a single bond or a double bond, Rn includes functional groups or atoms.

[0549] In any of the embodiments described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4 and Rn can independently be covalently linked to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0550] In any of the embodiments described herein, R 1 , R 2 , Q1, Q2, Q3, Q4 and Rn can independently be covalently linked to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0551] In any of the embodiments described herein, Q1, Q2, Q3, Q4 and Rn can independently be covalently linked to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0552] In any aspect or embodiment described herein, R n is modified to covalently attach 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.

[0553] In any aspect or embodiment described herein, the CLM is

[0554] [ka]

[0555] [ka]

[0556] wherein R' is halogen and R 1 as described in any aspect or embodiment described herein.

[0557] In certain cases, 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:

[0558] [ka]

[0559] Exemplary VLM In certain embodiments of the compounds described herein, the ULM is a VLM and comprises a chemical structure selected from the ULM-a group:

[0560] [ka]

[0561] 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 connecting at least one PTM, a ULM', or VLM' or CLM' or ILM' or MLM' to the other end of the linker; X in the formula ULM-a 1 , X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO; R in the formula ULM-a Y3 , R Y4 each independently represents a straight or branched chain C optionally substituted with H, one or more halo 1-6 alkyl, optionally substituted (e.g., 0-3 R P Optionally substituted with a C group 1-6 is selected from the group consisting of alkoxyl, R in the formula ULM-a P are each independently H, halo, -OH, C 1-3 alkyl, C=O; Formula ULM-a W 3 is an optionally substituted T, an optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-biheteroaryl, optionally substituted -T-heterocyclyl, optionally substituted -T-biheterocyclyl, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocyclyl, X in the formula ULM-a 3 is C=O, R 1 , R1a , R 1b and R 1 , R 1a , R 1b each independently represents 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, T of formula ULM-a is optionally substituted alkyl, —(CH) n - groups, wherein each methylene group is selected from the group consisting of halogen, methyl, a straight or branched C1-C6 alkyl group optionally substituted with one or more halogens, C(O)NR 1 R 1a , or NR 1 R 1a or R 1 and R 1a are connected to form an optionally substituted heterocyclyl, or an —OH group or an optionally substituted amino acid side chain, Formula ULM-a W 4 is an optionally substituted -NR1-T-aryl, wherein the aryl group can be an optionally substituted 5- to 6-membered heteroaryl, or an optionally substituted aryl, an optionally substituted -NR1-T-heterocycle, wherein -NR1 is X 2 covalently bonded to R 1 is H or CH3, preferably H, n is 0 to 6, often 0, 1, 2, or 3, and preferably 0 or 1.

[0562] In any of the embodiments described herein, T is optionally substituted alkyl, —(CH)n - groups, wherein each methylene group is selected from the group consisting of halogen, methyl, optionally substituted alkoxy, straight or branched C1-C6 alkyl groups optionally substituted with one or more halogens, C(O)NR 1 R 1a , or NR 1 R 1a Selected from the group optionally substituted with one or two substituents, or R 1 and R 1a are linked to form an optionally substituted heterocycle, or an —OH group, or an optionally substituted amino acid side chain, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

[0563] In certain embodiments, W of formula ULM-a 4 but,

[0564] [ka]

[0565] and W 5 is optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl (e.g., optionally substituted with one or more [1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy), and R 14a , R 14b are each independently selected from the group H, haloalkyl, or optionally substituted alkyl.

[0566] In any of the embodiments, W of formula ULM-a 5 is an optionally substituted phenyl or an optionally substituted 5- to 10-membered heteroaryl (e.g., W 5is selected from the group of optionally substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; R in the formula ULM-a 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

[0567] In additional embodiments, W for use in the present disclosure 4 Substituents may also be any of the W groups found in certain compounds disclosed herein. 4 These W groups are specifically included (and are not limited to the particular compounds disclosed). 4 Each of the substituents may be any number of W as also disclosed herein. 3 It may be used in conjunction with a substituent.

[0568] In certain additional embodiments, ULM-a has 0 to 3 R in the pyrrolidine moiety. P Each R is optionally substituted by a group. P are independently H, halo, -OH, C 1-3 Alkyl, C=O.

[0569] In any of the embodiments described herein, W of formula ULM-a 3 , W 4 can be independently covalently attached to a linker that is attached to one or more PTM groups; wherein the dashed lines indicate the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

[0570] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0571] [ka]

[0572] During the ceremony, W in formula ULM-b 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0573] [ka]

[0574] 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 optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0575] [ka]

[0576] 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 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; 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 an optionally substituted phenyl or an optionally substituted 5- to 10-membered heteroaryl (e.g., W 5 is selected from the group of optionally substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; R in formula ULM-b 15 H, halogen, CN, OH, NO2, NR 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; Each R in formula ULM-b 16 is independently selected from the group of halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; o of formula ULM-b is 0, 1, 2, 3, or 4; R in formula ULM-b 18is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; The p of formula ULM-b is 0, 1, 2, 3, or 4, where the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0577] In certain embodiments, R of formula ULM-b 15 teeth,

[0578] [ka]

[0579] where R 17 is H, halo, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl, and C 1-6 haloalkyl, and Xa is S or O.

[0580] In certain embodiments, R of formula ULM-b 17 is selected from the group of methyl, ethyl, isopropyl, and cyclopropyl.

[0581] In certain additional embodiments, R of formula ULM-b 15 is selected from the group consisting of:

[0582] [ka]

[0583] [ka]

[0584] In certain embodiments, R of formula ULM-b 11 is selected from the group consisting of:

[0585] [ka]

[0586] [ka]

[0587] In certain embodiments, ULM has a chemical structure selected from the group consisting of:

[0588] [ka]

[0589] During the ceremony, R1 of ULM-c, ULM-d and 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 ULM-c, ULM-d, and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R of ULM-c, ULM-d, and ULM-e 15 is selected from the group consisting of H, halogen, CN, OH, NO, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted and optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; X of ULM-c, ULM-d and ULM-e is C, CH or C=O; R3 of ULM-c, ULM-d and ULM-e is absent or an optionally substituted 5- or 6-membered heteroaryl; The dashed lines indicate the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

[0590] In certain embodiments, a ULM comprises a group according to the following chemical structure:

[0591] [ka]

[0592] During the ceremony, R in the formula ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f is H; R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 but,

[0593] [ka]

[0594] [ka]

[0595] or optionally substituted heteroaryl; of the formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18is 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 is H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl,

[0596] [ka]

[0597] 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 connects at least one PTM or ULM', or both, to ULM.

[0598] In certain embodiments, ULM is selected from the following structures:

[0599] [ka]

[0600] [ka]

[0601] In the formula, n is 0 or 1. In certain embodiments, ULM is selected from the following structures:

[0602] [ka]

[0603] [ka]

[0604] [ka]

[0605] wherein the phenyl rings in 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 that connects at least one PTM or ULM', or both, to ULM.

[0606] In one embodiment, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, U The phenyl rings in LM-c1 through ULM-c15, and ULM-d1 through ULM-d9 can be functionalized as esters to become part of a prodrug.

[0607] 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.

[0608] 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:

[0609] [ka]

[0610] or a pharmaceutically acceptable salt thereof, wherein: ULM-g R 1’ is an optionally substituted C1-C6 alkyl group, an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6) alkyl groups, optionally substituted (CH2) containing an epoxide moiety WCOCW, where each W is independently H or a C1-C3 alkyl group. n -WCOCW-(C0-C6) 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-C6 alkyl), optionally substituted -(CH2CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) nNHC(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 C=O, C=S, -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 R 2N group, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -(C=O) v NR1(SO2) w -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 -aryl-heteroaryl, 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 -(CH2) n -(O) u (NR1) v (SO2) w -alkyl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR1N R 2N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -NR1-(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 -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted -(CH2)n -(V) n’ -(CH2) n -(V) n’ -heterocyclic 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 -(CH2) 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, ULM-g R 1N and R 2N are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups and up to three halogen groups, or substituted with -(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, ULM-g R 1 and R 1’ are each independently H or a C1-C3 alkyl group; ULM-g X R2’ and X R3’ each independently represents an optionally substituted —(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' of ULM-g is independently 0 or 1; each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; each n' of ULM-g is independently 0 or 1; each u in ULM-g is independently 0 or 1; each v of ULM-g is independently 0 or 1; each w of ULM-g is independently 0 or 1; If the PTM is not ULM', the R of ULM-g 1’ , R 2’ , R 3’ any one or more of X and X′ are optionally modified and covalently linked to said PTM group via a linker group, or when PTM is ULM′, R of each of ULM and ULM′ 1’ , R 2’ , R 3’ 6. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, 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 via a linker group.

[0611] 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:

[0612] [ka]

[0613] During the ceremony, Each R of ULM-h 1’ , R 2’ , and R 3’ is the same as above, and X is a C=O, C=S, -S(O) or S(O) group, more preferably a C=O group; If the PTM is not ULM', the R of ULM-h 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to further covalently link to the PTM group, or when the PTM is a ULM′, R of each of the ULM and ULM′ 1’ , R 2’ , R 3’ Any one or more of the above may be optionally modified to be covalently bonded to each other directly or via a linker group. group, or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof.

[0614] 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:

[0615] [ka]

[0616] During the ceremony, If the PTM is not ULM', the R of ULM-I 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to further covalently link to the PTM group, or when the PTM is a ULM′, R of each of the ULM and ULM′ 1’ , R 2’ , R 3’ any one or more of which are optionally modified to be covalently linked to each other directly or via a linker group; or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof.

[0617] In a further preferred embodiment of the present disclosure, R of ULM-g to ULM-i 1’ is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxylic acid group such that the compound represents a prodrug form of the active compound. Exemplary preferred R 1’ Examples of the group include -(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. R 1’ is or contains a carboxylic acid group, a hydroxyl group, or an amine group, the hydroxyl group, carboxylic acid group, or amine (each of which may be optionally substituted) may be further chemically modified to provide a covalent bond to a linker group to which a PTM group (including a ULM' group) is attached.

[0618] 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.

[0619] ULM-g~ULM-i R 2’ is preferably an optionally substituted —NR 1 -T-aryl (e.g., optionally substituted NH-T-aryl or optionally substituted N(CH3)-T-aryl), optionally substituted -NR 1 -T-heteroaryl groups (e.g., optionally substituted NH-T-heteroaryl or optionally substituted N(CH3)-T-heteroaryl), or optionally substituted -NR 1 -T-heterocyclyl (e.g., optionally substituted NH-T-heterocyclyl or optionally substituted N(CH)-T-heterocyclyl), wherein R 1 is H or CH, preferably H, and T is an optionally substituted -(CH) n - group, each of the methylene groups preferably being optionally substituted with one or two substituents selected from halogen, an amino acid side chain as described elsewhere herein, or a C1-C3 alkyl group, preferably one or two methyl groups which may be optionally substituted, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T may also be -(CHO) n -group, a-(OCH2) n - group, a-(CH2CH2O) n - group, -(OCH2CH2) n - groups, all of which are optionally substituted.

[0620] ULM-g~ULM-i R 2’Preferred aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, where the phenyl or naphthyl group is linked to a PTM (including a ULM′ group) with a linker group and / or optionally a halogen (preferably F or Cl), an amine, a monoalkyl, or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which is ortho, meta, and / or CN groups) of the phenyl ring. optionally substituted phenyl groups (which themselves are optionally linked to a PTM group, including a ULM′ having a linker group) optionally substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), and / or naphthyl groups (which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), optionally substituted heteroaryls, preferably methyl-substituted isoxazoles optionally substituted isoxazoles, optionally substituted oxazoles including methyl 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 substituted diazole groups including methyldiazole groups, methyl optionally substituted triazole groups, including methyl-substituted triazole groups; optionally substituted pyridine groups, including halo (preferably F), or methyl-substituted pyridine groups, or oxapyridine groups (where the pyridine group is attached to the phenyl group by an oxygen); optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine, or azaindolizine (2, 3, or 4-azaindolizine); optionally substituted quinoline; optionally substituted groups according to the chemical structure:

[0621] [ka]

[0622] During the ceremony, ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or is an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or 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 methyl or 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 taken 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), 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), each of which groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0623] In certain preferred embodiments, ULM-g to ULM-i

[0624] [ka]

[0625] teeth,

[0626] [ka]

[0627] It is the basis, In the formula, R of ULM-g to ULM-i PRO and n is the same as above.

[0628] 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:

[0629] [ka]

[0630] During the ceremony, ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R of ULM-g to ULM-i a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 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 of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), each of which groups can be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0631] ULM-g~ULM-i R 2’ Preferred heterocyclic groups for include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidone, Examples of suitable aryl groups include aryl, aryl, aryl morpholine, aryl oxane, aryl thiane ...

[0632] [ka]

[0633] Preferably,

[0634] [ka]

[0635] It is the 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 heterocyclyl group; ULM-g~ULM-i R PRO1 and R PRO2are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of these groups can optionally be linked to a PTM group (including a ULM′ group) via a linker group.

[0636] Preferred R of ULM-g to ULM-i 2’ Substituents also include the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and its accompanying drawings. 2’ These R 2’ Each of the substituents may be any number of R 3’ It may be used in conjunction with a substituent.

[0637] R from ULM-g to ULM-i 3’ is preferably an optionally substituted T-aryl, an optionally substituted T-heteroaryl, an optionally substituted T-heterocyclyl, an optionally substituted NR 1 -T-aryl (e.g., optionally substituted NH-T-aryl, optionally substituted N(CH3)-T-aryl, or optionally substituted N(C1-C3 alkyl)-T-aryl), optionally substituted -NR 1 -T-heteroaryl (e.g., optionally substituted NH-T-heteroaryl, optionally substituted N(CH3)-T-aryl, or optionally substituted N(C1-C3 alkyl)-T-heteroaryl), or optionally substituted NR 1 -T-heterocyclyl (e.g., optionally substituted NH-T-heterocyclyl, optionally substituted N(CH)-T-heterocyclyl, or optionally substituted N(C-C alkyl)-T-heterocyclyl), wherein R 1 is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted -(CH2) n- group, each one of the methylene groups being optionally substituted with one or two substituents. It may be optionally substituted, preferably with a substituent selected from halogen, a C1-C3 alkyl group, or the side chain of an amino acid as otherwise described herein, preferably methyl, which may be optionally substituted, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T may also be -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - groups, each of which is optionally substituted.

[0638] ULM-g~ULM-i R 3’ Preferred aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, which are optionally linked to a PTM group (including a ULM′ group) via a linker group, and / or are selected from the group consisting of halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably dimethylamine), amide group (preferably —(CH) m -NR1C(O)R2 group (where m, R1, 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 heterocyclyl group, or -(CH2) mand (R″) groups), each of which may be substituted at the ortho, meta, and / or para positions on the phenyl ring (preferably the para position), or may be an aryl (preferably phenyl), heteroaryl, or heterocycle. Preferably, the substituted phenyl group is an optionally substituted phenyl group (i.e., the substituted 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), where the substitution occurs at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), a naphthyl group, which may be optionally substituted, including as described above, an optionally substituted heteroaryl (preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, an optionally substituted oxazole, including methyl-substituted oxazole, a ... optionally substituted thiazoles, including substituted thiazoles; optionally substituted pyrroles, including methyl-substituted pyrroles; optionally substituted imidazoles, including methylimidazoles; benzylimidazole or methoxybenzylimidazole; oximidazole or methyloximidazole; optionally substituted diazole groups, including methyldiazole groups; optionally substituted triazole groups, including methyl-substituted triazole groups; pyridine groups, including halo- (preferably F) or methyl-substituted pyridine groups, or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen); or optionally substituted heterocycles, such as tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane. Each of the aryl, heteroaryl, and heterocycle groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

[0639] 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- 1,2,3-triazole substituted with a C1-C6 alkyl group), optionally substituted pyridine (2-, 3, or 4-pyridine), or a group according to the following chemical structure:

[0640] [ka]

[0641] During the ceremony, ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 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 of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl). Each of said heteroaryl groups may optionally be linked / bonded to a PTM group (including a ULM' group) via a linker.

[0642] ULM-g~ULM-i R 3’ Preferred heterocyclic groups for the compound include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran ... tetrahydrothiophene, oxane, and thiane, each of which may be optionally substituted or a group conforming to the following chemical structure:

[0643] [ka]

[0644] , preferably

[0645] [ka]

[0646] It is the basis, During the ceremony, ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or 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 methyl or 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 taken together form a keto group; Each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of the heterocyclic groups may optionally be linked / bonded to a PTM group (including a ULM′ group) via a linker group.

[0647] Preferred R of ULM-g to ULM-i 3’ Substituents also include the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and its accompanying drawings. 3’ These R 3’ Each of the substituents may be any number of R 2’ It may be used in conjunction with a substituent.

[0648] In certain alternative preferred embodiments, the R of ULM-g to ULM-i 2’ is an optionally substituted -NR1-X R2’ -Alkyl group, -NR1-X R2’ -aryl group, optionally substituted -NR1-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 ) and ULM-g~ULM-i X R2’ 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; ULM-g~ULM-i 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; 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 end-capped 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); HET of ULM-g through ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

[0649] [ka]

[0650] ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), ), or an optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 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 of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YCwhere R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0651] ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or 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 methyl or 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 taken together form a keto group; Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0652] Each of the groups may optionally be linked / attached to a PTM group (including a ULM' group) via a linker.

[0653] In certain alternative preferred embodiments of the present disclosure, R of ULM-g to ULM-i 3’ is an optionally substituted -(CH2)n -(V) n’ -(CH2) n -(V) n’ -R S3’ group, 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’ But -(CH2) n -, -(CH2CH2O) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, or a C3-C6 cycloalkyl group, all of which are optionally substituted; X v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; alkyl is optionally substituted C-C 10 Alkyl (preferably C1-C6 alkyl) groups (in certain preferred embodiments, the alkyl group is a halo group, often Cl or is end-capped with Br), aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET 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 (each of which, if 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:

[0654] [ka]

[0655] ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 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 of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0656] ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or 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 methyl or 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 taken 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, Each n' of ULM-g to ULM-i is 0 or 1, wherein the compound, preferably each alkyl, aryl, or Het group, is optionally linked / bonded to a PTM group (including a ULM′ group) via a linker.

[0657] In an alternative embodiment, R of ULM-g to ULM-i 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET, or -(CH2CH2O) n -HET, During the ceremony, The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, and the substituent(s) is preferably —(CH) n OH, C1-C6 alkyl (itself optionally further substituted with CN), halo (up to 3 halo groups), OH, -(CH2)n selected from O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl groups on the amine are 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 groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG group, 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 optionally substituted with a carboxyl group), or The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrole optionally substituted with a heterocycle, including heteroaryl, selected from the group consisting of lysine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (wherein, if substituted, each is preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

[0658] [ka]

[0659] ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a 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 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i RURE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) C-C alkyl (e.g., CF), optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) C≡CR, an optionally substituted acetylenic group, or an optionally substituted acetylenic group, -C≡CR, substituted with a silyl group or up to three halo groups. a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0660] ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or 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 methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; HET of ULM-g through ULM-i is preferably oxazole, isoxazole, thiazole, 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 halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the following chemical structure:

[0661] [ka]

[0662] ULM-g~ULM-i S c But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS H, CN, NO, halo (preferably F or C l), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 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 of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But 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 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0663] 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 taken together form a keto group; each m' of ULM-g to ULM-i is independently 0 or 1; each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); wherein the compound, preferably each of the aryl or HET groups, is optionally linked / bonded to a PTM group (including a ULM′ group) via a linker group.

[0664] In yet additional embodiments, preferred compounds include compounds according to the following chemical structure:

[0665] [ka]

[0666] 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; ULM-i R 3’ But -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 C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted), -(CH2) n OCH3 group, where n is 1 or 2 (preferably 2), or

[0667] [ka]

[0668] 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 but,

[0669] [ka]

[0670] It is the basis, the aryl of ULM-i is phenyl, HET of ULM-i is an optionally substituted thiazole or isothiazole; ULM-i R HET is H or a halo group (preferably H), or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, each of which is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0671] In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[0672] [ka]

[0673] During the ceremony, each R5 and R6 of ULM-i 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, optionally substituted heterocycle, or

[0674] [ka]

[0675] and Each R9 and R of ULM-j 10 are independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulfide bonded to a ULM, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; ULM-j R 11 is an optionally substituted heterocycle, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, or

[0676] [ka]

[0677] and ULM-j R 12 is H or optionally substituted alkyl; ULM-j 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; 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, CN, 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 be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH, Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; ULM-j is a bifunctional compound or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein o of ULM-j is 0, 1, 2, 3, or 4.

[0678] In certain embodiments where G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and o is 0.

[0679] In certain embodiments where G of ULM-j is C=J, J is O, R7 is H, and each R14 is H and R 15 is an optionally substituted heteroaryl and o is 0. In other instances, E is C=O and M is

[0680] [ka]

[0681] is. In certain embodiments, E of ULM-j is C=O. 11 is an optionally substituted heterocycle or

[0682] [ka]

[0683] and M is

[0684] [ka]

[0685] is. In certain embodiments, E of ULM-j is C=O,

[0686] [ka]

[0687] and R 11 teeth

[0688] [ka]

[0689] 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.

[0690] In certain embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0691] [ka]

[0692] During the ceremony, G of ULM-k is C=J and J is O, R7 of ULM-k is H, Each R of ULM-k 14 is H, o of ULM-k is 0, ULM-k R 15 but,

[0693] [ka]

[0694] and ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

[0695] In other cases, the R of ULM-k 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0696] In other embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0697] [ka]

[0698] During the ceremony, G of ULM-k is C=J and J is O, R7 of ULM-k is H, Each R of ULM-k 14 is H, o of ULM-k is 0, ULM-k R 15 is as follows:

[0699] [ka]

[0700] [ka]

[0701] wherein R of ULM-k is selected from the group consisting of: 30 is H or optionally substituted alkyl.

[0702] In other embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0703] [ka]

[0704] During the ceremony, E of ULM-k is C=O, The M in ULM-k is

[0705] [ka]

[0706] and ULM-k R 11 is selected from the group consisting of:

[0707] [ka]

[0708] [ka]

[0709] In yet another embodiment, a compound of the following chemical structure:

[0710] [ka]

[0711] wherein E of ULM-k is C=O; ULM-k R 11 but,

[0712] [ka]

[0713] and The M in ULM-k is

[0714] [ka]

[0715] 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

[0716] [ka]

[0717] and ULM-k R 21 is H or optionally substituted alkyl; ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

[0718] In any embodiment described herein, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0719] [ka]

[0720] [ka]

[0721] [ka]

[0722] [ka]

[0723] In certain embodiments, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0724] [ka]

[0725] [ka]

[0726] In certain embodiments, ULM (or ULM′, if present) is a group according to the following chemical structure:

[0727] [ka]

[0728] During the ceremony, X of 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

[0729] [ka]

[0730] and R9 of ULM-1 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 heterocycle, an optionally substituted aryl, or

[0731] [ka]

[0732] and ULM-l R 12 is H or optionally substituted alkyl; ULM-l R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate.

[0733] In some embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0734] [ka]

[0735] During the ceremony, Y of ULM-m is H, methiol, or ethyl; R9 of ULM-m is H, R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocycle.

[0736] In other preferred embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0737] [ka]

[0738] During the ceremony, ULM-n R 17 is methyl, ethyl, or cyclopropyl; ULM-n R9, R 10 , and R 11 is as defined above. In other instances, R9 is H; ULM-n R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0739] 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. Additionally, in any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be attached to a PTM directly via a bond or by a chemical linker.

[0740] In certain aspects of the disclosure, the ULM moiety is selected from the group consisting of:

[0741] [ka]

[0742] [ka]

[0743] [ka]

[0744] [ka]

[0745] [ka]

[0746] [ka]

[0747] [ka]

[0748] [ka]

[0749]

change

[0750]

change

[0751]

change

[0752]

change

[0753]

change

[0754]

change

[0755]

change

[0756]

change

[0757]

change

[0758]

change

[0759] [ka]

[0760] [ka]

[0761] [ka]

[0762] [ka]

[0763] [ka]

[0764] wherein the VLM may be linked to the PTM via a linker as described herein, optionally via any suitable functional group, e.g., an amine, ester, ether, alkyl, or alkoxy, at any suitable location, including, e.g., an aryl, heteroaryl, phenyl, or phenyl of an indole group.

[0765] Exemplary Linkers In certain embodiments, compounds described herein comprise one or more PTMs chemically linked or coupled to one or more ULMs (e.g., one or more 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 linker group consisting of one or more covalently attached structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), and A L 1 is a group attached to the PTM, (A L ) qis a group attached to ULM.

[0766] In any aspect or embodiment described herein, the linker group L is of the formula -(A L ) q -, wherein A is a bond or chemical linker group represented by the formula L is a chemical moiety, q is an integer from 1 to 100, and A L is covalently linked to the PTM and ULM, providing sufficient binding of the PTM to the protein target and of the ULM to the E3 ubiquitin, resulting in target protein ubiquitination.

[0767] In certain embodiments, the linker group L is -(A L ) q - in which (A L ) q is a group linked to at least one of a ULM (e.g., a CLM or VLM), a PTM moiety, or a combination thereof; q of the linker is an integer of 1 or more, Each A L However, independently, combined, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO 2NR 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 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group3-11 Cycloalkyl, 0 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 8 R L1 and / or R L2 C optionally substituted with a group 5-13 Spiroheterocycloalkyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl optionally substituted with a group, wherein R L1 or R L2 are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, and optionally 0 to 4 R L5 is substituted with a group, R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, 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-C1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, 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.

[0768] 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.

[0769] 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).

[0770] In certain embodiments, for example, when the q of the linker is 2, (A L ) q is A L is a group connected to 1 and ULM.

[0771] In certain embodiments, for example, when q is 1, the structure of the linker group L2 is -A 1 - and A 1 is the group connecting the E3LB and PB moieties.

[0772] In certain embodiments, the unit A of the linker (L) L is the following: -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 -(heterocycloal Kill)-, -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-(heterocyclyl)-CH2, -NR(CH2CH2) n -(heterocyclyl)-(heterocyclyl)-CH, -N(R1R2)-(heterocyclyl)-CH, n in the linker may be 0 to 10; R of the linker may be H, lower alkyl, The linkers R1 and R2 can form a ring together with the N to which they are connected.

[0773] In any aspect or embodiment described herein, the unit A of the linker (L) L teeth,

[0774] [ka]

[0775] [ka]

[0776] [ka]

[0777] and C1-C6 alkyl, During the ceremony, Heterocycloalkyl * N is shared with the PTM, Each m, n, o, p, q, r and s is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0778] In certain embodiments, the unit A of the linker (L) Lis as follows: -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-

[0779]

Chem.

[0780] [ka]

[0781] [ka]

[0782] (In the formula, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20; If the number is zero, there are no NO or OO bonds, R of the linker is H, methyl and ethyl; X in the linker is H and F.

[0783] [ka]

[0784] (wherein m in the linker may be 2, 3, 4, or 5).

[0785] [ka]

[0786] [ka]

[0787] [ka]

[0788] [ka]

[0789] [ka]

[0790] [ka]

[0791] [ka]

[0792] [ka]

[0793] [ka]

[0794] wherein each n and m in the linker may independently be 0, 1, 2, 3, 4, 5, or 6.

[0795] In any aspect or embodiment described herein, the unit A of the linker (L) L teeth,

[0796] [ka]

[0797] [ka]

[0798] [ka]

[0799] [ka]

[0800] is selected from the group consisting of wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0801] In any aspect or embodiment described herein, the unit A of the linker (L) L teeth,

[0802] [ka]

[0803] [ka]

[0804] [ka]

[0805] [ka]

[0806] [ka]

[0807] [ka]

[0808] [ka]

[0809] [ka]

[0810] [ka]

[0811]

change

[0812]

change

[0813]

change

[0814]

change

[0815]

change

[0816]

change

[0817]

change

[0818]

change

[0819]

change

[0820]

change

[0821]

change

[0822]

change

[0823]

change

[0824]

change

[0825]

change

[0826]

change

[0827]

change

[0828]

change

[0829]

change

[0830]

change

[0831]

change

[0832] [ka]

[0833] [ka]

[0834] wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0835] In any aspect or embodiment described herein, the unit A of the linker (L) L is selected from the group consisting of:

[0836] [ka]

[0837] [ka]

[0838] [ka]

[0839] [ka]

[0840] [ka]

[0841] [ka]

[0842] [ka]

[0843] [ka]

[0844] [ka]

[0845] [ka]

[0846] [ka]

[0847] [ka]

[0848] [ka]

[0849] [ka]

[0850] 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:

[0851] [ka]

[0852] During the ceremony, W L1and W L2 are each independently absent or optionally R Q and each R is a 4- to 8-membered ring having 0 to 4 heteroatoms substituted with Q are independently H, halo, OH, CN, CF, optionally substituted straight or branched chain C-C alkyl, optionally substituted straight or branched chain C-C alkoxy, or two R Q groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, an optionally substituted straight or branched chain C1-C6 alkyl, optionally in which one or more C atoms are replaced by O, or an optionally substituted straight or branched chain C1-C6 alkoxy; n and m are independently 0 to 10;

[0853] [ka]

[0854] indicates the point of attachment to the PTM or ULM moiety. 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:

[0855] [ka]

[0856] During the ceremony, W L1 and W L2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclic, C 1-6 Alkyl and optionally one or more C atoms replaced by O or N, C 1-6 Alkenes and optionally one or more C atoms replaced by O, C 1-6Alkynes and optionally one or more C atoms replaced by O, bicyclic, biaryl, biheteroaryl, or biheterocyclic rings, each of which is R Q and each R Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH, NR Y1 R Y2 , CN or two R Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system having 0-4 heteroatoms; Y L1 each independently represents a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (optionally substituted linear or branched chain) and optionally one or more C atoms replaced by O, optionally substituted linear or branched C1-C6 alkoxy, 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, Q L is optionally bridged, and optionally has 0 to 6 R Q and each R is a 3- to 6-membered alicyclic or aromatic ring having 0 to 4 heteroatoms, substituted with Q are independently H, optionally substituted straight or branched chain C 1-6 Alkyl (e.g., one or more halo or C 1-6 optionally substituted by alkoxyl) or two R Q the groups, together with the atoms to which they are attached, form a 3- to 8-membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 each independently represents H, OH, an optionally substituted straight or branched chain C1-6 Alkyl (e.g., one or more halo or C 1-6 optionally substituted by alkoxyl) or R 1 , R 2 together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms; n and m are independently 0 to 10;

[0857] [ka]

[0858] indicates the point of attachment to the PTM or ULM moiety. In additional embodiments, the linker group comprises from 1 to about 100 ethylene glycol units (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc., ethylene glycol units). ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to about 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 interdispersed 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 can be asymmetric or symmetric.

[0859] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety as 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 about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0860] In any aspect or embodiment described herein, the linker (L) can be an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50alkyl), where each carbon is optionally substituted with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens, substitutions, or both to complete the valence, provided that there are no heteroatom-to-heteroatom bonds (e.g., the heteroatoms are not covalently bonded or adjacently positioned).

[0861] In any aspect or embodiment described herein, the linker (L) comprises about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, wherein carbon or oxygen may be replaced with a heteroatom selected from N, S, P, or Si atoms bearing the appropriate number of hydrogens to complete the valence. For example, in any aspect or embodiment described herein, the linker (L) may be

[0862] [ka]

[0863] [ka]

[0864] wherein carbon or oxygen may be optionally replaced with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens to complete the valence, and each m, n, o, p, q, r, and s is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0865] In another embodiment, the disclosure is directed to compounds comprising a PTM group as described above, wherein the PTM group binds a target protein or polypeptide (e.g., Kirsten rat sarcoma protein (KRas or KRAS) and / or a gain-of-function KRas mutant) that has been ubiquitinated by a ubiquitin ligase and is chemically linked to a ULM group, either directly or via a linker moiety, L; or the PTM is alternatively a ULM' group that is also a ubiquitin ligase-binding moiety, which ULM' group may be the same or different from a ULM group as described above, and L is a linker moiety, which may be present or absent, as described above, and which chemically (covalently) links ULM to the PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[0866] 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:

[0867] [ka]

[0868] X is selected from the group consisting of O, N, S, S(O), and SO2, n is an integer from 1 to 5, and R L1 is hydrogen or alkyl,

[0869] [ka]

[0870] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

[0871] [ka]

[0872] is a monocyclic or bicyclic cycloalkyl or heterocyclyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano, and the phenyl ring fragment may be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In one embodiment, the linker group L comprises up to 10 covalently linked structural units as described above.

[0873] While the ULM and PTM groups can 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 linkers are independently covalently attached to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, and each group can be inserted anywhere on the ULM and PTM groups to provide maximal coupling between the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself.) In certain embodiments, the linker can be attached to an optionally substituted alkyl, alkylene, alkene, or alkyne group, an aryl group, or a 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 are selected from proteins expressed in cells, so that at least a portion of the sequence is found in the cell and can be bound to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length so that they can be bound to the PTM group of the present disclosure. Any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi as described elsewhere herein, is a target for ubiquitination mediated by the compounds of the present disclosure. Preferably, the target protein is a eukaryotic protein.

[0874] PTM groups of the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), including the following non-limiting examples of small molecule target protein moieties: KRas inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds that target human BET bromodomain-containing proteins, H, among many others. DAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR). The compositions described below exemplify some of these 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, such as KRas. G12C These binding moieties preferably are linked to the ubiquitin ligase binding moiety through a linker to present the target protein (to which the protein binds), e.g., KRas and / or gain-of-function KRas mutants, in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0875] The present disclosure may be used to treat numerous disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and in which the patient would benefit from the degradation and / or inhibition of the protein.

[0876] In a further aspect, the present description provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition can be used to regulate protein degradation in a patient or subject, for example, an animal, such as a human, and treat or improve a disease state or condition regulated by degraded proteins. In certain embodiments, the therapeutic compositions described herein can be used to cause the degradation of a protein of interest for the treatment or improvement of a disease, for example, cancer (e.g., pancreatic cancer, colon cancer, lung cancer, or non-small cell lung cancer, or a combination thereof). In certain additional embodiments, the disease includes or is pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancy, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer, or a combination thereof.

[0877] In another aspect, the present disclosure relates to a method for treating a disease state or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading the protein or polypeptide that regulates the disease state or condition, the method comprising administering to the patient or subject an effective amount, for example, a therapeutically effective amount, of at least one compound described hereinabove, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient, and optionally with an additional bioactive agent, wherein the composition is effective for treating or ameliorating a disease or disorder or its symptoms in the subject.The method according to the present disclosure can be used to treat a number of disease states or conditions, including cancer (including, for example, pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer, or a combination thereof), by administering an effective amount of at least one compound described herein. The disease state or condition may be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that leads to the disease state and / or condition.

[0878] In another aspect, the description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0879] The term "target protein" is used to describe a protein or polypeptide that is targeted for conjugation to a compound according to the present disclosure and subsequent degradation by a ubiquitin ligase. For example, in any aspect or embodiment described herein, the PTM is a small molecule that includes a KRas protein targeting moiety. Such small molecule targeting moieties are also useful. Protein-binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties are attached to at least one ULM group (e.g., a VLM, a CLM, an ILM, and / or an MLM) via at least one linker group, L.

[0880] Target proteins include any protein or peptide that binds to a protein target moiety and can be degraded by a ligase to which a ubiquitin ligase binding moiety is bound, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides that have any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport, and signal transduction. For example, in any aspect or embodiment described herein, the PTM is a KRas protein binding moiety.

[0881] These various protein targets, such as the KRas protein, may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the compounds of the present disclosure, the activity level of the protein can be altered for therapeutic end results.

[0882] 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, positioning / presenting the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide can occur via the ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include, among many others, KRas 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). The compositions described below exemplify some of these small molecule target protein members. Exemplary protein targeting moieties of the present disclosure include KRas 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).

[0883] The compositions described herein exemplify some of the components of these types of small molecule target protein binding moieties, and also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest.

[0884] In any aspect or embodiment described herein, the PTM is a KRas protein binding / targeting moiety, e.g., a small molecule comprising a KRas protein binding / targeting moiety. In any aspect or embodiment described herein, the PTM is a mutant KRas, e.g., a gain-of-function mutant KRas (e.g., KRas G12C In any aspect or embodiment described herein, the PTM binds to

[0885] [ka]

[0886] wherein:

[0887] [ka]

[0888] is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X PTM is C or N, W PTM is selected from the group consisting of optionally substituted C3-C6 cycloalkyl, and optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), and optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl); R PTM1A is NR PTM9 R PTM10 , OR PTM9 R PTM10 , H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted O—(C3-C6 cycloalkyl), optionally substituted C3-C6 heteroalkyl, optionally substituted OC 1-4 Alkyl-C 3-6 Cycloalkyl, optionally substituted O-(C3-C6 heteroalkyl), optionally substituted OC 1-4 Alkyl-C 3-6 Heteroalkyl, optionally substituted OC 1-4 Alkyl-C 3- 6 heterocycloalkyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted O-aryl (e.g., optionally substituted O—(C5-C7 aryl)), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), optionally substituted O-heteroaryl (e.g., optionally substituted O—(C5-C7 heteroaryl)), optionally substituted

[0889] [ka]

[0890] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0891] [ka]

[0892] , optionally substituted

[0893] [ka]

[0894] , optionally substituted

[0895] [ka]

[0896] , optionally substituted

[0897] [ka]

[0898] , optionally substituted

[0899] [ka]

[0900] , optionally substituted

[0901] [ka]

[0902] , optionally substituted

[0903] [ka]

[0904] , optionally substituted

[0905] [ka]

[0906] , optionally substituted

[0907] [ka]

[0908] , optionally substituted

[0909] [ka]

[0910] , optionally substituted

[0911] [ka]

[0912] , optionally substituted

[0913] [ka]

[0914] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0915] [ka]

[0916] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0917] [ka]

[0918] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0919] [ka]

[0920] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0921] [ka]

[0922] (e.g., optionally substituted with at least one alkyl, e.g., *The carbon may be optionally substituted with alkyl), optionally substituted

[0923] [ka]

[0924] (e.g., optionally substituted with at least one alkyl, e.g., * carbon may be optionally substituted with alkyl), and N * is the N atom of the heterocycloalkyl (e.g., C4-C8 heterocycloalkyl) of the linker (L), R PTM1B is NR PTM9 R PTM10 , OR PTM9 R PTM10 , H, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted O—(C3-C6 cycloalkyl), optionally substituted —OC 1-4 Alkyl-C 3-6 Cycloalkyl, optionally substituted C3-C6 heteroalkyl, optionally substituted O—(C3-C6 heteroalkyl), optionally substituted OC 1-4 Alkyl-C 3-6 Heteroalkyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted O-aryl (e.g., optionally substituted O-(C5-C7 aryl)), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), optionally substituted O-heteroaryl (e.g., optionally substituted O(C5-C7 heteroaryl)), optionally substituted

[0925] [ka]

[0926] (e.g., optionally substituted with at least one alkyl, e.g., * The carbon may be optionally substituted with alkyl), optionally substituted

[0927] [ka]

[0928] , optionally substituted

[0929] [ka]

[0930] , optionally substituted

[0931] [ka]

[0932] , optionally substituted

[0933] [ka]

[0934] , optionally substituted

[0935] [ka]

[0936] , optionally substituted

[0937] [ka]

[0938] , optionally substituted

[0939] [ka]

[0940] , optionally substituted

[0941] [ka]

[0942] and R PTM9 and R PTM10 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, or optionally substituted aliphatic amide; R PTM2 But H, (C=O)R PTM2 ', optionally substituted straight or branched chain alkyl; R PTM2’ is an optionally substituted straight or branched chain alkyl, an optionally substituted alkene, -N(R PTM8 )2 or -C(OH)2, R PTM3 is alkyl, alkoxy, phenyl, or naphthalene, each independently substituted with OH, H, or halogen; R PTM4A is OH, H, halogen, optionally substituted straight or branched chain C1-C6 alkyl; R PTM4B is OH, H, halogen, optionally substituted straight or branched chain C1-C6 alkyl; R PTM5 is selected from the group consisting of optionally substituted aryl, optionally substituted biaryl, optionally substituted heteroaryl, optionally substituted biheteroaryl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloheteroalkyl, halogen, H, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl), OH, and alkoxy; R PTM8 is H or alkyl (e.g., C alkyl, C alkyl, C alkyl, or C alkyl); t is 0, 1, 2, 3, 4, 5, 6 (e.g., 0, 1, 2, 3, etc.),

[0943] [ka]

[0944] indicates at least one connection site of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM', or a combination thereof.

[0945] In any aspect or embodiment described herein, the PTM is

[0946] [ka]

[0947] [ka]

[0948] [ka]

[0949] [ka]

[0950] [ka]

[0951] wherein: X PTM1 is NH or O, R PTM6 is aryl, heteroaryl,

[0952] [ka]

[0953] where N * is the N atom of the heterocycloalkyl (C4-C8 heterocycloalkyl) of the linker (L), R PTM7 is H, aryl, O-aryl, heteroaryl, O-heteroaryl,

[0954] [ka]

[0955] and t is 0, 1, 2, 3, 4, 5, 6 (e.g., 1, 2, or 3); R PTM9 is H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, optionally substituted aliphatic amide, optionally substituted

[0956] [ka]

[0957] (e.g., optionally substituted with at least one alkyl, e.g., * carbon may be optionally substituted with alkyl;

[0958] [ka]

[0959] may be a single or double bond,

[0960] [ka]

[0961] indicates at least one connection site of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM', or a combination thereof.

[0962] In any aspect or embodiment described herein, the PTM is

[0963] [ka]

[0964] [ka]

[0965] [ka]

[0966] [ka]

[0967] [ka]

[0968] [ka]

[0969] [ka]

[0970] [ka]

[0971] [ka]

[0972] [ka]

[0973] [ka]

[0974] [ka]

[0975] [ka]

[0976] [ka]

[0977] [ka]

[0978] [ka]

[0979] is selected from. In any aspect or embodiment described herein, the PTM is (i) a PTM selected from the compounds of Tables 4, 6, 8, 10, and 12, or (ii) a PTM of Table 1. Therapeutic Compositions Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein in combination with an effective amount of one or more compounds otherwise described herein, all in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent a further aspect of the present disclosure.

[0980] The present disclosure includes compositions containing pharmaceutically acceptable salts, where applicable, particularly acid or base addition salts of the compounds described herein. The acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful according to this aspect are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, among others. and those which form the following salts: phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0981] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure.Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to, water-soluble amine addition salts, such as alkali metal cations (e.g., potassium and sodium), and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0982] The compounds described herein may be administered in single or divided doses via oral, parenteral, or topical routes in accordance with the present disclosure. Administration of the active compounds may range from continuous administration (intravenous infusion) to several oral doses per day (e.g., QID), and include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes. Enteric-coated oral tablets may also be used to enhance the bioavailability of the compounds from oral administration. The most effective dosage form will depend on the pharmacokinetics of the specific agent selected and the severity of the disease in the patient. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or intrapulmonary administration may also be used. Accordingly, the present disclosure is also directed to pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. Compounds according to the present disc...

Claims

1. A compound having the following chemical structure: ULM-L-PTM During the ceremony, (a) L is a group of the formula -(A L ) q -, where q is an integer from 1 to 50; Each A L is independently L1 R L2 , O, N.R. L3 , CO, C≡C, 1 to 3 R L1 and / or R L2 C containing one or two N atoms optionally substituted with groups 3-11 Heterocyclyl, 1 to 3 R L1 and / or R L2 phenyl optionally substituted with a group; R L1 , R L2 and R L3 are each independently H or C 1-8 is alkyl; (b) ULM is 【Chemical 1】 and Here, X 1 and X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO 2 and R Y3 and R Y4 are independently H, C 1-6 Alkyl, 1 to 3 R P C substituted with a group 1-6 Alkoxy and one or more halogens or C 1-6 Alkoxy-substituted C 1-6 alkyl; Each R P The groups are independently H, halogen, -OH, and C 1-3 alkyl; W 3 is C 1-6 Phenyl optionally substituted with alkyl, C 1-6 5-10 membered heteroaryl optionally substituted with alkyl, and 【Chemistry 2】 wherein W is selected from 3 of 【Chemistry 3】 is X 1 indicates the connection site to R 9 and R 10 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 independently selected from haloalkyl; R 11 is 3- to 11-membered heterocyclyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 6-10 aryl, and 【Chemistry 4】 wherein heterocyclyl, heteroaryl, and aryl are optionally selected from C 1-6 substituted with alkyl; 11 of 【Chemistry 5】 is C(R 9 )(R 10 ) and R 12 is H or C 1-6 is alkyl; R 13 is H, alkyl, C 1-6 Alkylcarbonyl, (3- to 11-membered cycloalkyl)C 1-6 Alkyl carbonyl, C 6-10 Aralkylcarbonyl, C 6-10 arylcarbonyl, (3- to 11-membered heterocyclyl)carbonyl, or C 6-10 is aralkyl; W 4 teeth, 【Chemistry 6】 where W 4 of 【Chemistry 7】 is X 2 indicates the connection point of R 14a and R 14b are independently H, C 1-6 Haloalkyl, and C 1-6 alkyl; W 5 is an optionally substituted phenyl or an optionally substituted 5- to 10-membered heteroaryl, wherein the phenyl and heteroaryl are independently selected from halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, hydroxy, and C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkoxy; R 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , alkyl, haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl, and ULM's 【Chemistry 8】 is W 3 , W 5 or R 13 indicates the connection site of L via W 3 , W 5 and R 13 One of them is directly connected to L by a covalent bond, Here, R 15 The optional substituents in are independently selected from C 1-6 Alkyl, hydroxyl, =O, thiol, carboxyl, CN, NO 2 , halogen, C 1-6 Alkoxy, C 1-6 Achill, C 1-6 Ester with alkyl, amino, C 1-6 Alkylamino, C 1-6 Dialkylamino, unsubstituted amide, 1 or 2 C 1-6 Alkyl-substituted amides, C 1-6 Alkanol, C 1-6 Alkanoic acid, -(CH 2 ) n OH, -(CH 2 ) n COOH, and -(CH 2 ) m -NR1R2 groups, where each m and n is independently an integer from 1 to 6, and R1 and R2 are each independently H, or C optionally substituted with 1 or 2 hydroxyl groups or up to 3 halogen groups. 1-6 is an alkyl group; (c) PTM is 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 【Chemistry 9-6】 【Chemistry 9-7】 【Chemistry 9-8】 【Hua 9-9】 【Chemistry 9-10】 【9-11】 【Chemistry 9-12】 【Chemistry 9-13】 【Chemistry 9-14】 【Chemistry 9-15】 【Chemistry 9-16】 【Chemistry 9-17】 where PTM 【Chemistry 10】 indicates the attachment site of L, and N★ of PTM is the nitrogen atom of the heterocycloalkyl of L, or a pharmaceutically acceptable salt thereof.

2. The L is 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 wherein L is selected from the group consisting of 【Chemistry 12】 The compound according to claim 1, wherein represents a site of attachment to a ULM or a PTM, and the N★ of the heterocycloalkyl of L is a nitrogen atom shared with the PTM.

3. 2. The compound of claim 1, wherein L is a polyethyleneoxy group containing 1 to 10 ethylene glycol units. 【Request 4】 【Chemical 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 【Chemistry 13-4】 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】 or a pharmaceutically acceptable salt thereof. 【Request 5】 【Chemical 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 or a pharmaceutically acceptable salt thereof.

6. ULM, 【Chemistry 15】 2. The compound of claim 1, wherein:

7. The L is 【Chemistry 16】 2. The compound of claim 1 selected from:

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

9. 10. The pharmaceutical composition of claim 8, further comprising an additional bioactive agent.

10. 10. The pharmaceutical composition of claim 9, wherein the additional bioactive agent is an anti-cancer agent.

11. The pharmaceutical composition of claim 10, wherein the anticancer agent is an epidermal growth factor receptor inhibitor.

12. 10. Use of a compound according to claim 1 in the manufacture of a medicament for treating a disease or disorder associated with one or more of the accumulation, aggregation, and hyperactivation of KRas in a subject.

13. 13. The use according to claim 12, wherein the disease or disorder is cancer.

14. 13. The use according to claim 12, wherein the disease or disorder is pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancy, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia or breast cancer.

15. 15. The composition of claim 14, wherein the disease or disorder is pancreatic cancer, colon cancer, lung cancer, or non-small cell lung cancer.

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