Proteolysis modulators and related methods of use

Abstract

The invention relates to modulators of proteolysis and related methods of use. The present disclosure relates to bifunctional compounds that are useful as modulators of Kirsteen rat sarcoma proteins (target proteins). In particular, the present disclosure relates to bifunctional compounds having one end containing a Von Hippel-Lindau, cerebron, an apoptotic protein inhibitor or a mouse double minute 2 homolog ligand that binds to the respective E3 ubiquitin ligase and the other end containing a moiety that binds to a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities related to degradation / inhibition of a target protein. Treatment or prevention of diseases or conditions caused by aggregation, accumulation and / or overactivity of target proteins with the compounds and compositions of the invention.

Description

[0001] This application is a divisional application of Chinese patent application No. 201980037236.3, entitled “Proteolysis Regulators and Related Methods of Use,” filed on April 4, 2019.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] 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.

[0004] Incorporated by Reference

[0005] U.S. patent application serial number 15 / 230,354, filed on August 5, 2016, and published as application publication number 2017 / 0065719, and U.S. patent application serial number 15 / 206,497, filed on July 11, 2016, and published as U.S. patent application publication number 2017 / 0008904; and U.S. patent application serial number 15 / 209,648, filed on July 13, 2016, and published as U.S. patent application publication number 2017 / 0037004; and U.S. patent application serial number 15 / 730,728, filed on October 11, 2017, and published as U.S. patent application publication number 2018 / 0099940; and U.S. patent application serial number 14 / 686,640, filed on April 14, 2015, and published as U.S. patent application publication number 2015 / 0291562; and U.S. patent application serial number 14 / 686,640, filed on April 14, 2015, and published as U.S. patent application publication number 2015 / 0291562 No. 14 / 792,414, published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application Serial No. 14 / 371,956, filed on July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and U.S. Patent Application Serial No. 15 / 074,820, filed on March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639; and U.S. Provisional Patent Application Serial No. 15 / 885,671, filed on January 31, 2018, published as U.S. Patent Application Publication No. 2018 / 0215731A1; and International Patent Application No. PCT / US2016 / 023258, filed on March 18, 2016, published as International Patent Application Publication No. WO2016 / 149668, are hereby incorporated by reference in their entireties. Furthermore, all references cited herein are hereby incorporated by reference in their entirety. Technical Field

[0006] The present disclosure provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators of targeted ubiquitination, particularly for Kirsten ras sarcoma protein (KRas or KRAS), such as mutant KRas or gain-of-function KRas, which are degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0007] Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. On the other hand, it is notoriously difficult to target protein-protein interactions using small molecules due to the large contact surfaces and shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer specificity to ubiquitinated substrates, making them more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands for E3 ligases has proven challenging, in part because they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of Nutlins, the first small molecule E3 ligase inhibitors, additional compounds targeting E3 ligases have been reported, but the field remains underdeveloped. For example, since the discovery of Nutlins, the first small molecule E3 ligase mouse double minute 2 homolog (MDM2) inhibitors, additional compounds targeting MDM2 (i.e., human double minute 2 or HDM2) E3 ligase have been reported (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0008] One E3 ligase with exciting therapeutic potential is the substrate-recognition subunit of the von Hippel-Lindau (VHL) tumor suppressor, the E3 ligase complex VCB, which also consists of elongins B and C, Cul2, and Rbx1. VHL's primary substrate is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low oxygen levels. The first small-molecule ligand targeting the substrate-recognition subunit of the Von Hippel-Lindau (VHL) E3 ligase has been generated, and a crystal structure has been obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0009] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which emphasizes 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 many other proteins. Cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10) through mechanisms that have not yet been fully elucidated. FGF8, in turn, regulates many developmental processes, such as limb and auditory vesicle formation. The end result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0010] Inhibitors of apoptosis proteins (IAPs) are a family of proteins involved in inhibiting apoptosis, i.e., cell death. The human IAP family includes eight members, and many other organisms contain IAP homologs. IAPs contain an E3 ligase-specific domain and a baculovirus IAP repeat (BIR) domain that recognize substrates and promote their ubiquitination. IAPs promote ubiquitination and can directly bind to and inhibit caspases. Caspases are proteases that promote apoptosis (e.g., caspase-3, caspase-7, and caspase-9). Therefore, IAPs inhibit cell death by binding to caspases. However, pro-apoptotic stimuli can lead to the release of the mitochondrial proteins DIABLO (also known as a mitochondrial-derived activator of a second caspase or SMAC) and HTRA2 (also known as Omi). The combination of DIABLO and HTRA2 appears to block IAP activity.

[0011] 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 the IAPs, which is thought to be necessary to block the anti-apoptotic effects of IAPs.

[0012] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), act to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, these disclosures describe bifunctional or proteolysis targeting chimera (PROTAC) compounds that can be used as modulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds.

[0013] The Kirsten rat sarcoma (KRAS) gene is an oncogene encoding KRas, a small GTPase signal transduction protein. Ras protein is associated with the plasma membrane and acts as a switch that transduces extracellular signals into intracellular responses, thereby regulating, for example, cell division. Many activation or gain-of-function mutations of the KRas gene are known, and in fact, KRas is the most frequently mutated gene in cancer. Gain-of-function KRas mutations are present in approximately 30% of human cancers, including, for example, pancreatic cancer (>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. It has been determined that mutant KRas plays a key role in the initiation, maintenance, progression, and metastasis of various cancers, and mutations are often associated with poor prognosis and increased resistance to chemotherapy and biological therapies, including, for example, those targeting epidermal growth factor receptors. However, despite its critical role in cancer and high incidence, the lack of effective therapies directly targeting this oncogene has led to its being considered "undruggable."

[0014] Therefore, there is a continuing need in the art for effective treatments for diseases associated with overexpression, aggregation, and / or overactivation of KRas (e.g., aggregation of active KRas), such as gain-of-function KRas mutants (i.e., KRas with gain-of-function mutations). However, nonspecific effects and the inability to target and modulate mutant KRas 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 very useful. Summary of the Invention

[0015] The present disclosure describes bifunctional compounds having the function of recruiting endogenous proteins to E3 ubiquitin ligases for degradation and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimera (PROTAC) compounds that can be used as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that a wide range of pharmacological activities are possible, consistent with the degradation / inhibition of targeted polypeptides from virtually any protein class or family. In addition, the instructions provide methods of using an effective amount of the compounds described herein to treat or ameliorate disease conditions such as cancer, e.g., 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, and breast cancer.

[0016] Thus, in one aspect, the present disclosure provides bifunctional or PROTAC compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or "ULM" group) and a target protein binding moiety (i.e., a protein / polypeptide targeting ligand or "PTM" group) such that the target protein / polypeptide (e.g., Kirsten rat sarcoma protein (KRas or KRAS) and / or mutant KRas, such as KRas G12C ) is placed near a ubiquitin ligase to affect the degradation (and inhibition) of the protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) can be a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM) or a cereblon E3 ubiquitin ligase binding moiety (CLM) or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM) or an IAP E3 ubiquitin ligase binding moiety (i.e., "ILM"). For example, the structure of the bifunctional compound can be described as:

[0017]

[0018] The respective positions of the PTM and ULM moieties (e.g., VLM, CLM, MLM, or ILM) shown herein and their numbers are provided as examples only and are not intended to limit the compounds in any way. As will be appreciated by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and position of the various functional moieties can be varied as desired.

[0019] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be described as:

[0020]

[0021] wherein PTM is a protein / peptide targeting moiety, L is a linker, e.g., a bond or chemical group that couples the PTM to the ULM, and the ULM 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).

[0022] For example, the structure of a bifunctional compound can be described as:

[0023]

[0024] wherein: PTM is a protein / polypeptide targeting moiety; "L" is a linker (e.g., a bond or chemical linker group) that couples the PTM and at least one of VLM, CLM, MLM, ILM, or a combination thereof; VLM is a Von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds VHL E3 ligase; CLM is a cereblon E3 ubiquitin ligase binding moiety that binds cereblon; MLM is an MDM2 E3 ubiquitin ligase binding moiety that binds MDM2; and ILM is an IAP binding moiety that binds IAP.

[0025] In certain preferred embodiments, the ILM is an AVPI tetrapeptide fragment. Thus, in certain further embodiments, the ILM of the bifunctional compound comprises the amino acids alanine (A), valine (V), proline (P), and isoleucine (I), respectively, or non-natural mimetics thereof. In further embodiments, the amino acids of the AVPI tetrapeptide fragment are linked to each other via amide bonds (i.e., -C(O)NH- or -NHC(O)-).

[0026] In certain embodiments, the compounds described herein comprise a plurality of independently selected ULMs, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof.

[0027] In certain embodiments, the ILM comprises chemical moieties, such as those described herein.

[0028] In further embodiments, the VLM may 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 noted above.

[0029] In one embodiment, the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. In a specific embodiment, the chemical group is a phthalimido 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, which is incorporated herein in its entirety.

[0030] In certain embodiments, the MLM can be Nutlin or a derivative thereof. Additionally, other contemplated MLMs are included in U.S. patent application Ser. No. 15 / 206,497, filed on July 11, 2016, and published as U.S. Patent Application Publication No. 2017 / 0008904, as discussed above, which is incorporated herein in its entirety. In certain additional embodiments, the MLM of the bifunctional compound comprises a chemical moiety such as a substituted imidazoline, a substituted spiroindolinone, a substituted pyrrolidine, a substituted piperidone, a substituted morpholinone, a substituted pyrrolopyrimidine, a substituted imidazopyridine, a substituted thiazolimidazoline, a substituted pyrrolopyrrolidone, and a substituted isoquinolinone.

[0031] In further embodiments, the MLM comprises the above-mentioned core structure with adjacent bisaryl substitutions positioned in either a cis or trans configuration.

[0032] In certain embodiments, "L" is a bond. In other embodiments, the linker "L" is a linker having a linear non-hydrogen atom count ranging from 1 to 20. The linker "L" may contain, but is not limited to, functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Halogen substitutions such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitutions, single or multiple fluorines may be included.

[0033] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, wherein both the nitrogen and the carboxylic acid of trans-3-hydroxyproline are functionalized as amides.

[0034] In certain embodiments, a CLM is a derivative of piperidine-2,6-dione, wherein the piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic compound connected via a CN or CC bond. Examples of CLMs include, but are not limited to, pomalidomide, lenalidomide, and thalidomide, and their derivatives.

[0035] On the other hand, this specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition regulates the degradation and / or inhibition of protein in a patient or subject (e.g., an animal such as a human), and can be used to treat or improve a disease state or condition regulated by the protein of degradation / inhibition. In certain embodiments, the therapeutic composition as described herein can be used to achieve degradation of a protein of interest, to treat or improve a disease, such as cancer (such as pancreatic cancer, colon cancer, colorectal cancer, lung cancer or non-small cell lung cancer). On the other hand, the present disclosure provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein, comprising ILM and PTM, PTM and VLM, or PTM and CLM, or PTM and MLM, preferably connected by a linker moiety, and as described herein in other respects, wherein VLM / ILM / CLM / MLM is coupled to PTM by a linker to target the protein bound to PTM for degradation. Similarly, PTMs can be coupled to VLMs or CLMs or MLMs or ILMs via linkers to target proteins or polypeptides for degradation. When a target protein is placed in proximity to an E3 ubiquitin ligase, the target protein will be degraded, thereby degrading / inhibiting the action of the target protein and controlling protein levels. The control of protein levels provided by the present disclosure provides treatment for disease states or conditions that are regulated by the protein by reducing the level of the target protein in the patient's cells.

[0036] In another aspect, the present disclosure provides a method for treating or improving a disease, disorder or symptom in a subject or patient (e.g., an animal such as a human), 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 in treating or improving the disease, disorder or symptom of the subject.

[0037] In another aspect, the present description provides methods of identifying degradation of a target protein in a biological system using compounds according to the present disclosure.

[0038] The foregoing general areas of application are given by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Based on the claims, the description, and the examples, one of ordinary skill in the art will recognize other objects and advantages associated with the compositions, methods, and processes of the present disclosure. For example, the various aspects and embodiments of the present disclosure may be utilized in a variety of 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. The disclosures and other materials cited herein are incorporated by reference to illustrate the background of the present disclosure and, in certain cases, to provide additional details about practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The accompanying drawings are for the purpose of illustrating the embodiments of the present disclosure only and should not be construed as limiting the present disclosure. Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description and the accompanying drawings which illustrate exemplary embodiments of the present disclosure, in which:

[0040] Figure 1A and Figure 1B .General schematic diagram of PROTAC function. ( Figure 1A ) An exemplary PROTAC comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that couples or tethers the PTM to the ULM. ( Figure 1B ) shows the functional use of PROTACs as described herein. In short, ULM recognizes and binds to a specific E3 ubiquitin ligase, and PTM binds and recruits the target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and, alone or through the E2 protein, catalyzes the attachment of ubiquitin (black circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome machinery.

[0041] Figure 2A and Figure 2B . Figure 2A is a Western blot showing an effective degradant, exemplary compound 399. Figure 2B is a Western blot showing a less potent degrader, exemplary compound 432. As seen in the gel migration, both compounds covalently modified KRas G12C . DETAILED DESCRIPTION

[0042] A detailed description is provided below to assist those skilled in the art in implementing the present disclosure. Modifications and variations to the embodiments described herein may be made by those skilled in the art without departing from the spirit or scope of the present disclosure. All disclosures, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0043] The presently described compositions and methods surprisingly and unexpectedly discovered that upon placing an E3 ubiquitin ligase protein (e.g., inhibitor of apoptosis protein (IAP), von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon E3 ubiquitin ligase, or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) in proximity to a target protein via a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein, the target protein is ubiquitinated. Thus, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein target binding moiety ("PTM") that results in ubiquitination of a selected target protein, thereby leading to proteasomal degradation of the target protein (see Figure 1A and Figure 1B The present disclosure also provides a composition library and uses thereof.

[0044] In certain aspects, the present disclosure provides compounds comprising a ligand capable of binding to an ubiquitin ligase such as IAP, VHL, MDM2 or cereblon, such as a small molecule ligand (i.e., a molecular weight of less than 2,000, 1,000, 500 or 200 Daltons). The compound further comprises a portion capable of binding to a target protein by placing the target protein near the ubiquitin ligase to achieve degradation (and / or inhibition) of the protein. In addition to the above, a small molecule can mean that the molecule is non-peptidyl, i.e., it is not generally considered a peptide, for example, comprising less than 4, 3 or 2 amino acids. According to the present specification, a PTM, ULM or PROTAC molecule can be a small molecule.

[0045] 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 terms used in this specification are for describing specific embodiments only and are not intended to limit the disclosure.

[0046] Where a range of values ​​is provided, it is understood that the disclosure includes each intervening value to the tenth of the unit of the lower limit (such as in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided) between the upper and lower limits of the range and any other stated or intervening value in that range, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed in the disclosure, and are subject to any express exclusions in the stated ranges. Where the stated range includes one or both limits, ranges excluding either limit are also encompassed in the disclosure.

[0047] The following terms are used to describe the present disclosure. In the absence of specific definitions of terms herein, those of ordinary skill in the art will assign the terms their art-recognized meanings and apply the terms in the context to describe the present disclosure.

[0048] As used herein and in 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. For example, "an element" means one element or more than one element.

[0049] The phrase "and / or" as used in the specification and claims should be understood to refer to "one or both" of the elements so connected, i.e., elements that are present together in some cases and discontinuously in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so connected. In addition to the elements explicitly identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, in one embodiment, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to only A (optionally including elements other than B); in another embodiment, to only B (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so on.

[0050] As used in the specification and claims of this article, "or" should be understood to have the same meaning as "and / or" defined above. For example, when the items in the list are separated, "or" or "and / or" should be interpreted as inclusive, that is, including at least one of many elements or lists of elements, also including more than one of many elements or lists of elements, and optional other unlisted items. Only explicitly point out the opposite terms, such as "only one" or "just one", or when used in the claims, "consisting of will refer to including only one element in many elements or lists of elements. Usually, the term "or" used in this article should only be interpreted as representing a specific alternative (i.e., "one or the other, but not two") when it is before an exclusive term (e.g., "either", "one", "only one" or "just one").

[0051] In the claims and the foregoing description, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," and the like are to be construed as open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are to be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0052] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, in one embodiment, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") may refer to at least one, optionally including more than one A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0053] It will 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 listed unless the context dictates otherwise.

[0054] The terms "co-administration" and "co-administered" or "combination therapy" refer to simultaneous administration (administration of two or more therapeutic agents at the same time) and time-varying administration (administration of one or more therapeutic agents at a time different from the time of administration of the other therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent simultaneously, preferably simultaneously in effective amounts. In certain preferred aspects, one or more compounds of the present invention as described herein are co-administered with at least one additional bioactive agent, particularly including anticancer agents, such as chemotherapy or biotherapy targeting epidermal growth factor receptor (e.g., gefitinib, erlotinib, neratinib, lapatinib, cetuximab, vandetanib, necituzumab, osimertinib, or at least one of a combination thereof). In particularly preferred aspects, co-administration of the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0055] Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein and includes, in the context of the invention, tautomers, regioisomers, geometric isomers, and (where applicable) stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and (where applicable) pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or deuterated forms thereof. Deuterated small molecules are those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0056] In the context of its use, 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) and specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the active site. Note that when describing the compounds of the present invention, a number of substituents and variables associated therewith are described. It should be understood by those of ordinary skill in the art that the molecules described herein are stable compounds as generally described below. When bonds are shown, both double and single bonds are represented or understood in the context of the compounds shown and the well-known rules for valence bond interactions.

[0057] 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 are E3 ubiquitin ligase proteins that, alone or in combination with E2 ubiquitin-conjugating enzymes, bind ubiquitin to a lysine on the target protein and subsequently target the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin-conjugating enzymes, are responsible for transferring ubiquitin to the target protein. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to the first; a third ubiquitin is attached to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome but can instead alter their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating matters, E3s can target different lysines on ubiquitin to create chains. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0058] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to whom treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. For treatment of 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, cattle, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient unless otherwise stated or implied by the context in which the term is used.

[0059] The term "effective" is used to describe an amount of a compound, composition, or ingredient that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amounts or effective concentrations otherwise described or used in this application.

[0060] Compounds and compositions

[0061] In one aspect, the disclosure provides compounds comprising an E3 ubiquitin ligase binding moiety ("ULM"), including an IAP E3 ubiquitin ligase binding moiety ("ILM"), a cereblon E3 ubiquitin ligase binding moiety ("CLM"), a Von Hippel-Lindae E3 ubiquitin ligase (VHL) binding moiety (VLM), and / or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, the ULM is conjugated to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure:

[0062] (A)PTM-L-ULM

[0063] Wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of moieties in the compounds shown herein are provided as examples only. As will be appreciated by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of the various functional moieties.

[0064] 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 IAP (i.e., ILM), MDM2 (i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Further, the term ILM includes all possible IAP E3 ubiquitin ligase binding moieties, the term MLM includes all possible MDM2 E3 ubiquitin ligase binding moieties, the term VLM includes all possible VHL binding moieties, and the term CLM includes all cereblon binding moieties.

[0065] On the other hand, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) that can be used to modulate protein activity by inducing degradation of a target protein. In certain embodiments, the compound comprises a coupled ILM or VLM or CLM or MLM, which is, for example, covalently linked directly or indirectly to a portion that binds to a target protein (i.e., a protein targeting portion or "PTM"). In certain embodiments, the ILM / VLM / CLM / MLM and the PTM are connected or coupled via a chemical linker (L). ILM binds to an IAP E3 ubiquitin ligase, VLM binds to VHL, CLM binds to a cereblon E3 ubiquitin ligase, MLM binds to an MDM2 E3 ubiquitin ligase, and the PTM recognizes the target protein, and the interaction of each portion with its target degrades the target protein by placing the target protein near the ubiquitin ligase protein. Exemplary bifunctional compounds can be described as:

[0066] (B)PTM-ILM

[0067] (C)PTM-CLM

[0068] (D)PTM-VLM

[0069] (E)PTM-MLM

[0070] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be described as:

[0071] (F)PTM-L-ILM

[0072] (G)PTM-L-CLM

[0073] (H)PTM-L-VLM

[0074] (I) PTM-L-MLM

[0075] Wherein PTM is the protein / peptide targeting moiety, L is a chemical linker, ILM is the IAP E3 ubiquitin ligase binding moiety, CLM is the cereblon E3 ubiquitin ligase binding moiety, VLM is the VHL binding moiety, and MLM is the MDM2 E3 ubiquitin ligase binding moiety.

[0076] In certain embodiments, a ULM (e.g., an ILM, a CLM, a VLM, or an MLM) exhibits activity or binds to an E3 ubiquitin ligase (e.g., an IAP E3 ubiquitin ligase, a cereblon E3 ubiquitin ligase, a VHL, or an MDM2 E3 ubiquitin ligase), 50 Less than about 200 μM. IC can be determined according to any method known in the art, such as fluorescence polarization assay. 50 .

[0077] In certain additional embodiments, the bifunctional compounds described herein exhibit an activity of IC 50 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.

[0078] In certain embodiments, the compounds described herein comprise multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that specifically bind to multiple / different E3 ubiquitin ligases, such as VHL, IAP, cereblon, and / or MDM2), or a combination thereof. In any aspect or embodiment described herein, the PTM and ULM (e.g., ILM, VLM, CLM, and / or MLM) can be coupled directly or via one or more chemical linkers, or a combination thereof. In further embodiments, when a compound has multiple ULMs, the ULMs can target the same E3 ubiquitin ligase, or each corresponding ULM can specifically bind to a different E3 ubiquitin ligase. In further embodiments, when a compound has multiple PTMs, the PTMs can bind to the same target protein, or each corresponding PTM can specifically bind to a different target protein.

[0079] In certain embodiments, where a compound comprises multiple ULMs, the ULMs are identical. In further embodiments, a compound comprises multiple ULMs (e.g., ULMs, ULM's, etc.), at least one PTM coupled to the ULMs directly, via a chemical linker (L), or both. In certain further embodiments, a compound comprising multiple ULMs also comprises multiple PTMs. In still further embodiments, the PTMs are identical or, optionally, different. In further embodiments, where the PTMs are different, each PTM may bind to the same protein target or specifically bind to different protein targets.

[0080] 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 coupled to the ULM or ULM' directly, via a chemical linker, or both. In any embodiment described herein, a compound comprising at least two different ULMs may further comprise multiple PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, where the PTMs are different, each PTM may bind to the same protein target or specifically bind to different protein targets. In still other embodiments, the PTM itself is a ULM (or ULM'), such as an ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

[0081] In further embodiments, the description provides compounds described herein, including enantiomers, diastereomers, solvates, and polymorphs thereof, including pharmaceutically acceptable salt forms, such as acid and base salt forms.

[0082] Exemplary ILM

[0083] AVPI tetrapeptide fragment

[0084] 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 selected from the group consisting of chemical structures represented by formula (I), (II), (III), (IV), and (V):

[0085]

[0086] in:

[0087] R of formula (I), (II), (III), (IV) and (V) 1 Selected from H or alkyl;

[0088] R of formula (I), (II), (III), (IV) and (V) 2 Selected from H or alkyl;

[0089] R of formula (I), (II), (III), (IV) and (V) 3 is selected from H, alkyl, cycloalkyl and heterocycloalkyl;

[0090] R of formula (I), (II), (III), (IV) and (V) 5 and R 6 R is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably, R of formula (I), (II), (III), (IV) and (V) 5 and R 6 together forming a pyrrolidine or piperidine ring, which is optionally further fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which may in turn be further fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

[0091] R of formula (I), (II), (III), (IV) and (V) 3 and R 5 Together they may form a 5-8 membered ring, which is optionally further fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;

[0092] R of formula (I), (II), (III), (IV) and (V) 7 Selected from 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-R4 , each of which is optionally further substituted by 1-3 substituents selected from halogen, alkyl, haloalkyl, hydroxy, alkoxy, cyano, (hetero)cycloalkyl, aryl, (hetero)aryl, -C(O)NH-R 4 or C(O)-R 4 ;and

[0093] R 4 Selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl (e.g., bicyclic aryl), arylalkyl, heteroaryl (e.g., bicyclic heteroaryl), heteroarylalkyl, which are optionally further substituted with 1-3 substituents as mentioned above.

[0094] As shown above, P1, P2, P3 and P4 of formula (II) are respectively related to A, V, P and I of the AVPI tetrapeptide fragment or its non-natural mimetic. Similarly, each of formulas (I) and (III) to (V) has a portion related to A, V, P and I of the AVPI tetrapeptide fragment or its non-natural mimetic.

[0095] In any of the compounds described herein, the ILM may have the structure of Formula (VI), which is a derivative of the IAP antagonists described in WO Publication No. 2008 / 014236; or a non-natural mimetic thereof:

[0096]

[0097] in:

[0098] R1 of formula (VI) is independently selected from H, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 1O - cycloalkyl, which is unsubstituted or substituted;

[0099] R2 of formula (VI) is independently selected from H, C1-C4-alkenyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 1O - cycloalkyl, which is unsubstituted or substituted;

[0100] R3 of formula (VI) is independently selected from H, -CF3, -C2H5, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, -CH2-Z or any of R2 and R3 together form a heterocycle;

[0101] Each Z of formula (VI) is independently selected from H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F or -CH2OH;

[0102] R4 of formula (VI) is independently selected from C1-C 16 Straight or branched alkyl, C1-C16 -alkenyl, C1-C 16 -alkynyl, C3-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;

[0103] R5 of formula (VI) is independently selected from H, C 1-10 -alkyl, aryl, phenyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl, -C 1-10 -alkyl-aryl, -(CH2) 0-6 -C 3-7 -cycloalkyl-(CH2) 0-6 -phenyl, -(CH2) 0-4 -CH[(CH2) 1-4 -phenyl]2, indanyl, -C(O)-C 1-10 -alkyl, -C(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-(CH2) 0-6 -phenyl, -(CH2) 0-6 -C(O)-phenyl, -(CH2) 0-6 -het, -C(O)-(CH2) 1-6 -het or R5 is selected from the residues of amino acids in which alkyl, cycloalkyl, phenyl and aryl substituents are unsubstituted or substituted;

[0104] Z1 of formula (VI) is independently selected from -N(R 10 )-C(O)-C 1-10 -alkyl, -N(R 1O )-C(O)-(CH2) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH2) 0-6 -phenyl, -N(R 10 )-C(O)(CH2) 1-6 -het、-C(O)-N(R 11 )(R 12 )、-C(O)-OC 1-10 -alkyl, -C(O)-O-(CH2) 1-6 -C 3-7 -cycloalkyl, -C(O)-O-(CH2) 0-6-phenyl, -C(O)-O-(CH2) 1-6 -het、-OC(O)-C 1-10 -alkyl, -OC(O)-(CH2) 1-6 -C 3-7 -cycloalkyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

[0105] het of formula (VI) is independently selected from a 5-7 membered heterocyclic ring or an 8-12 membered fused ring system containing 1-4 heteroatoms selected from N, O and S, including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S, said heterocyclic ring or fused ring system being unsubstituted or substituted on a carbon or nitrogen atom;

[0106] R of formula (VI) 10 Selected from H, -CH3, -CF3, -CH2OH or -CH2Cl;

[0107] R of formula (VI) 11 and R 12 Independently selected from H, C 1-4 -alkyl, C 3-7 -cycloalkyl, -(CH2) 1-6 -C 3-7 -cycloalkyl, (CH2) 0-6 -phenyl, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; or R 11 and R 12 Together with nitrogen, it forms het, and

[0108] U in formula (VI) is independently represented by formula (VII):

[0109]

[0110] in:

[0111] Each n of formula (VII) is independently selected from 0-5;

[0112] X of formula (VII) is selected from -CH and N;

[0113] R of formula (VII) a and R b independently selected from O, S or N atoms or C 0-8 -alkyl, wherein one or more carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S or N, and wherein each alkyl group is independently unsubstituted or substituted;

[0114] R of formula (VII) d Selected from Re-Q-(R f ) p (R g ) q and Ar1-D-Ar2;

[0115] R of formula (VII) c Selected from H or any R c and R d together form a cycloalkyl group or het; wherein if R c and R d forming a cycloalkyl or het, then R5 is attached to the formed ring at a C or N atom;

[0116] p and q of formula (VII) are independently selected from 0 or 1;

[0117] R of formula (VII) e Selected from C 1-8 - alkyl and alkylene, and each Re is unsubstituted or substituted;

[0118] Q is selected from N, O, S, S(O) and S(O)2;

[0119] Ar1 and Ar2 of formula (VII) are independently selected from substituted or unsubstituted aryl and het;

[0120] R of formula (VII) f and R g independently selected from H, -C1-10-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 、-SCt-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 forming a ring selected from het or aryl;

[0121] D of formula (VII) is selected from -CO-, -C(O)-C 1-7 -alkylene or arylene, -CF2-, -O-, -S(O) r , where r is 0-2, 1,3-dioxolane or C 1-7 -alkyl-OH; wherein the alkyl, alkylene or arylene group is unsubstituted or substituted by one or more halogen, OH, -OC 1-6 -alkyl, -SC 1-6 -alkyl or -CF3 substituted; or each D is independently selected from N(R h );

[0122] Rh is selected from 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);

[0123] R6, R7, R8 and R9 of formula (VII) are independently selected from 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 together form a ring system;

[0124] R of formula (VII) 13 and R 14 Independently selected from 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 Together with nitrogen atoms, it forms het;

[0125] wherein R of formula (VII) 13 and R 14The alkyl substituents are unsubstituted or substituted, and when substituted, are substituted with one or more substituents selected from C 1-10 -alkyl, halogen, OH, -OC 1-6 -alkyl, -SC 1-6 -alkyl and -CF3; and R 13 and R 14 The substituted phenyl or aryl is substituted by one or more substituents selected from halogen, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, nitro, -CN, -OC(O)-C 1-4 -alkyl and -C(O)-OC 1-4 -aryl; or a pharmaceutically acceptable salt or hydrate thereof.

[0126] In certain embodiments, the compound further comprises a second ILM independently selected to be connected to an ILM of formula (VI) or its non-natural mimics by at least one additional independently selected linker group. In one embodiment, the second ILM is a derivative of formula (VI) or its non-natural mimics. In one embodiment, at least one additional independently selected linker group comprises two additional independently selected linker groups that chemically connect the ILM and the second ILM. In one embodiment, the ILM of formula (VI) or its non-natural mimics is chemically connected to a group selected from R4 and R5. For example, the ILM of formula (VI) and the second ILM of formula (VI) or its non-natural mimics can be connected as shown below:

[0127]

[0128] In certain embodiments, the ILM, at least one additional independently selected linker group L, and the second ILM have a structure selected from the group consisting of:

[0129]

[0130]

[0131] They are derivatives of the IAP antagonists described in WO Publication No. 2008 / 014236.

[0132] In any of the compounds described herein, the ILM may have the structure of Formula (VIII), which is based on the IAP ligand described in Ndubaku, C., et al. Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4(7) (2009); or a non-natural mimetic thereof:

[0133]

[0134] wherein A1 and A2 of formula (VIII) are each independently selected from optionally substituted monocyclic, fused ring, aryl and heteroaryl; and R of formula (VIII) is selected from H or Me.

[0135] In a specific embodiment, the linker group L is attached to A1 of formula (VIII). In another embodiment, the linker group L is attached to A2 of formula (VIII).

[0136] In a particular embodiment, the ILM is selected from the group consisting of:

[0137]

[0138] In any of the compounds described herein, the ILM may have the structure of Formula (IX), which is derived from the chemotype 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:

[0139]

[0140] where R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, and most preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl and R of formula (IX) 2 Selected from -OPh or H.

[0141] In any of the compounds described herein, the ILM may have a structure of formula (X), which is derived from the chemotype 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:

[0142]

[0143] in:

[0144] R in formula (X) 1 Selected from H, -CH2OH, --CH2CH2OH, --CH2NH2, --CH2CH2NH2;

[0145] X of formula (X) is selected from S or CH2;

[0146] R in formula (X) 2 Selected from:

[0147]

[0148] R in formula (X) 3 and R 4 Independently selected from H or Me

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

[0150]

[0151] wherein R in formula (XI) 1 is selected from H or Me, and R of formula (XI) 2 Select H or

[0152]

[0153] In any of the compounds described herein, the ILM may have the structure of Formula (XII), which is derived from the chemotype 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:

[0154]

[0155] in:

[0156] R in formula (XII) 1 Selected from:

[0157] And R of formula (XII) 2 Selected from:

[0158]

[0159] In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0160]

[0161]

[0162] In any of the compounds described herein, the ILM may have a structure of formula (XIII), which is derived from the IAP ligands summarized in Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010); or a non-natural mimetic thereof:

[0163]

[0164] in:

[0165] Z of formula (XIII) is absent or is O;

[0166] R in formula (XIII) 1 Selected from:

[0167]

[0168] R 10 is selected from H, alkyl or aryl;

[0169] X is selected from CH2 and O; and

[0170] It is a nitrogen-containing heteroaryl group.

[0171] In any of the compounds described herein, the ILM may have the structure of Formula (XIV), which is derived from the IAP ligands summarized in Flygare, JA, et al. Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010); or a non-natural mimetic thereof:

[0172]

[0173] in:

[0174] Z of formula (XIV) is absent or is O;

[0175] R in formula (XIV) 3 and R 4 independently selected from H or Me;

[0176] R in formula (XIV) 1 Selected from:

[0177]

[0178] R 10 is selected from H, alkyl or aryl;

[0179] X is selected from CH2 and O; and

[0180] of It is a nitrogen-containing heteroaryl group.

[0181] In any of the compounds described herein, the ILM is selected from the group consisting of:

[0182]

[0183] It is a ligand derivative disclosed in US Patent Publication No. 2008 / 0269140 and US Patent No. 7,244,851.

[0184] In any of the compounds described herein, the ILM may have the structure of Formula (XV), which is a derivative of the IAP ligand described in WO Publication No. 2008 / 128171; or a non-natural mimetic thereof:

[0185]

[0186] in:

[0187] Z of formula (XV) is absent or is O;

[0188] R in formula (XV) 1 Selected from:

[0189]

[0190] R 10 is selected from H, alkyl or aryl;

[0191] X is selected from CH2 and O; and

[0192] is a nitrogen-containing heteroaryl group; and

[0193] R in formula (XV) 2 is selected from H, alkyl or acyl.

[0194] In a specific embodiment, the ILM has the following structure:

[0195]

[0196] In any of the compounds described herein, the ILM may have the structure of Formula (XVI), which is based on the IAP ligand described in WO Publication No. 2006 / 069063; or a non-natural mimetic thereof:

[0197]

[0198] in:

[0199] R in formula (XVI) 2 is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably selected from cyclohexyl;

[0200] Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl; more preferably a 5-membered nitrogen-containing heteroaryl and most preferably thiazole; and

[0201] Ar of formula (XVI) is an aryl group or a heteroaryl group.

[0202] In any of the compounds described herein, the ILM may have the structure of Formula (XVII), which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazoleamide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010); or a non-natural mimetic thereof:

[0203]

[0204] in:

[0205] R of formula (XVII) 1 is selected from halogen (eg, fluorine), cyano,

[0206] X of formula (XVII) is selected from O or CH2.

[0207] In any of the compounds described herein, the ILM may have the structure of Formula (XVIII), which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010); or a non-natural mimetic thereof:

[0208]

[0209] wherein R of formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halogen (in variable substitution positions).

[0210] In any of the compounds described herein, the ILM may have the structure of Formula (XIX), which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazoleamide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010); or a non-natural mimetic thereof:

[0211]

[0212] in It is a 6-membered nitrogen-containing heteroaryl group.

[0213] In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0214]

[0215] In certain embodiments, the ILM of the composition is selected from the group consisting of:

[0216]

[0217]

[0218] In any of the compounds described herein, the ILM may have the structure of Formula (XX), which is based on the IAP ligand described in WO Publication No. 2007 / 101347; or a non-natural mimetic thereof:

[0219]

[0220] wherein X of formula (XX) is selected from CH2, O, NH or S.

[0221] In any of the compounds described herein, the ILM can have the structure of Formula (XXI), which is based on the IAP ligands described in U.S. Patent No. 7,345,081 and U.S. Patent No. 7,419,975; or non-natural mimetics thereof:

[0222] in:

[0223] R in formula (XXI) 2 Selected from:

[0224] R in formula (XXI) 5 Selected from: and

[0225] W of formula (XXI) is selected from CH or N; and

[0226] R 6 is independently a mono- or bicyclic fused aryl or heteroaryl group.

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

[0228]

[0229] In certain embodiments, the ILM of the compound is selected from the group consisting of:

[0230]

[0231]

[0232] It is described in WO Publication No. 2009 / 060292, U.S. Patent Publication No. 7,517,906, WO Publication No. 2008 / 134679, WO Publication No. 2007 / 130626, and WO Publication No. 2008 / 128121.

[0233] In any of the compounds described herein, the ILM may have a structure of Formula (XXII) or (XXIII), which is derived from an IAP ligand described in WO Publication No. 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015); or a non-natural mimetic thereof:

[0234]

[0235]

[0236] in:

[0237] 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;

[0238] 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;

[0239] Alternatively, R of formula (XXII) or (XXIII) 1 and R 2 are independently optionally substituted sulfanyl groups, wherein the substituent attached to the S atom of the sulfanyl group is an optionally substituted alkyl group, an optionally substituted branched alkyl group, an optionally substituted heterocyclic group, -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ;

[0240] in:

[0241] v is an integer from 1 to 3;

[0242] -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0243] -CH2CHR 21 COR 2 R 21 Selected from the group NR 24 R 25 ;

[0244] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0245] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0246] NR 24 R 25 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclic group, -CH2(OCH2CH2O) m CH3 or polyamine chains, such as spermine or spermidine;

[0247] OR 26 R 26 is selected from optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2; and

[0248] m is an integer from 1 to 8;

[0249] R of formula (XXII) or (XXIII) 3 and R 4 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituent is alkyl, halogen, or OH;

[0250] R of formula (XXII) or (XXIII) 5 、R6 、R 7 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and

[0251] X is selected from a bond or a chemical linker group, and / or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In certain embodiments, X is a bond or a group consisting of:

[0252]

[0253] Where "*" is the connection point of PTM, L or ULM such as ILM.

[0254] In any of the compounds described herein, the ILM may have a structure of Formula (XXIV) or (XXVI), which is derived from an IAP ligand described in WO Publication No. 2015 / 006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015); or a non-natural mimetic thereof; and a chemical linker with a linker group L, as shown:

[0255]

[0256] in:

[0257] 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;

[0258] 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;

[0259] Or alternatively,

[0260] R of formula (XXIV), (XXV) or (XXVI) 1 and R 2 are independently selected from optionally substituted sulfanyl groups, wherein the substituent attached to the S atom of the sulfanyl group is an optionally substituted alkyl group, an optionally substituted branched alkyl group, an optionally substituted heterocyclic group,

[0261] -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ,

[0262] in:

[0263] v is an integer from 1 to 3;

[0264] -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0265] -CH2CHR 21 COR 2 R 21 Selected from NR 24 R 25 ;

[0266] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0267] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0268] NR 24 R 25 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclic group, -CH2(OCH2CH2O) m CH3 or polyamine chains, such as spermine or spermidine;

[0269] OR 26 R 26 is selected from optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2; and

[0270] m is an integer from 1 to 8;

[0271] R of formula (XXIV), (XXV) or (XXVI) 3 and R 4is 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 substituent is alkyl, halogen, or OH;

[0272] 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; and / or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

[0273] In certain embodiments, the ILMs according to formula (XXII) to (XXVI):

[0274] R 7 and R 8 selected from H or Me;

[0275] R 5 and R 6 Select from the group consisting of:

[0276]

[0277] R 3 and R 4 Select from the group consisting of:

[0278]

[0279] In any of the compounds described herein, the ILM may have the structure of Formula (XXVII) or (XXVII), which is derived from the IAP ligands described in WO Publication No. 2014 / 055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalentheterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014); or a non-natural mimetic thereof:

[0280]

[0281] in:

[0282] R 35 is 1-2 substituents selected from alkyl, halogen, alkoxy, cyano and haloalkoxy;

[0283] 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;

[0284] 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;

[0285] Or alternatively,

[0286] R of formula (XXVII) and (XXVIII) 1 and R 2 independently selected from optionally substituted sulfanyl-CR 60 R 61 SR 70 , where R 60 and R 61 is selected from H or methyl, and R 70 is selected from optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclic group, -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ,

[0287] in:

[0288] v is an integer from 1 to 3;

[0289] -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0290] -CH2CHR 21 COR 22 R 21 Selected from NR 24 R 25 ;

[0291] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0292] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0293] NR 24 R 25 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3 or polyamine chain

[0294] Such as spermine or spermidine;

[0295] Where δ=0-2、ψ=1-3、

[0296] OR 26 R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2; and

[0297] m is an integer from 1 to 8,

[0298] R of formula (XXVII) and (XXVIII) 3 and R 4 is independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl, or optionally substituted heterocycloalkyl, wherein the substituent is alkyl, halogen, or OH;

[0299] R of formula (XXVII) and (XXVIII) 5 、R 6 、R 7 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0300] R of formula (XXVII) and (XXVIII) 31 is selected from optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably selected from the group consisting of:

[0301]

[0302] X of formula (XXVII) and (XXVIII) is selected from -(CR 81 R 82 ) m -, optionally substituted heteroaryl or heterocyclic group,

[0303]

[0304] Z of formula (XXVII) is selected from C═O, —O—, —NR, —CONH—, —NHCO— or may be absent;

[0305] -(CR 81 R 82 ) m -R 81 and R 82 are independently selected from hydrogen, halogen, alkyl or cycloalkyl, or R 81 and R 82 can form carbon rings together;

[0306] R 10 and R 11 independently selected from hydrogen, halogen or alkyl;

[0307] R 12 、R 13 、R 14 、R 15 and R 16 are independently selected from hydrogen, halogen or optionally substituted alkyl or OR 17 ;

[0308] R 17 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

[0309] -(CR 21 R 22 ) m -and m and n are independently 0, 1, 2, 3 or 4;

[0310] o and p are independently 0, 1, 2 or 3;

[0311] q and t are independently 0, 1, 2, 3 or 4;

[0312] r is 0 or 1;

[0313] and / or pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

[0314] In any of the compounds described herein, the ILM may have a structure of Formula (XXIX), (XXX), (XXXI), or (XXXII), which is derived from an IAP ligand described in WO Publication No. 2014 / 055461 and Kim, KS, Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014); or a non-natural mimetic thereof; and a chemical linker to a linker group L, as shown:

[0315]

[0316]

[0317] in:

[0318] R in formula (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;

[0319] or alternatively;

[0320] R of formula (XXVII) and (XXVIII) 1 and R 2 independently selected from H, optionally substituted sulfanyl-CR 60 R 61 SR 70 , where R 60 and R 61 Selected from H or methyl and R 70 is an optionally substituted alkyl group, an optionally substituted branched alkyl group, an optionally substituted heterocyclic group, -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ;

[0321] in:

[0322] v is an integer from 1 to 3;

[0323] -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 Independently selected from OH, NR24 R 25 OR 26 ;

[0324] -CH2CHR 21 COR 22 R 21 Selected from NR 24 R 25 ;

[0325] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0326] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0327] NR 24 R 25 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH2CH2(OCH2CH2) m CH3 or polyamine chain Such as spermine or spermidine,

[0328] Where δ=0-2、ψ=1-3、

[0329] OR 26 R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2;

[0330] m is an integer from 1 to 8;

[0331] R in formula (XXIX) to (XXXII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0332] and

[0333] R in formula (XXIX) to (XXXII) 31 is selected from optionally further substituted alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, preferably selected from the group consisting of:

[0334]

[0335] In certain embodiments, the ILM of the compound is:

[0336]

[0337] 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 Publication No. 2014 / 074658 and WO Publication No. 2013 / 071035; or non-natural mimetics thereof:

[0338]

[0339] in:

[0340] 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;

[0341] R in formula (XXXIII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0342] R in formula (XXXIII) 32 Selected from (C1-C4 alkylene)-R 33 , where R 33 is selected from hydrogen, optionally further substituted aryl, heteroaryl or cycloalkyl;

[0343] X of formula (XXXIII) is selected from:

[0344]

[0345] Z and Z' of formula (XXXIII) are independently selected from:

[0346] Each of these represents the point of attachment to the compound, and in any given compound Z and Z' cannot both be

[0347] Y of formula (XXXIII) is selected from:

[0348]

[0349] wherein Z and Z' of formula (XXXIII) are the same, and Z is Each of these represents the point of connection to the compound, and X is selected from:

[0350]

[0351] and

[0352] Y of formula (XXXIII) is independently selected from:

[0353]

[0354]

[0355] in:

[0356] represents the point of attachment to the -C=O portion of the compound;

[0357] represents the point of attachment to the -NH portion of the compound;

[0358] represents the first connection point with Z;

[0359] represents the second connection point with Z;

[0360] m is an integer from 0 to 3;

[0361] n is an integer from 1 to 3;

[0362] p is an integer from 0 to 4; and

[0363] A is -C(O)R 3 ;

[0364] -C(O)R 3 R 3 Selected from OH, NHCN, NHSO2R 10 NHOR 11 or N(R 12 )(R 13 );

[0365] NHSO2R 10 and NHOR 11 R 10 and F 11 independently selected from hydrogen, optionally substituted -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocycloalkyl;

[0366] N(R 12 )(R 13 ) of R 12 and R 13 independently selected from hydrogen, -C1-C4 alkyl, -(C1-C4)alkylene)-NH-(C1-C4 alkyl) and -(C1-C4 alkylene)-O-(C1-C4 hydroxyalkyl), or R12 and R 13 Together with the nitrogen atom to which they are commonly attached, they form a saturated heterocyclic group, which optionally contains one additional heteroatom selected from N, O and S, and wherein the saturated heterocyclic ring is optionally substituted by methyl.

[0367] In any of the compounds described herein, the ILM may have a structure of Formula (XXXIV) or (XXXV), which is derived from an IAP ligand described in WO Publication No. 2014 / 047024; or a non-natural mimetic thereof:

[0368]

[0369] in:

[0370] X in formula (XXXIV) or (XXXV) is absent or is a group selected from: -(CR 10 R 11 ) m -, optionally substituted heteroaryl or optionally substituted heterocyclic group,

[0371]

[0372]

[0373] Y and Z of formula (XXXIV) or (XXXV) are independently selected from C=0, -0-, -NR 9 -, -CONH-, -NHCO- or may not exist;

[0374] 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

[0375] R of formula (XXXIV) or (XXXV) 1 and R 2 are independently selected from optionally substituted sulfanyl groups, wherein the substituent attached to the S atom of the sulfanyl group is an optionally substituted alkyl group, an optionally substituted branched alkyl group, an optionally substituted heterocyclic group, -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ;in

[0376] v is an integer from 1 to 3;

[0377] -(CH2) v COR 20and -CH2CHR 21 COR 22 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0378] -CH2CHR 21 COR 22 R 21 Selected from NR 24 R 25 ;

[0379] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0380] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0381] NR 24 R 25 R 25 selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclic group, -CH2(OCH2CH 20 )mCH3 or polyamine chains;

[0382] R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2;

[0383] -(CR 10 R 11 ) m -m is an integer from 1 to 8;

[0384] 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 substituent is alkyl, halogen, or OH;

[0385] R of formula (XXXIV) or (XXXV) 5 、R 6 、R 7 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0386] -(CR 10 R 11 ) m -R 10 and R 11 are independently selected from hydrogen, halogen, or optionally substituted alkyl;

[0387] R 12 and R 13 are independently selected from hydrogen, halogen or optionally substituted alkyl, or R 12 and R 13 can form carbon rings together;

[0388] R 14 、R 15 、R 16 、R 17 and R 18 are independently selected from hydrogen, halogen, optionally substituted alkyl or OR 19 ;

[0389] OR 19 R 19 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

[0390] -(CR 10 R 11 ) m -m and n are independently 0, 1, 2, 3 or 4;

[0391] -(CR 10 R 11 ) m - o and p are independently 0, 1, 2 or 3;

[0392] -(CR 10 R 11 ) m -q is 0, 1, 2, 3 or 4; r is 0 or 1;

[0393] -(CR 10 R 11 ) m -t is 1, 2 or 3; and / or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In any compound described herein, the ILM may have a structure of Formula (XXXVI), which is derived from an IAP ligand described in WO Publication No. 2014 / 025759; or a non-natural mimetic thereof:

[0394]

[0395] in:

[0396] A of formula (XXXVI) is selected from: Wherein the dotted line represents an optional double bond;

[0397] X of formula (XXXVI) is selected from: -(CR 21 R 22 ) m -、

[0398]

[0399] Y and Z of formula (XXXVI) are independently selected from -O-, -NR 6 - or does not exist;

[0400] V of formula (XXXVI) is selected from -N- or -CH-;

[0401] W of formula (XXXVI) is selected from -CH- or -N-;

[0402] R of formula (XXXVI) 1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl or optionally substituted aryl;

[0403] R of formula (XXXVI) 3 and R 4 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;

[0404] R of formula (XXIV), (XXV) or (XXVI) 5 、R 6 、R 7 and R 8 independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl or preferably methyl;

[0405] R 9 and R 10 are independently selected from hydrogen, halogen or optionally substituted alkyl, or R 9 and R 10 can form a ring together;

[0406] R 11 、R 12 、R 13 and R 14 are independently selected from hydrogen, halogen, optionally substituted alkyl or OR 15 ;

[0407] OR 15 R 15 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

[0408] -(CR 21 R 22 ) m -and m and n are independently selected from 0, 1, 2, 3 or 4;

[0409] o and p are independently selected from 0, 1, 2 or 3;

[0410] q is selected from 0, 1, 2, 3 or 4;

[0411] wherein r is selected from 0 or 1, and / or pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

[0412] In any of the compounds described herein, the ILM may have a structure of Formula (XXXVII) or (XXXVIII), which is derived from an IAP ligand described in WO Publication No. 2014 / 011712; or a non-natural mimetic thereof:

[0413]

[0414]

[0415] in:

[0416] X of formula (XXXVII) and (XXXVIII) is -(CR 16 R 17 ) m -、

[0417]

[0418] or does not exist;

[0419] Y and Z of formula (XXXVII) and (XXXVIII) are independently selected from -0-, C=0, NR 6 or does not exist;

[0420] 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;

[0421] R of formula (XXXVII) and (XXXVIII) 3 and R 4independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylalkyl, or optionally substituted aryl;

[0422] R of formula (XXXVII) and (XXXVIII) 5 and R 6 are independently selected from optionally substituted alkyl or optionally substituted cycloalkyl;

[0423] R of formula (XXXVII) and (XXXVIII) 7 and R 8 independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl or preferably methyl;

[0424] R 9 and R 10 are independently selected from hydrogen, optionally substituted alkyl, or R 9 and R 10 can form a ring together;

[0425] R 11 to R 14 are independently selected from hydrogen, halogen, optionally substituted alkyl or OR 15 ;

[0426] OR 15 R 15 is selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

[0427] -(CR 16 R 17 ) m -R 16 and R 17 are independently selected from hydrogen, halogen, or optionally substituted alkyl;

[0428] R of formula (XXXVII) and (XXXVIII) 50 and R 51 are independently selected from optionally substituted alkyl, or R 50 and R 51 together to form a ring;

[0429] -(CR 16 R 17 ) m -and m and n are independently integers from 0 to 4;

[0430] o and p are independently integers from 0 to 3;

[0431] q is an integer from 0 to 4; and

[0432] r is an integer between 0 and 1;

[0433] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0434] In one embodiment, R of the ILM of formula (XXXVII) or (XXXVIII) 1 and R 2 is tert-butyl, and R of the ILM of formula (XXXVII) or (XXXVIII) 3 and R 4 It's tetralin.

[0435] In any of the compounds described herein, the ILM may have a structure of Formula (XXXIX) or (XL), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039; or a non-natural mimetic thereof:

[0436]

[0437] in:

[0438] R of formula (XXXIX) and (XL) 43 and R 44 are independently selected from hydrogen, optionally further substituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, and

[0439] R of formula (XXXIX) and (XL) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl.

[0440] Each X of formula (XXXIX) and (XL) is independently selected from:

[0441]

[0442]

[0443] Each Z of formula (XXXIX) and (XL) is selected from Each of these represents the point of attachment to the compound; and

[0444] Each Y is selected from:

[0445]

[0446]

[0447]

[0448] in:

[0449] represents the point of attachment to the -C=O portion of the compound;

[0450] represents the point of attachment to the amino moiety of the compound;

[0451] represents the first connection point with Z;

[0452] represents the second connection point with Z; and

[0453] A is selected from -C(O)R 3 or

[0454]

[0455] or a tautomeric form of any of the foregoing, wherein:

[0456] -C(O)R 3 R 3 Selected from OH, NHCN, NHS02R 10 NHOR 11 or N(R 12 )(R 13 );

[0457] NHS02R 10 and NHOR 11 R 10 and R 11 independently selected from -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl (any of which is optionally substituted) and hydrogen;

[0458] N(R 12 )(R 13 ) of R 12 and R 13 each 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 ) of R 12 and R 13Together with the nitrogen atom to which they are commonly attached, they form a saturated heterocyclic group, which optionally contains one additional heteroatom selected from N, O and S, and wherein the saturated heterocyclic ring is optionally substituted by methyl.

[0459] In any of the compounds described herein, the ILM may have the structure of Formula (XLI), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039; or a non-natural mimetic thereof:

[0460]

[0461] in:

[0462] W in formula (XLI) 1 Selected from O, S, NR A or C(R 8a )(R 8b );

[0463] W in formula (XLI) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); the condition is W 1 and W 2 Not all O or not all S;

[0464] R in formula (XLI) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0465] When X 1 Selected from O, NR A , S, S(O) or S(O)2, X 2 It is C(R 2a R 2b );

[0466] or:

[0467] X in formula (XLI) 1 Selected from CR 2c R 2d And X 2 It's CR 2a R 2b , and R 2c and R 2a together to form a bond;

[0468] or:

[0469] X in formula (XLI) 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, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring;

[0470] or:

[0471] X in formula (XLI) 1 selected from CH2 and X 2 C=0、C=C(R C )2 or C=NR C ; where each R c 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);

[0472] NR A R A is selected from H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0473] CR 2c R 2d and CR 2a R 2b R 2a 、R 2b 、R 2c 、R 2d independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O)RB ;

[0474] -C(=O)R B R B is selected from 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 ;

[0475] NR D R E R D and R E independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0476] m of formula (XLI) is selected from 0, 1 or 2;

[0477] -U- of 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-;

[0478] R in formula (XLI) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0479] R in formula (XLI) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0480] -NHR 5 、-N(R 5 )2、-N+(R5 )3 and -OR 5 Each R 5 independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl);

[0481] or:

[0482] R in formula (XLI) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0483] or:

[0484] R in formula (XLI) 3 Bonded to the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0485] R in formula (XLI) 6 Selected from -NHC(=O)R 7 、-C(=O)NHR 7 、-NHS(=O)2R 7 、-S(=O)2NHR 7 ;-NHC(=O)NHR 7 、-NHS(=O)2NHR 7 、-(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 、-(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ; -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0486] -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 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 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-C10 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);

[0487] R 7 p is selected from 0, 1 or 2;

[0488] C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a 、R 8b 、R 8c and R 8d Independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl and substituted or unsubstituted aryl;

[0489] or:

[0490] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0491] or:

[0492] R 8a and R 8d As defined above, and R 8b and R 8c Together with the atoms to which they are attached, they form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

[0493] or:

[0494] R 8c and R 8d As defined above, and R 8a and R 8b Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0495] or:

[0496] R 8a and R 8b As defined above, and R 8c and R 8d Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0497] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 replace; and

[0498] R 8a 、R 8b 、R 8c and R 8d Each R 9independently 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-(C1-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, they form a methylenedioxy or ethylenedioxy ring which may be substituted or unsubstituted by halogen, -OH or C1-C3 alkyl.

[0499] In any of the compounds described herein, the ILM may have the structure of Formula (XLII), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039; or a non-natural mimetic thereof:

[0500]

[0501] in:

[0502] W in formula (XLII) 1 O, S, NR A or C(R 8a )(R 8b );

[0503] W in formula (XLII) 2 O, S, NR A or C(R 8c )(R 8d ); the condition is W 1 and W 2 Not all O or not all S;

[0504] R in formula (XLII) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0505] When X in formula (XLII) 1 It is NR A When X 2 Is C=O or CR 2c R2d and X 3 It's CR 2a R 2b ;

[0506] or:

[0507] When X in formula (XLII) 1 When selected from S, S(O) or S(O)2, X 2 It's CR 2c R 2d and X 3 It's CR 2a R 2b ;

[0508] or:

[0509] When X in formula (XLII) 1 When it is O, X 2 It's CR 2c R 2d and NR A And X 3 It's CR 2a R 2b ;

[0510] or:

[0511] When X in formula (XLII) 1 When it is CH3, X 2 Selected from O, NR A , S, S(O) or S(O)2 and X 3 It's CR 2a R 2b ;

[0512] When X in formula (XLII) 1 It's CR 2e R 2f And X2 is CR 2c R 2d When, and R 2e and R 2c Together they form a bond, and X of formula (VLII) 3 It's CR 2a R 2b ;

[0513] or:

[0514] X in formula (XLII) 1 and X 3 are all CH2 and X of formula (XLII) 2 C=0、C=C(R C )2 or C=NR C ; where each R CIndependently 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);

[0515] or:

[0516] 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, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X 3 It's CR 2a R 2b ;

[0517] or:

[0518] X in formula (XLII) 2 and X 3 is independently selected from C and N, and is a member of a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X of formula (VLII) 1 It's CR 2e R 2f ;

[0519] NR A R A is selected from H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0520] CR 2c R 2d , CR 2a R 2b and CR 2e R 2f R 2a 、R 2b 、R 2c 、R2d 、R 2e and R 2f independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O)R B ;

[0521] -C(=O)R B R B is selected from 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 ;

[0522] NR D R E R D and R E independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0523] m of formula (XLII) is selected from 0, 1 or 2;

[0524] -U- of 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-;

[0525] R in formula (XLII) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0526] R in formula (XLII) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0527] -NHR 5 、-N(R 5 )2、-N+(R 5 )3 and -OR 5 Each R 5 independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl);

[0528] or:

[0529] R in formula (XLII) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0530] or:

[0531] R in formula (XLII) 3 Bonded to the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0532] R in formula (XLII) 6 Selected from -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-C10 heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0533] -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 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 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-C10 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);

[0534] R 7 p is selected from 0, 1 or 2;

[0535] C(R 8a )(R 8b ) and C(R8c )(R 8d ) of R 8a 、R 8b 、R 8c and R 8d Independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl and substituted or unsubstituted aryl;

[0536] or:

[0537] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0538] or:

[0539] R 8a and R 8d As defined above, and R 8b and R 8c Together with the atoms to which they are attached, they form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

[0540] or:

[0541] R 8c and R 8d As defined above, and R 8a and R 8b Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0542] or:

[0543] R 8a and R 8b As defined above, and R 8c and R 8d Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0544] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 replace; and

[0545] R 8a 、R8b 、R 8c and R 8d Each R 9 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-(C1-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, they form a methylenedioxy or ethylenedioxy ring which may be substituted or unsubstituted by halogen, -OH or C1-C3 alkyl.

[0546] In any of the compounds described herein, the ILM may have the structure of Formula (XLIII), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039; or a non-natural mimetic thereof:

[0547]

[0548] in:

[0549] W in formula (XLIII) 1 Selected from O, S, NR A or C(R 8a )(R 8b );

[0550] W in formula (XLIII) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); the condition is W 1 and W 2 Not all O or not all S;

[0551] R of formula (XLIII) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0552] When X in formula (XLIII)1 Selected from NR A , S, S(O) or S(O)2, X in formula (XLIII) 2 It's CR 2c R 2d , and X of formula (XLIII) 3 It's CR 2a R 2b ;

[0553] or:

[0554] When X in formula (XLIII) 1 When X is O, 2 Selected from O, NR A , S, S(O) or S(O)2, and X of formula (XLIII) 3 It's CR 2a R 2b ;

[0555] or:

[0556] When X in formula (XLIII) 1 It's CR 2e R 2f And X of formula (XLIII) 2 It's CR 2c R 2d When, and R 2e and R 2c together to form a bond,

[0557] And X of formula (XLIII) 3 It's CR 2a R 2b ;

[0558] or:

[0559] X in formula (XLIII) 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, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X of formula (XLIII) 3 It's CR 2a R 2b ;

[0560] or:

[0561] X in formula (XLIII) 2 and X 3is independently selected from C and N, and is a member of a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X of formula (VLII) 1 It's CR 2e R 2f ;

[0562] NR A R A is H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0563] CR 2c R 2d , CR 2a R 2b and CR 2e R 2f R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O)R B ;

[0564] -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-(unsubstituted or substituted heteroaryl) or -NR D R E ;

[0565] NR D R E R D and R E independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0566] m of formula (XLIII) is 0, 1 or 2;

[0567] -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-;

[0568] R of formula (XLIII) 3 is a C1-C3 alkyl group or a C1-C3 fluoroalkyl group;

[0569] R of formula (XLIII) 4 Yes-NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0570] -NHR 5 、-N(R 5 )2、-N+(R 5 )3 and -OR 5 Each R 5 independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl);

[0571] or:

[0572] R of formula (XLIII) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0573] or:

[0574] R of formula (XLIII)3 Bonded to the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0575] R of formula (XLIII) 6 Selected from -NHC(=O)R 7 、-C(=O)NHR 7 、-NHS(=O)2R 7 、-S(=O)2NHR 7 ;-NHC(=O)NHR 7 、-NHS(=O)2NHR 7 、-(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 、-(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ; -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0576] -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 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C 10Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C 10 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C10 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);

[0577] R 7 p is 0, 1, or 2;

[0578] C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a 、R 8b 、R 8c and R 8d Independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl and substituted or unsubstituted aryl;

[0579] or:

[0580] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0581] or:

[0582] R 8a and R 8d As defined above, and R 8b and R 8cTogether with the atoms to which they are attached, they form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

[0583] or:

[0584] R 8c and R 8d As defined above, and R 8a and R 8b Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0585] or:

[0586] R 8a and R 8b As defined above, and R 8c and R 8d Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0587] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 replace; and

[0588] R 8a 、R 8b 、R 8c and R 8d Each R 9 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-(C1-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, they form a methylenedioxy or ethylenedioxy ring which may be substituted or unsubstituted by halogen, -OH or C1-C3 alkyl.

[0589] In any of the compounds described herein, the ILM may have the structure of Formula (XLIV), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039; or a non-natural mimetic thereof:

[0590]

[0591] in:

[0592] W in formula (XLIV) 1 Selected from O, S, NR A or C(R 8a )(R 8b );

[0593] W in formula (XLIV) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); the condition is W 1 and W 2 Not all O or not all S;

[0594] W in formula (XLIV) 3 Selected from O, S, NR A or C(R 8e )(R 8f ), provided that W is included 1 、W 2 and W 3 The ring does not contain two adjacent oxygen atoms or sulfur atoms;

[0595] R of formula (XLIV) 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0596] When X in formula (XLIV) 1 When X is O, 2 Selected from CR 2c R 2d and NR A , and X of formula (XLIV) 3 It's CR 2a R 2b ;

[0597] or:

[0598] When X in formula (XLIV) 1When CH2, then X in formula (XLIV) 2 Selected from O, NR A , S, S(O) or S(O)2, and X of formula (XLIV) 3 It's CR 2a R 2b ;

[0599] or:

[0600] When X in formula (XLIV) 1 It's CR 2e R 2f And X of formula (XLIV) 2 It's CR 2c R 2d When, and R 2e and R 2c Together they form a bond, and X of formula (XLIV) 3 It's CR 2a R 2b ;

[0601] or:

[0602] X in formula (XLIV) 1 and X 3 are all CH2 and X of formula (XLII) 2 C=0、C=C(R C )2 or C=NR C ; where each R C 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);

[0603] or:

[0604] X in formula (XLIV) 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, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X of formula (XLIV) 3 It's CR2a R 2b ;

[0605] or:

[0606] X in formula (XLIV) 2 and X 3 is independently selected from C and N, and is a member of a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered cycloalkyl ring, a fused, substituted or unsubstituted, saturated or partially saturated, 3-10 membered heterocycloalkyl ring, a fused, substituted or unsubstituted, 5-10 membered aryl ring, or a fused, substituted or unsubstituted, 5-10 membered heteroaryl ring, and X of formula (VLIV) 1 It's CR 2e R 2f ;

[0607] NR A R A is selected from H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0608] CR 2c R 2d , CR 2a R 2b and CR 2e R 2f R 2a 、R 2b 、R 2c 、R 2d 、R 2e and R 2f independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl) and -C(=O)R B ;

[0609] -C(=O)R B R Bis selected from 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 ;

[0610] NR D R E R D and R E independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl) or -C1-C6 alkyl-(substituted or unsubstituted heteroaryl);

[0611] m of formula (XLIV) is selected from 0, 1 or 2;

[0612] -U- of formula (XLIV) is selected from -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH- or -NHS(=O)2NH-;

[0613] R of formula (XLIV) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0614] R of formula (XLIV) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0615] -NHR 5 、-N(R 5 )2、-N+(R 5 )3 and -OR 5 Each R 5independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 heteroalkyl, and -C1-C3 alkyl-(C3-C5 cycloalkyl);

[0616] or:

[0617] R of formula (XLIV) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0618] or:

[0619] R of formula (XLIII) 3 Bonded to the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0620] R of formula (XLIII) 6 Selected from -NHC(=O)R 7 、-C(=O)NHR 7 、-NHS(=O)2R 7 、-S(=O)2NHR 7 ;-NHC(=O)NHR 7 、-NHS(=O)2NHR 7 、-(C1-C3 alkyl)-NHC(=O)R 7 , -(C1-C3 alkyl)-C(=O)NHR 7 、-(C1-C3 alkyl)-NHS(=O)2R 7 , -(C1-C3 alkyl)-S(=O)2NHR 7 ; -(C1-C3 alkyl)-NHC(=O)NHR 7 , -(C1-C3 alkyl)-NHS(=O)2NHR 7 , substituted or unsubstituted C2-C 10 heterocycloalkyl or substituted or unsubstituted heteroaryl;

[0621] -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 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, substituted or unsubstituted C3-C10 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-C10 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);

[0622] R 7 p is selected from 0, 1 or 2;

[0623] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a 、R 8b 、R 8c 、R 8d 、R 8e and R 8f independently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl and substituted or unsubstituted aryl; or:

[0624] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R8e )(R 8f ) of R 8a 、R 8d 、R 8e and R 8f As defined above, and R 8b and R 8c together to form a bond;

[0625] or:

[0626] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a 、R 8b 、R 8d and R 8f As defined above, and R 8c and R 8e together to form a bond;

[0627] or:

[0628] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a 、R 8d 、R 8e and R 8f As defined above, and R 8b and R 8c together with the atoms to which they are attached, form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

[0629] or:

[0630] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8a 、R 8b 、R 8d and R 8f As defined above, and R 8c and R8e Together with the atoms to which they are attached, they form a substituted or unsubstituted fused 5-7 membered saturated or partially saturated carbocyclic or heterocyclic ring containing 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring containing 1-3 heteroatoms selected from S, O and N;

[0631] or:

[0632] C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8c 、R 8d 、R 8e and R 8f As defined above, and R 8a and R 8b Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0633] or:

[0634] C(R 8a )(R 8b ) and C(R 8e )(R 8f ) of R 8a 、R 8b 、R 8e and R 8f As defined above, and R 8c and R 8d Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0635] or:

[0636] C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a 、R 8b 、R 8c and R 8d As defined above, and R 8e and R 8f Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or heterospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0637] or:

[0638] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, heterospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 replace; and

[0639] R 8a 、R 8b 、R 8c 、R 8d 、R 8e and R 8f Each R 9 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-(C1-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, they form a methylenedioxy or ethylenedioxy ring which may be substituted or unsubstituted by halogen, -OH or C1-C3 alkyl.

[0640] In any of the compounds described herein, the ILM may have the structure of Formula (XLV), (XLVI), or (XLVII), which is derived from an IAP ligand described in Vamos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACSChem. Biol., 8(4), 725-32 (2013); or a non-natural mimetic thereof:

[0641]

[0642]

[0643] in:

[0644] R of formula (XLV) 2 、R 3 and R 4 independently selected from H or ME;

[0645] X of formula (XLV) is independently selected from O or S; and

[0646] R of formula (XLV) 1 Selected from:

[0647]

[0648] In certain embodiments, the ILM has a structure according to Formula (XLVIII):

[0649] Wherein R 3 and R 4 independently selected from H or ME;

[0650] is a 5-membered heterocyclic ring selected from the following:

[0651]

[0652] In a specific embodiment, the yes

[0653] In certain embodiments, the ILM has the structure shown below and is attached to the linker group L:

[0654]

[0655] In certain embodiments, the ILM has a structure according to Formula (XLIX), (L), or (LI):

[0656]

[0657]

[0658] in:

[0659] R of formula (XLIX), (L) or (LI) 3 independently selected from H or ME;

[0660] is a 5-membered heterocyclic ring selected from the following:

[0661] and

[0662] L of formula (XLIX), (L) or (LI) is selected from:

[0663]

[0664] In certain embodiments, L of (XLIX), (L) or (LI)

[0665]

[0666] In a specific embodiment, the ILM has a structure according to Formula (LII):

[0667]

[0668] In a specific embodiment, the ILM according to formula (LII) is chemically linked to The linker group L in the region indicated and shown below:

[0669]

[0670] In any of the compounds described herein, the ILM may have the structure of Formula (LIII) or (LIV), which is based on the IAP ligands described in Hennessy, EJ, et al., Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4 (2012); or a non-natural mimetic thereof:

[0671]

[0672] in:

[0673] R of formula (LIII) and (LIV) 1 Selected from:

[0674]

[0675] R of formula (LIII) and (LIV) 2 selected from H or Me;

[0676] R of formula (LIII) and (LIV) 3 Selected from:

[0677]

[0678] X is selected from H, halogen, methyl, methoxy, hydroxy, nitro or trifluoromethyl.

[0679] In any of the compounds described herein, the ILM may have a structure of Formula (LV) or (LVI) or a non-natural mimetic thereof, and be chemically linked to the linker shown therein:

[0680]

[0681]

[0682] In any of the compounds described herein, the ILM may have the structure of Formula (LVII), which is based on the IAP ligand described in Cohen, F, et al., Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6), 1723-30 (2009); or a non-natural mimetic thereof:

[0683]

[0684] in:

[0685] R1 of formula (LVII) is selected from:

[0686]

[0687] X is selected from H, fluorine, methyl or methoxy.

[0688] In a specific embodiment, the ILM is represented by the following structure:

[0689]

[0690] In a specific embodiment, the ILM is selected from the group consisting of and the chemical linkage between the ILM and the linker group L is as follows:

[0691]

[0692] In any of the compounds described herein, the ILM is selected from the group consisting of the following structures, which are based on the IAP ligands described in Asano, M, et al., Design, sterioselective synthesis and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013); or non-natural mimetics thereof:

[0693]

[0694] In a specific embodiment, the ILM is selected from the group consisting of and the chemical linkage between the ILM and the linker group L is as follows:

[0695]

[0696] In any of the compounds described herein, the ILM may have the structure of formula (LVIII), which is based on the IAP ligand described in Asano, M, et al., Design, sterioselective synthesis and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem., 21(18):5725-37 (2013); or a non-natural mimetic thereof:

[0697]

[0698] wherein X of formula (LVIII) is one or two substituents independently selected from H, halogen or cyano.

[0699] In any of the compounds described herein, the ILM may have a structure of formula (LIX) or (LX) or a non-natural mimetic thereof, and be chemically linked to a linker group L as shown therein:

[0700]

[0701] wherein X of formula (LIX) and (LX) is one or two substituents independently selected from H, halogen or cyano; and L of formula (LIX) and (LX) is a linker group as described herein.

[0702] In any of the compounds described herein, the ILM can have the structure of formula (LXI), which is based on the IAP ligand described in Ardecky, RJ, et al., Design, sysnthesis and evaluation of inhibitor of apoptosis (IAP) antagonists that are highly selective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14):4253-7 (2013); or a non-natural mimetic thereof:

[0703]

[0704] in:

[0705] Formula (LXI) is a natural or unnatural amino acid; and

[0706] R of formula (LXI) 2 Selected from:

[0707] In any of the compounds described herein, the ILM may have a structure as shown in Formula (LXII) or (LLXIII) or a non-natural mimetic thereof, and be chemically linked to a linker group L as shown therein:

[0708]

[0709]

[0710] Formula (LXI) is a natural or unnatural amino acid; and

[0711] L of formula (LXI) is a linker group as described herein.

[0712] In any of the compounds described herein, the ILM can have a structure selected from the group consisting of 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 a non-natural mimetic thereof:

[0713]

[0714] In any of the compounds described herein, the ILM has a structure according to formula (LXIX), which is based on the IAP ligand described in Hird, AW, et al., Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem. Lett., 24(7): 1820-4 (2014); or a non-natural mimetic thereof:

[0715]

[0716] wherein R of the formula LIX is selected from the group consisting of:

[0717]

[0718] R1 is selected from H or ME;

[0719] R2 is selected from alkyl or cycloalkyl;

[0720] X is 1-2 substituents independently selected from halogen, hydroxy, methoxy, nitro and trifluoromethyl

[0721] Z is O or NH;

[0722] HET is a mono- or fused-bicyclic heteroaryl; and

[0723] In formula (LIX), --- is an optional double bond.

[0724] In certain embodiments, the ILM of the compound has a chemical structure represented by:

[0725]

[0726] In certain embodiments, the ILM of the compound has a chemical structure selected from the group consisting of:

[0727]

[0728]

[0729] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0730] The term "alkyl" in this context refers to an optionally substituted linear, branched or cyclic fully saturated hydrocarbon or alkyl group, preferably a C1-C 10 , more preferably C1-C6, or C1-C3 alkyl.The example of alkyl is 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 etc.In certain embodiments, alkyl is by a halogen group (At, Br, Cl, F or I) end-blocking.In some preferred embodiments, according to compound of the present disclosure, can be used for being covalently bound to dehalogenase.These compounds contain side chain (being usually connected by polyethylene glycol group), and described side chain stops with alkyl, and this alkyl has halogen substituent (usually chlorine or bromine) at its far end, and this causes the compound containing this part to be covalently bound to protein.

[0731] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0732] The term "alkynyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0733] The term "alkylene" when used herein refers to -(CH2) n -group (n is typically an integer from 0 to 6). When substituted, the alkylene group is preferably substituted on one or more methylene groups with a C1-C6 alkyl group (including a cyclopropyl or tert-butyl group), but may also be substituted with one or more halogen groups, preferably 1-3 halogen groups or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or amino acid side chains, as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a carbamate or alkoxy group (or other groups), which is further substituted with a polyethylene glycol chain (having 1 to 10, preferably 1 to 6, typically 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with a single halogen group, preferably a chloro group (preferably, but not exclusively, at the distal end of the polyethylene glycol chain). In still other embodiments, the alkylene group (typically a methylene group) can be substituted with an amino acid side chain group, such as a side chain group of a natural or unnatural amino acid, for example, 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.

[0734] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A series of carbon atoms including CO means that the carbon is absent and replaced by H, thus a series of carbon atoms from CO to C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for CO, H replaces the carbon.

[0735] The term "substituted" or "optionally substituted" shall refer independently (i.e., each substituent is independent of the other when more than one substituent is present) to one or more substituents (independently up to five substituents, preferably up to three substituents, typically 1 or 2 substituents, and which may themselves be further substituted on a moiety of a compound according to the present disclosure) on a carbon (or nitrogen) position anywhere on the molecule in the context, and includes as substituents hydroxy; mercapto; carboxyl; cyano (C≡N); nitro (NO2); halogen (preferably 1, 2 or 3 halogens, especially on an alkyl group, especially methyl such as trifluoromethyl); alkyl (preferably C1-C1 10, more preferably C1-C6); aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl); alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl); thioether (C1-C6 alkyl or aryl); acyl (preferably C1-C6 acyl); ester or thioester (preferably C1-C6 alkyl or aryl), including alkylene ester (so that the bond is on the alkylene group rather than on the ester function, the ester function is preferably substituted by C1-C6 alkyl or aryl), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl); amine (including five-membered or six-membered cyclic alkylene amine, Further include C1-C6 alkylamine or C1-C6 dialkylamine, the alkyl group may be substituted with one or two hydroxy groups) or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) (which may be optionally substituted with a polyethylene glycol chain, the polyethylene glycol chain further bonded to an alkyl group containing a single halogen, preferably chlorine, substituent); hydrazine; acylamino, which is preferably substituted with one or two C1-C6 alkyl groups (including carboxamide, which is optionally substituted with one or two C1-C6 alkyl groups); alkanol (preferably C1-C6 alkyl or aryl); or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, wherein R1 and R2 are each as otherwise described herein, R3 is H or C1-C6 alkyl, preferably R1, R2, R3 in this context are C1-C3 alkyl (including isopropyl or tert-butyl). Each of the above groups may be directly attached to the substituted moiety, or alternatively, the substituent may be attached via an optionally substituted -(CH2) m - or alternatively optionally substituted -(OCH2) m -、-(OCH2CH2) m -or-(CH2CH2O) m -group is attached to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety), which optionally substituted group may be substituted by any one or more of the substituents described above. m -or-(CH2) n-Groups or other chains such as ethylene glycol chains can be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F) or amino acid side chains as otherwise described herein and optionally substituted amides (preferably carboxamides substituted as described above) or urethane groups (the groups may typically be further substituted with one or two C0-C6 alkyl substituents). In certain embodiments, the alkylene group (typically a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most typically methyl or O-methyl or amino acid side chains as otherwise described herein. In the present disclosure, a portion of the molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most typically, in the present disclosure, a substituted portion is substituted with one or two substituents.

[0736] The term "substituted" (each substituent being independent of any other substituent) in the context in which it is used shall also refer to C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone including sulfonamide, keto, carboxyl, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, urethane -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano and amine (especially including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl substituted amine, which may be optionally substituted with one or two hydroxyl groups). Unless otherwise indicated, each of these groups in the context contains 1-6 carbon atoms. In certain embodiments, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m -(wherein m and n are in this context 1, 2, 3, 4, 5 or 6), -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, -(CH2O)n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S 、-S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. In this context, R1 and R2 are each H or C1-C6 alkyl (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). Within the chemical context of the defined compounds and substituents used, the term "substituted" shall also mean optionally substituted aryl or heteroaryl or optionally substituted heterocyclyl as otherwise described herein. Alkylene may also be substituted as otherwise disclosed herein, preferably with optionally substituted C1-C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), the side chain of an amino acid group as otherwise described herein, such as the amido group described above, or a urethane group OC(O)-NR1R2 group (wherein R1 and R2 are as otherwise described herein), although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents. It should be noted that in compounds where a particular position in the molecule requires substitution (primarily due to valence), but where no substitution is indicated, the substituent should be interpreted or understood as H unless the context of the substitution implies otherwise.

[0737] In the context, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), and can be bonded to the compounds of the present disclosure at any available stable position on the ring or otherwise as described by the chemical structure presented. In the context, other examples of aryl groups can include heterocyclic aromatic ring systems, "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofuran, etc., which can be optionally substituted as described above. Among the heteroaryl groups that may be mentioned are nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrole and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, and the like, all of which may be optionally substituted.

[0738] The term "substituted aryl" refers to an aromatic carbocyclic radical consisting of at least one aromatic ring or multiple fused rings, at least one of which is aromatic, wherein the ring is substituted with one or more substituents. For example, an aryl group may contain a substituent selected from: -(CH2) n OH, -(CH2) n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, wherein the alkyl group on the amine is optionally substituted by: 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups; OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2 or CN groups (each of which may be substituted in the ortho, meta and / or para position, preferably the para position, of the phenyl ring); optionally substituted phenyl (the phenyl group itself is preferably linked / attached to the PTM group, including the ULM group, via a linker group) and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (in the ortho, meta and / or para position, preferably the para position, of the phenyl ring); naphthyl (which may be optionally substituted); optionally substituted heteroaryl, preferably optionally substituted isoxazole (including methyl substituted isoxazole), optionally substituted oxazole (including methyl substituted oxazole), optionally substituted thiazole (including methyl substituted thiazole), optionally substituted isothiazole (including methyl substituted isothiazole), optionally substituted pyrrole (including methyl substituted pyrrole), optionally substituted imidazole (including methyl substituted imidazole), optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted oxadiazolyl (including methyloxadiazolyl), optionally substituted triazolyl (including methyl substituted triazolyl), optionally substituted pyridyl (including halogen- (preferably F) or methyl substituted pyridyl or oxapyridyl (wherein the pyridyl is attached to the phenyl group through an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0739] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and these general substituents have the same meanings as those defined herein.

[0740] The term "heteroaryl" or "heteroaromatic group" may refer to, but is in no way limited to, optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzofuran, 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 mercapto substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted -(CH2)m -O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), optionally substituted pyridine (2-, 3- or 4-pyridine), or a group according to the following chemical structure:

[0741]

[0742] in:

[0743] S c It is CHR SS NR URE or O;

[0744] R HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0745] R SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0746] R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted), and

[0747] Y C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CRa , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl).

[0748] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both an aryl group, or respectively a heteroaryl group, according to the above definition and an alkyl and / or heteroalkyl and / or a carbocyclic and / or heterocycloalkyl ring system.

[0749] As used herein, the term "arylalkyl" refers to an aryl group as defined above appended to an alkyl group as defined above. The arylalkyl group is attached to the parent moiety via the alkyl group, wherein the alkyl group is one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0750] 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, depending on the context in which it is used, heteroaryl moieties are included under the definition of heterocycle. Exemplary heteroaryl groups are described above.

[0751] Exemplary heterocycles include: 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, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazole alkyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxirane, oxetanyl, oxathiolanyl, thiane, and the like.

[0752] The heterocyclic group 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, hydroxy, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, mercapto, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (═O), and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, dihydroindole, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen heterocycles. The term "heterocycle" also includes bicyclic groups in which any heterocycle is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and the like).

[0753] The term "cycloalkyl" may refer to, but is in no way limited 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 three to twenty carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may refer to, but is in no way limited to, a monocyclic or polycyclic alkyl group, substituted by one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthiol, aryl, nitro, thiol, or sulfo, and the meanings of these general substituents are the same as those of the corresponding groups defined in this specification.

[0754] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group wherein at least one ring carbon atom of the cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group wherein at least one ring carbon atom of the cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthiol, aryl, nitro, thiol or sulfo, and the meanings of these general substituents are the same as those of the corresponding groups defined in this specification.

[0755] The term "hydrocarbyl" refers to compounds containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl, alkyl, alkenyl and alkynyl groups.

[0756] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0757] The term "lower alkyl" refers to methyl, ethyl or propyl

[0758] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0759] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A, and Rn can be independently covalently attached to a linker and / or a linker to which one or more PTM, ULM, ILM, or ILM' groups are attached.

[0760] Exemplary MLM

[0761] In certain further embodiments, the MLM of the bifunctional compound comprises chemical moieties such as substituted imidazolines, substituted spiro-indolones, substituted pyrrolidines, substituted piperidones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazopyridines, substituted thiazolidinidazolines, substituted pyrrolopyrrolidones, and substituted isoquinolinones.

[0762] In further embodiments, the MLM comprises the above-mentioned core structure with adjacent bisaryl substitutions positioned in either a cis or trans configuration.

[0763] In other embodiments, the MLM includes some of the structural features of RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272, MK-8242, and NVP-CGM-097, as well as analogs or derivatives thereof.

[0764] In certain preferred embodiments, MLM is a substituted imidazoline represented by formula (A-1), or a thiazolimidazolidine represented by formula (A-2), or a spiroindolinone represented by formula (A-3), or a pyrrolidine represented by formula (A-4), or a piperidone / morpholinone represented by formula (A-5), or an isoquinolinone represented by formula (A-6), or a pyrrolopyrimidine / imidazopyridine represented by formula (A-7), or a derivative of a pyrrolopyrrolidone / imidazopyrrolidone represented by formula (A-8).

[0765]

[0766] Wherein the above formula (A-1) to formula (A-8),

[0767] X of formula (A-1) to formula (A-8) is selected from the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone and NR a ;

[0768] R a are independently H or an alkyl group having 1-6 carbon numbers;

[0769] Y and Z of formula (A-1) to formula (A-8) are independently carbon or nitrogen;

[0770] A, A' and A" of formula (A-1) to formula (A-8) are independently selected from C, N, O or S, and may also be one or two atoms forming a fused bicyclic or 6,5- and 5,5-fused aromatic bicyclic group;

[0771] R1 and R2 of Formula (A-1) to Formula (A-8) are independently selected from the group consisting of: aryl or heteroaryl, heteroaryl having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl or heteroaryl group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of:

[0772] Halogen, -CN, C1-C6 alkyl, 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, and dialkylamine having 2-6 carbons;

[0773] R3 and R4 of formula (A-1) to formula (A-8) are independently selected from the group consisting of: H, methyl and C1-C6 alkyl;

[0774] R5 of formula (A-1) to formula (A-8) is selected from the group consisting of an aryl group or a heteroaryl group, a heteroaryl group having one or two heteroatoms independently selected from sulfur or nitrogen, wherein the aryl group or the heteroaryl group may be monocyclic or bicyclic or unsubstituted or substituted with one to three substituents independently selected from the group consisting of:

[0775] Halogen, -CN, C1-C6 alkyl, 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), morpholino, alkyl ester (C3-C6), alkyl cyanide (C3-C6);

[0776] R6 in formula (A-1) to formula (A-8) is H or -C(=O)Rb ,in

[0777] R in formula (A-1) to formula (A-8) b Selected from the group consisting of: alkyl; cycloalkyl; mono-, di- or tri-substituted aryl or heteroaryl; 4-morpholinyl; 1-(3-oxopiperazinyl); 1-piperidinyl; 4-NR c -morpholinyl; 4-R c -1-piperidinyl and 3-R c -1-piperidinyl, wherein

[0778] R in formula (A-1) to formula (A-8) c Selected from the group consisting of: alkyl; fluoro-substituted alkyl; cyanoalkyl; hydroxy-substituted alkyl; cycloalkyl; alkoxyalkyl; amidealkyl; alkylsulfone; alkylsulfoxide; alkylamide; aryl; heteroaryl; mono-, di- or tri-substituted aryl or heteroaryl; CH2CH2R d and CH2CH2CH2R d ,in

[0779] R in formula (A-1) to formula (A-8) d Selected from the group consisting of: alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[0780] R7 of formula (A-1) to formula (A-8) is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, fluoro-substituted alkyl, cyano-substituted alkyl, 5- or 6-membered heteroaryl or aryl, substituted 5- or 6-membered heteroaryl or aryl;

[0781] R8 of formula (A-1) to formula (A-8) is selected from the group consisting of: 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 ,in:

[0782] R in formula (A-1) to formula (A-8) e is an alkylene group having 1 to 6 carbons or a bond;

[0783] R in formula (A-1) to formula (A-8) f is a substituted 4- to 7-membered heterocycle;

[0784] R in formula (A-1) to formula (A-8) g selected from the group consisting of aryl, heteroaryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocyclic ring;

[0785] R9 of formula (A-1) to formula (A-8) is selected from the group consisting of: a mono-, di- or tri-substituent on the fused aromatic heterocycle in formula (A-3), wherein the substituents are independently selected from the group consisting of: halogen, alkene, alkyne, alkyl, which is unsubstituted or substituted with Cl or F;

[0786] R in formula (A-1) to formula (A-8) 10 Selected from the group consisting of: aryl or heteroaryl, wherein the heteroaryl may contain one or two heteroatoms that are sulfur or nitrogen, the aryl or heteroaryl may be monocyclic or bicyclic, and the aryl or heteroaryl may be substituted or unsubstituted with one to three substituents, the substituents including halogen, F, Cl, -CN, alkene, alkyne, C1-C6 alkyl, C1-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;

[0787] R in formula (A-1) to formula (A-8) 11 Yes -C(O)-N(R h )(R i ), where R h and R i Select from the group consisting of:

[0788] H; optionally substituted linear or branched C1-C6 alkyl; alkoxy-substituted alkyl; mono- and di-hydroxy-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, alkyl carboxylic acid; optionally substituted heteroaryl carboxylic acid; alkyl carboxylic acid; fluoro-substituted alkyl carboxylic acid; optionally substituted cycloalkyl, 3-hydroxycyclobutane, 4-hydroxycyclohexane, aryl-substituted cycloalkyl; heteroaryl-substituted cycloalkyl; or Rh and Ri together form a ring;

[0789] R in formula (A-1) to formula (A-8) 12 and R 13 independently selected from H, lower alkyl (C1-C6), lower alkenyl (C2-C6), lower alkynyl (C2-C6), cycloalkyl (4, 5 and 6-membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl, R12 and R13 can be linked to form 5- and 6-membered rings with or without substitution on the ring;

[0790] R in formula (A-1) to formula (A-8) 14 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;

[0791] R in formula (A-1) to formula (A-8) 15 It is CN;

[0792] R in formula (A-1) to formula (A-8) 16 Selected from the group consisting of: C1-6 alkyl; C1-6 cycloalkyl; C2-6 alkenyl; C1-6 alkyl or C3-6 cycloalkyl in which one or more hydrogens are replaced by fluorine; an alkyl or cycloalkyl in which one CH2 is replaced by S(=O), -S or -S(=O)2; an 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); a hydrogen is replaced by a hydroxyl group C1-6 alkyl or alkyl-cycloalkyl; a 3-7 membered cycloalkyl or heterocycloalkyl group optionally containing a -(C=0)- group, or a 5-6 membered aryl or heteroaryl group, wherein the heterocycloalkyl or heteroaryl group may contain one to three heteroatoms independently selected from O, N or S, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be substituted or unsubstituted by one to three substituents independently selected from halogen, C1-6 alkyl, hydroxylated C1-6 alkyl, C1-6 alkyl containing a thioether, ether, sulfone, sulfoxide, fluorine-substituted ether or cyano group;

[0793] R in formula (A-1) to formula (A-8) 17 Selected from the group consisting of: (CH2)nC(O)NR k R l , where R k and R l independently selected from H, C1-6 alkyl, hydroxylated C1-6 alkyl, C1-6 alkoxyalkyl, C1-6 alkyl with one or more hydrogens replaced by fluorine, C1-6 alkyl with one carbon replaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or more hydrogens replaced by fluorine, C1-6 alkyl with a hydrogen replaced by cyano, 5- and 6-membered aryl or heteroaryl, alkylaryl (wherein the alkyl group contains 1-6 carbons) and alkylheteroaryl (wherein the alkyl group contains 1-6 carbons), wherein the aryl or heteroaryl group may be further substituted;

[0794] R in formula (A-1) to formula (A-8) 18Selected from the group consisting of substituted aryl, heteroaryl, alkyl, cycloalkyl, preferably substituted by -N(C1-4alkyl)(cycloalkyl), -N(C1-4alkyl)alkyl-cycloalkyl and -N(C1-4alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];

[0795] R in formula (A-1) to formula (A-8) 19 Selected from the group consisting of: aryl, heteroaryl, bicyclic heteroaryl, and these aryl or heteroaryl groups may be substituted by halogen, C1-6 alkyl, C1-6 cycloalkyl, CF3, F, CN, alkyne, alkylsulfone, and the halogen substitution may be mono-, di- or tri-substituted;

[0796] R in formula (A-1) to formula (A-8) 20 and R 21 are independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, hydroxylated C1-6 alkoxy and fluorine-substituted C1-6 alkoxy, wherein R 20 and R 21 can be further linked to form 5-, 6-, and 7-membered rings or heterocyclic rings which may be further substituted;

[0797] R in formula (A-1) to formula (A-8) 22 selected from the group consisting of H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverse amide, sulfonamide, reverse sulfonamide, N-acylurea, nitrogen-containing 5-membered heterocyclic ring, which may be further substituted with C1-6 alkyl, alkoxy, fluoro-substituted alkyl, CN and alkylsulfone;

[0798] R in formula (A-1) to formula (A-8) 23 is selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, -O-alkyl, -O-alkyl-cycloalkyl, -NH-alkyl, -NH-alkyl-cycloalkyl, -N(H)-aryl, -N(H)-heteroaryl, -N(alkyl)-aryl, -N(alkyl)-heteroaryl, wherein the aryl or heteroaryl may be substituted by halogen, C1-6 alkyl, hydroxylated C1-6 alkyl, cycloalkyl, fluoro-substituted C1-6 alkyl, CN, alkoxy, alkylsulfone, amide and sulfonamide;

[0799] R in formula (A-1) to formula (A-8) 24 Selected from the group consisting of: -CH2-(C1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl groups may be substituted with halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl and substituted cycloalkyl;

[0800] R in formula (A-1) to formula (A-8)25 Selected from the group consisting of: C1-6 alkyl, C1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-, 6- and 7-membered nitrogen-containing saturated heterocyclic rings, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocyclic rings, and these saturated heterocyclic rings may be substituted by C1-6 alkyl, fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl;

[0801] R in formula (A-1) to formula (A-8) 26 Selected from the group consisting of: C1-6 alkyl, C3-6 cycloalkyl, wherein the alkyl or cycloalkyl may be substituted with -OH, alkoxy, fluoro-substituted alkoxy, fluoro-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl and -S(O)2-alkyl;

[0802] R in formula (A-1) to formula (A-8) 27 Selected from the group consisting of: aryl, heteroaryl, bicyclic heteroaryl, wherein the aryl or heteroaryl may be substituted by C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen or -CN, and the substitutions may independently be mono-, di- and tri-substituted;

[0803] R in formula (A-1) to formula (A-8) 28 is selected from the group consisting of: aryl, 5- and 6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle such as piperidine, piperidone, tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl, saturated heterocycle, aryl or heteroaryl may be further substituted with -OH; alkoxy; mono-, di- or tri-substituted, including halogen; -CN; alkylsulfone and fluoro-substituted alkyl; and

[0804] R in formula (A-1) to formula (A-8) 1” Selected from the group consisting of H, alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0805] In certain embodiments, R of Formula (A-1) to Formula (A-8) f and R g The heterocyclic ring is substituted pyrrolidine, substituted piperidine, substituted piperazine.

[0806] More specifically, non-limiting examples of MLMs include those shown below as well as those "hybrid" molecules resulting from a combination of one or more of the different features shown in the following molecules.

[0807] Using the MLMs in A-1 to A-8, the following PROTACs can be prepared to target specific proteins for degradation, where “L” is a linker (i.e., a linker group) and “PTM” is a ligand that binds to the target protein.

[0808] In certain embodiments, the disclosure provides a bifunctional molecule comprising a structure selected from the group consisting of:

[0809]

[0810] Among them, 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 defined herein for formulae (A-1) to (A-8).

[0811] In certain embodiments, the disclosure provides bifunctional or chimeric molecules having the following structure: PTM-L-MLM, wherein PTM is a protein target binding moiety coupled to MLM via L, wherein L is a bond (i.e., absent) or a chemical linker. In certain embodiments, MLM has a structure selected from the group consisting of: structures A-1-1, A-1-2, A-1-3, and A-1-4:

[0812]

[0813] in:

[0814] R1' and R2' of formulas A-1-1 to A-1-4 (i.e., A-1-1, A-1-2, A-1-3, and A-1-4) are independently selected from the group consisting of F, Cl, Br, I, acetylene, CN, CF3, and NO2;

[0815] R3' is selected from the group consisting of: -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3 and -OCH(CH3)2;

[0816] R4' of formula A-1-1 to A-1-4 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)2CH2OCH2CH2O H, -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;

[0817] R5' of formula A-1-1 to A-1-4 is selected from the group consisting of: halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1-pyrrolidinyl, -NH2, -N(CH3)2 and -NHC(CH3)3; and

[0818] R6' in formulae A-1-1 to A-1-4 is selected from the structures shown below, wherein the linker connection point is represented by "*".

[0819] In addition to R6' as a linker attachment point, R4' can also serve as a linker attachment position. If R4' is a linker attachment site, the linker will be attached to the terminal atom of the R4' group shown above.

[0820] In certain embodiments, the linker attachment position of Formulas A-1-1 to A-1-4 is R4' or R6' or at least one of the two.

[0821] In certain embodiments, R6' of formulas A-1-1 to A-1-4 are independently selected from the group consisting of: H,

[0822]

[0823] Where "*" indicates the connection point of the linker.

[0824] In certain embodiments, the linker of formula A-4-1 to A-4-6 is connected to at least one of R1', R2', R3', R4', R5', R6', or a combination thereof.

[0825] In certain embodiments, the disclosure provides bifunctional or chimeric molecules having the following structure: PTM-L-MLM, wherein PTM is a protein target binding moiety coupled to MLM via L, wherein 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:

[0826]

[0827] in:

[0828] R7' of 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) is one or more (e.g., 1, 2, 3, 4) halogen;

[0829] R8' of formula A-4-1 to A-4-6 is one or more groups (e.g., 1, 2, 3, or 4 groups) selected from the group consisting of: H, -F, -Cl, -Br, -I, -CN, -NO2, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy, isopropoxy, -OH, other C1-6 alkyl, other C1-6 alkenyl, and C1-6 alkynyl, which is mono-, di-, or tri-substituted;

[0830] R9' of formulas A-4-1 to A-4-6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted cycloalkenyl;

[0831] Z of formula A-4-1 to A-4-6 is selected from the group consisting of H, -OCH3, -OCH2CH3 and halogen;

[0832] R10' and R11' of formula A-4-1 to A-4-6 are each independently selected from the group consisting of: 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, where alkyl can be replaced by OR' and heteroaryl-(CH2) n - heterocyclic substitution, wherein the heterocyclic ring may be optionally substituted by alkyl, hydroxy, COOR' and COR'; wherein R' and R" are selected from H, alkyl, alkyl substituted by halogen, hydroxy, NH2, NH(alkyl), N(alkyl)2, oxo, carboxyl, cycloalkyl and heteroaryl;

[0833] m, n and p are independently 0-6;

[0834] R12' of formulas A-4-1 to A-4-6 is selected from the group consisting of: -O-(alkyl), -O-(alkyl)-alkoxy, -C(O)-(alkyl), -C(OH)-alkyl-alkoxy, -C(O)-NH-(alkyl), -C(O)-N-(alkyl)2, -S(O)-(alkyl), S(O)2-(alkyl), -C(O)-(cyclic amine), and -O-aryl-(alkyl), -O-aryl-(alkoxy);

[0835] R1" of formulae A-4-1 to A-4-6 is selected from the group consisting of H, alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[0836] In any aspect or embodiment described herein, the alkyl group, alkoxy group, etc. can be lower alkyl group or lower alkoxy group.

[0837] In certain embodiments, the linker connection position of Formulas A-4-1 to A-4-6 is at least one of Z, R8', R9', R10', R11", R12", or R1".

[0838] The methods used to design the chimeric molecules presented in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLMs having formulas A-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent-exposed region in the MLM can be connected to a linker "L", which will be connected to the target protein ligand "PTM" to construct a PROTAC.

[0839] In any aspect or embodiment described herein, the MLM is selected from:

[0840]

[0841]

[0842] Exemplary MDM2 binding moieties include, but are not limited to, the following:

[0843] 1. HDM2 / MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol: 303, pag: 844-848 (2004) and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, (or in addition) include the following compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized) and all derivatives and analogs thereof:

[0844]

[0845] (derivatized, wherein the linker group L or -(L-MLM) group is attached, for example, to a methoxy group or as a hydroxyl group);

[0846]

[0847] (derivatized, wherein the linker group L or -(L-MLM) group is attached, for example, to a methoxy or hydroxyl group);

[0848]

[0849] (derivatized, wherein 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'-boryl-chalcone

[0850]

[0851] (derivatized, wherein the linker group L or -(L-MLM) group is attached, for example, via a hydroxyl group).

[0852] Exemplary CLM

[0853] New imide compounds

[0854] In one aspect, the present disclosure provides compounds that can be used to bind and / or inhibit cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures:

[0855]

[0856]

[0857] in:

[0858] W of formula (a) to (f) is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0859] X of formulas (a) to (f) is independently selected from the group consisting of O, S and H2;

[0860] Y of formulas (a) to (f) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0861] Z of formulas (a) to (f) is independently selected from the group consisting of O and S or H2, except that X and Z cannot both be H2;

[0862] G and G' of formulae (a) to (f) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0863] Q1-Q4 of formulae (a) to (f) represent carbon C substituted by a group independently selected from R', N or N-oxide;

[0864] A of formulae (a) to (f) is independently selected from the group consisting of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl, and F;

[0865] R in formulas (a) to (f) includes but is not limited to: -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’R", -aryl, -heteroaryl, -optionally substituted linear or branched 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'CO R", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3

[0866] R' and R" of formulae (a) to (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, -C(=O)R, heterocyclyl, each of which is optionally substituted;

[0867] n' of formulas (a) to (f) is an integer of 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0868] Formulas (a) to (f) represents a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; and

[0869] R in formulas (a) to (f) n Contains 1-4 independently selected functional groups or atoms, such as O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl, including at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide or carboxyl.

[0870] Exemplary CLM

[0871] In any of the compounds described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0872]

[0873] in:

[0874] W of formula (a) to (f) is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0875] X of formulas (a) to (f) is independently selected from the group consisting of O, S and H2;

[0876] Y of formulas (a) to (f) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0877] Z of formulas (a) to (f) is independently selected from the group consisting of O and S or H2, except that X and Z cannot both be H2;

[0878] G and G' of formulae (a) to (f) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0879] Q1-Q4 of formulae (a) to (f) represent carbon C substituted by a group independently selected from R', N or N-oxide;

[0880] A of formulas (a) to (f) is independently selected from the group consisting of H, alkyl (straight chain, branched, optionally substituted), cycloalkyl, Cl, and F;

[0881] R in formulas (a) to (f) includes, but is not limited to: -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", -aryl, -heteroaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -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

[0882] R' and R" of formulae (a) to (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, -C(=O)R, heterocyclyl, each of which is optionally substituted;

[0883] n of formulas (a) to (f) is an integer of 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0884] Formulas (a) to (f) represents a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; and

[0885] Rn of formula (a) to (f) comprises 1-4 independently selected functional groups or atoms, such as O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl, including at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide or carboxyl, and optionally, one of which is modified to be covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM') or a combination thereof.

[0886] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of:

[0887]

[0888] in:

[0889] W of formula (g) is independently selected from the group consisting of CH2, C=O, NH and N-alkyl;

[0890] R of formula (g) is independently selected from H, methyl, or an optionally substituted linear or branched alkyl group (e.g., an optionally substituted linear or branched C1-C6 alkyl group);

[0891] Formula (g) represents a bond, which may be stereospecific ((R) or (S)) or non-stereospecific; and

[0892] Rn of formula (g) comprises 1-4 independently selected functional groups or atoms, such as O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl, including at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide or carboxyl, and optionally, one of which is modified to be covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM') or a combination thereof.

[0893] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A, and Rn of Formulas (a) to (g) can be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, CLM, or CLM' groups attached thereto.

[0894] In any aspect or embodiment described herein, Rn includes 1-4 independently selected functional groups or atoms, such as O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl, including at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl and optionally, one of which is modified to be covalently linked to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0895] In any aspect or embodiment described herein, Rn includes 1-4 functional groups or atoms, such as O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, amine, amide or carboxyl, and optionally, one of which is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM') or a combination thereof.

[0896] More specifically, non-limiting examples of CLMs include those shown below as well as those "hybrid" molecules resulting from the combination of one or more of the different features shown in the following molecules.

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907] In any of the compounds described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0908]

[0909]

[0910]

[0911] in:

[0912] W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0913] Q1, Q2, Q3, Q4, Q5 each independently represent carbon C or N substituted by a group independently selected from R', N or N-oxide;

[0914] R 1 Selected from absent, H, OH, CN, C1-C3 alkyl, C=O;

[0915] R 2 Selected from the group consisting of: absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2;

[0916] R 3 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 alkoxy), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

[0917] R 4 is selected from H, alkyl, substituted alkyl;

[0918] R 5 and R 6 Each is independently H, halogen, C(=O)R', CN, OH, CF3;

[0919] X is C, CH, C═O or N;

[0920] X1 is C=O, N, CH or CH2;

[0921] R' is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), NR 2 R 3 、C(=O)OR 2 , optionally substituted phenyl;

[0922] n is 0-4;

[0923] is a single bond or a double bond; and

[0924] The CLM is covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0925] In any aspect or embodiment described herein, CLM or CLM' is substituted with an R group (e.g., R, R 1 、R 2 、R 3 、R 4 or R'), W, X, or a Q group (eg, Q1, Q2, Q3, Q4, or Q5) is covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof.

[0926] In any embodiment described herein, CLM or CLM' is defined by W, X, R, R 1 、R 2 、R 3 、R 4 、R 5 , R', Q1, Q2, Q3, Q4 and Q5 are covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM' or a combination thereof.

[0927] 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 be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, ULM', CLM or CLM' groups attached thereto.

[0928] More specifically, non-limiting examples of CLMs include those shown below as well as "hybrid" molecules or compounds resulting from one or more characteristics of the following compounds.

[0929]

[0930]

[0931]

[0932] in:

[0933] W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0934] R 1 Selected from the group consisting of: absent, H, CH, CN, C1-C3 alkyl;

[0935] R 2 is H or C1-C3 alkyl;

[0936] R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

[0937] R 4 is methyl or ethyl;

[0938] R 5 is H or halogen;

[0939] R 6 is H or halogen;

[0940] The R of CLM is H;

[0941] R' is H or the point of attachment of PTM, PTM', chemical linker group (L), ULM, CLM, CLM',

[0942] Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;

[0943] is a single bond or a double bond; and

[0944] Rn includes a functional group or an atom.

[0945] In any of the embodiments described herein, W, R 1 、R 2 , Q1, Q2, Q3, Q4 and Rn can be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, ULM', CLM or CLM' groups attached thereto.

[0946] In any of the embodiments described herein, R 1 、R 2 , Q1, Q2, Q3, Q4 and Rn can be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, ULM', CLM or CLM' groups attached thereto.

[0947] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn can be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, ULM', CLM, or CLM' groups attached thereto.

[0948] In any aspect or embodiment described herein, R n Modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0949] In any aspect or embodiment described herein, the CLM is selected from:

[0950]

[0951] Where R' is a halogen, and R 1As described in any aspect or embodiment described herein.

[0952] In some cases, a "CLM" can be an imide that binds to a cereblon E3 ligase. These imide and linker attachment points can be, but are not limited to, the following structures:

[0953]

[0954] Exemplary VLM

[0955] In certain embodiments of the compounds described herein, the ULM is a VLM and comprises a chemical structure selected from the group consisting of: ULM-a:

[0956]

[0957] in:

[0958] The dotted line indicates the connection of at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM' or VLM' or CLM' or ILM' or MLM') or a chemical linker moiety coupling at least one PTM, ULM' or VLM' or CLM' or ILM' or MLM' to the other end of the linker;

[0959] Formula ULM-a X 1 、X 2 are each independently selected from the following group: bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2;

[0960] R of formula ULM-a Y3 、R Y4 Each independently selected from the following groups: H, a linear or branched C optionally substituted by one or more halogens 1-6 Alkyl, optionally substituted C 1-6 Alkoxy (eg, optionally with 0-3 R P group substitution);

[0961] R of formula ULM-a P is 0, 1, 2 or 3 groups independently selected from the following groups: H, halogen, -OH, C 1-3 Alkyl, C=O;

[0962] W of ULM-a 3 Selected from optionally substituted T, optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R1b ), 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-heterocycle;

[0963] Formula ULM-a X 3 C=O、R 1 、R 1a 、R 1b ;

[0964] R 1 、R 1a 、R 1b Each is independently selected from the group consisting of: H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halogen 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;

[0965] T of formula ULM-a is selected from the group consisting of optionally substituted alkyl, -(CH2) n - group, wherein each methylene group is optionally substituted by one or two substituents selected from the following groups: halogen, methyl, linear or branched C1-C6 alkyl optionally substituted by one or more halogens, C(O)NR 1 R 1a or NR 1 R 1a , or R 1 and R 1a linked to form an optionally substituted heterocyclic group or an -OH group or an optionally substituted amino acid side chain;

[0966] W of ULM-a 4 is optionally substituted -NR1-T-aryl, wherein aryl may be optionally substituted with an optionally substituted 5-6 membered heteroaryl, an optionally substituted -NR1-T-heteroaryl, or an optionally substituted -NR1-T-heterocycle, wherein -NR1 is covalently bonded to X 2 And R 1is H or CH3, preferably H; and

[0967] n is 0-6, usually 0, 1, 2 or 3, preferably 0 or 1.

[0968] In any of the embodiments described herein, T is selected from the group consisting of optionally substituted alkyl, -(CH2) n - group, wherein each methylene group is optionally substituted by one or two substituents selected from the following groups: halogen, methyl, optionally substituted alkoxy, linear or branched C1-C6 alkyl optionally substituted by one or more halogens, C(O)NR 1 R 1a or NR 1 R 1a , or R 1 and R 1a is linked to form an optionally substituted heterocycle or an -OH group or an optionally substituted amino acid side chain; and n is 0-6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0969] In certain embodiments, W of Formula ULM-a 4 yes Where W 5 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl (e.g., optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy), and R 14a 、R 14b Each is independently selected from the group consisting of H, haloalkyl, or optionally substituted alkyl.

[0970] In any embodiment, W of Formula ULM-a 5 is selected from the group consisting of an optionally substituted phenyl group or an optionally substituted 5-10 membered heteroaryl group (e.g., W 5 optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy), and

[0971] R of formula ULM-a 15 Selected from the following group: H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a 、CONR 14a R 14b NR 14a COR 14b 、SO2NR 14a R 14b NR14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

[0972] In another embodiment, the W used in the present disclosure 4 Substituents also specifically include (and are not limited to the specific compounds disclosed) W found in the identified compounds disclosed herein. 4 Substituents. These W 4 Each of the substituents may be combined with any number of W also disclosed herein. 3 Substituents are used in combination.

[0973] In certain additional embodiments, ULM-a is optionally replaced by 0-3 R P Each R P are independently H, halogen, -OH, C1-3 alkyl, or C=O.

[0974] In any of the embodiments described herein, W of Formula ULM-a 3 、W 4 Can be independently covalently coupled to a linker to which one or more PTM groups are attached.

[0975] And wherein the dashed line represents the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.

[0976] In certain embodiments, the ULM is a VHL and is represented by the following structure:

[0977]

[0978] in:

[0979] W of ULM-b 3 Selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, or

[0980] 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 R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[0981] R of formula ULM-b 11 is selected from the group consisting of optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0982] R of formula ULM-b 12 is selected from the group consisting of: H or optionally substituted alkyl;

[0983] R of formula ULM-b 13 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

[0984] R of formula ULM-b 14a 、R 14b are each independently selected from the group consisting of H, haloalkyl, or optionally substituted alkyl;

[0985] W of ULM-b 5 is selected from the group consisting of an optionally substituted phenyl group or an optionally substituted 5-10 membered heteroaryl group (e.g., W 5 optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy),

[0986] R of formula ULM-b 15 Selected from H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a 、CONR 14a R 14b NR 14a COR 14b 、SO2NR 14a R 14b NR 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each optionally substituted);

[0987] Each R of the formula ULM-b 16 independently selected from the group consisting of halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy;

[0988] o of formula ULM-b is 0, 1, 2, 3 or 4;

[0989] R of formula ULM-b 18is independently selected from the group consisting of H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and

[0990] p of formula ULM-b is 0, 1, 2, 3 or 4, and wherein the dashed line represents the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM' or both to the ULM.

[0991] In certain embodiments, R of Formula ULM-b 15 yes where R 17 is H, halogen, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl and C 1-6 haloalkyl; and Xa is S or O.

[0992] In certain embodiments, R of Formula ULM-b 17 Selected from the group consisting of methyl, ethyl, isopropyl and cyclopropyl.

[0993] In certain additional embodiments, R of Formula ULM-b 15 Select from the group consisting of:

[0994]

[0995] In certain embodiments, R of Formula ULM-b 11 Select from the group consisting of:

[0996]

[0997]

[0998] In certain embodiments, the ULM has a chemical structure selected from the group consisting of:

[0999]

[1000] in:

[1001] R1 of formula 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;

[1002] R of formula ULM-c, ULM-d and ULM-e 14ais H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[1003] R of formula ULM-c, ULM-d and ULM-e 15 is selected from the group consisting of H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl;

[1004] X of formula ULM-c, ULM-d and ULM-e is C, CH2 or C=O

[1005] R3 of formula ULM-c, ULM-d and ULM-e is absent or is an optionally substituted 5- or 6-membered heteroaryl; and

[1006] Dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM', or both, to a ULM.

[1007] In certain embodiments, the ULM includes a group according to the following chemical structure:

[1008]

[1009] in:

[1010] R of ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[1011] R9 of formula ULM-f is H;

[1012] R of ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[1013] R of ULM-f 11 yes

[1014] or optionally substituted heteroaryl;

[1015] p of the formula ULM-f is 0, 1, 2, 3 or 4;

[1016] Each R of the formula ULM-f 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;

[1017] R of ULM-f 12 It is H, C=O;

[1018] R of 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,

[1019] R of ULM-f 15 Selected from the group consisting of: H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl;

[1020] and

[1021] The dashed line in the formula ULM-f represents the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.

[1022] In certain embodiments, the ULM is selected from the following structures:

[1023]

[1024] where n is 0 or 1.

[1025] In certain embodiments, the ULM is selected from the following structures:

[1026]

[1027]

[1028]

[1029]

[1030] wherein the phenyl rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, and wherein the dashed line represents the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM', or both, to ULM-a.

[1031] In one embodiment, the phenyl rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 can be functionalized as esters to make them part of a prodrug.

[1032] In certain embodiments, the hydroxyl groups on the pyrrolidine ring of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9, respectively, comprise an ester-linked prodrug moiety.

[1033] In any aspect or embodiment described herein, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1034]

[1035] or a pharmaceutically acceptable salt thereof, wherein:

[1036] ULM-g R 1’ is an optionally substituted C1-C6 alkyl, an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6)alkyl, optionally substituted (CH2) containing an epoxide moiety WCOCW n -WCOCW-(C0-C6)alkyl, wherein each W is independently H or C1-C3 alkyl, 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, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), optionally substituted-(CH2) n C(O)-O-(C1-C6 alkyl), optionally substituted-(CH2O) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), optionally substituted-(CH2O) n C(O)-(C1-C6 alkyl), optionally substituted-(OCH2) nNHC(O)-R1, optionally substituted -(CH2O) 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) n NHC(O)-R1, optionally substituted-(CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl);

[1037] R1 and R2 of ULM-g are each independently H or C1-C6 alkyl which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

[1038] ULM-g R S is C1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclic or -(CH2) m NR1R2 group;

[1039] X and X' of ULM-g are each independently C═O, C═S, -S(O), S(O)2 (preferably X and X' are both C═O);

[1040] ULM-g R 2’ is optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w alkyl, 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; optionally substituted-X R2’ -aryl; optionally substituted -X R2’ -heteroaryl; optionally substituted -X R2’ -heterocyclyl; optionally substituted;

[1041] ULM-g R 3’ is optionally substituted alkyl, optionally substituted -(CH2) n -(O) u (NR1) v (SO2) w -alkyl, optionally substituted-(CH2)n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , 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-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2)n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocyclic, 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-(CH2) n -(C=O) u (NR1) v (SO2) w -heterocycle; -(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl, optionally substituted-(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl, 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, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclic group, optionally substituted -X R3’ -alkyl; optionally substituted-X R3’ -aryl; optionally substituted -X R3’ -heteroaryl; optionally substituted -X R3’ -heterocyclic groups;

[1042] 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 optionally substituted -(CH2) n -aryl, -(CH2) n -heteroaryl or -(CH2) n -heterocyclic groups;

[1043] V of ULM-g is O, S or NR1;

[1044] R1 of ULM-g is the same as above;

[1045] ULM-g R 1 and R 1’ Each independently is H or C1-C3 alkyl;

[1046] ULM-gX R2’ and X R3’ each independently an optionally substituted -(CH2) n -、-(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CH2CH2O) n - or C3-C6 cycloalkyl, wherein Xv is H, halogen or optionally substituted C1-C3 alkyl;

[1047] Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[1048] Each m' of ULM-g is independently 0 or 1;

[1049] Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[1050] Each n' of ULM-g is independently 0 or 1;

[1051] Each u of ULM-g is independently 0 or 1;

[1052] Each v of ULM-g is independently 0 or 1;

[1053] Each w of ULM-g is independently 0 or 1; and

[1054] When the PTM is not ULM', R of ULM-g 1’ 、R 2’ 、R 3’ Any one or more of X, X and X' is optionally modified to be covalently bonded to the PTM group through a linker group, or when the PTM is ULM', each of ULM and ULM' R 1’ 、R 2’ 、R 3’ Any one or more of X, X and X' are optionally modified to be covalently bonded directly to each other or covalently bonded through a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[1055] In any aspect or embodiment described herein, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1056]

[1057] in:

[1058] ULM-h R 1’ 、R 2’ and R 3’ Each is the same as above, and X is a C=O, C=S, -S(O) group or a S(O)2 group, more preferably a C=O group, and

[1059] When the PTM is not ULM', the R of ULM-h 1’ 、R 2’ and R 3’Any one or more of R is optionally modified to bond to a linker group that is further covalently bonded to the PTM group, or when the PTM is ULM', any one or more of R in each of ULM and ULM' 1’ 、R 2’ and R 3’ are optionally modified to be covalently bonded to each other directly or through a linker group, or

[1060] Pharmaceutically acceptable salts, enantiomers, diastereomers, solvates or polymorphs thereof.

[1061] In any aspect or embodiment described herein, ULM and ULM' (when present) are each independently according to the following chemical structure:

[1062]

[1063] in:

[1064] When the PTM is not ULM', R of ULM-I 1’ 、R 2’ and R 3’ Any one or more of is optionally modified to bond to a linker group that is further covalently bonded to the PTM group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ and R 3’ Any one or more of are optionally modified to be covalently bonded to each other directly or through a linker group, or

[1065] Pharmaceutically acceptable salts, enantiomers, diastereomers, solvates or polymorphs thereof.

[1066] In a further preferred aspect of the present disclosure, R of ULM-g to ULM-i 1’ Preferably, it is a hydroxyl group or a group that can be metabolized to a hydroxyl group or a carboxyl group, so that the compound represents a prodrug form of the active compound. 1’ Groups include, for example, -(CH2) n OH, (CH2) n -O-(C1-C6)alkyl, -(CH2) n COOH, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl) or optionally substituted-(CH2) n C(O)-O-(C1-C6 alkyl), wherein n is 0 or 1. wherein R 1’is or contains a carboxylic acid group, a hydroxyl group, or an amino group, each of which may be optionally substituted, which may be further chemically modified to provide a covalent linker group to which a PTM group (including a ULM' group) is bonded;

[1067] When present, X and X' of ULM-g and ULM-h are preferably C=O, C=S, -S(O) groups or S(O)2 groups, more preferably C=O groups;

[1068] R from ULM-g to ULM-i 2’ Preferably, 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 (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(CH3)-T-heterocyclyl), wherein R 1 is H or CH3, preferably H and T are optionally substituted -(CH2) n - group, wherein each methylene group may be optionally substituted by one or two substituents, preferably 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 0-6, typically 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be -(CH2O) n - group, -(OCH2) n -group, -(CH2CH2O) n - group, -(OCH2CH2) n - groups, all of which are optionally substituted.

[1069] R from ULM-g to ULM-i 2’Preferred aryl groups include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is linked to the PTM (including ULM') group via a linker group, and / or is optionally substituted by a halogen (preferably F or Cl), an amine, a mono- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, a C1-C6 alkyl, preferably a CH3, CF3, OMe, OCF3, NO2 or a CN group (each of which may be substituted in the ortho, meta and / or para position, preferably the para position, of the phenyl ring), an optionally substituted phenyl (which itself is optionally linked to the PTM group, including ULM') via a linker group, and / or is optionally substituted by at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or a CN group (in the ortho, meta and / or para position, preferably the para position, of the phenyl ring); an optionally substituted naphthyl; an optionally substituted heteroaryl, preferably an optionally substituted isoxazole (including a methyl substituted isoxazole), optionally substituted oxazole (including methyl substituted oxazole), optionally substituted thiazole (including methyl substituted thiazole), optionally substituted isothiazole (including methyl substituted isothiazole), optionally substituted pyrrole (including methyl substituted pyrrole), optionally substituted imidazole (including methylimidazole), optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted oxadiazolyl (including methyloxadiazolyl), optionally substituted triazolyl (including methyl substituted triazolyl), optionally substituted pyridyl (including halogen- (preferably F)) or methyl substituted pyridyl or oxapyridyl (wherein the pyridyl is attached to the phenyl group through 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 following chemical structure:

[1070]

[1071] in:

[1072] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1073] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R ais H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1074] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1075] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted heterocycle (preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran);

[1076] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[1077] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl, or together form a keto group; and

[1078] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1) or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine or morpholine (each of said groups, when substituted, is preferably substituted with methyl or halogen (F, Br, Cl), and each of said groups can be selectively linked to a PTM group (including a ULM' group) via a linker).

[1079] In certain preferred aspects, ULM-g to ULM-i yes

[1080] Group,

[1081] Among them, R PRO and n are the same as above.

[1082] R from ULM-g to ULM-i 2’ Preferred heteroaryl groups 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:

[1083]

[1084] in:

[1085] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1086] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R of ULM-g to ULM-i a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1087] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1088] R from ULM-g to ULM-i UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen, preferably fluoro, groups or optionally substituted heterocycles such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted), and

[1089] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl), each of which is optionally linked to a PTM group (including a ULM' group) via a linker group.

[1090] R from ULM-g to ULM-i 2’ Preferred heterocyclic groups include tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxirane or thiazole (each of which is optionally substituted), or a group according to the following chemical structure:

[1091]

[1092] Preferred Group,

[1093] in:

[1094] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl, or heterocyclyl;

[1095] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[1096] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (typically 0 or 1), each of which is optionally linked to a PTM group (including a ULM' group) through a linker group.

[1097] Preferred R for ULM-g to ULM-i 2’Substituents also specifically include (and are not limited to the specific compounds disclosed) R 2’ Substituents (including specific compounds disclosed in this specification and accompanying drawings). 2’ Each of the substituents may be combined with any number of R 3’ Substituents are used in combination.

[1098] R from ULM-g to ULM-i 3’ Preferred are optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-heterocyclyl, 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-heteroaryl, 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(CH3)-T-heterocyclyl, or optionally substituted N(C1-C3 alkyl)-T-heterocyclyl), wherein R 1 is H or C1-C3 alkyl, preferably H or CH3, T is optionally substituted -(CH2) n - group, wherein each methylene group may be optionally substituted with one or two substituents, preferably selected from halogen, C1-C3 alkyl or an amino acid side chain as otherwise described herein, preferably methyl, which may be optionally substituted; and n is 0-6, typically 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be -(CH2O) n - group, -(OCH2) n -group, -(CH2CH2O) n - group, -(OCH2CH2) n - group, each of which is optionally substituted.

[1099] R from ULM-g to ULM-i 3’ Preferred aryl groups include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl group is optionally linked to the PTM group (including the ULM' group) via a linker group and / or is optionally substituted by halogen (preferably F or Cl), amine, mono- or dialkylamine (preferably dimethylamine), amido (preferably -(CH2) m-NR1C(O)R2 group, where m, R1 and R2 are the same as above), halogen (usually F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN or S(O)2R S Group (R S is C1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclic or -(CH2) m NR1R2 groups) (each of which may be substituted at the ortho, meta and / or para position, preferably the para position, of the phenyl ring) or 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, CH3, CF3, OMe, OCF3, NO2, CN or a linker group to which a PTM group (including a ULM' group) is attached, wherein the substitution occurs at the ortho, meta and / or para position, preferably the para position, of the phenyl ring); naphthyl, which may be optionally substituted, including those described above; optionally substituted heteroaryl (preferably optionally substituted isoxazole (including methyl-substituted isoxazole), optionally substituted oxazole (including methyl-substituted oxazole), optionally substituted thiazole (including methyl-substituted thiazole), optionally substituted pyrrole (including methyl-substituted pyrrole), optionally substituted imidazole (including methylimidazole, benzylimidazole or methoxybenzylimidazole), oximidazole or methyloximidazole, optionally substituted oxadiazolyl (including methyloxadiazolyl), optionally substituted triazolyl (including methyl-substituted triazolyl), pyridinyl (including halogen (preferably F) or methyl-substituted pyridinyl or oxapyridinyl (wherein the pyridinyl is linked to the phenyl group through an oxygen)); or optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxirane or thiazole). The aryl, heteroaryl or heterocyclic group can be optionally linked to the PTM group (including the ULM' group) through a linker group.

[1100] R from ULM-g to ULM-i 3’ Preferred heteroaryl groups 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, benzofuran, 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 mercapto substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with methyl), triisopropylsilyl, optionally substituted -(CH2) m-O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl), optionally substituted pyridine (2-, 3- or 4-pyridine) or a group according to the following chemical structure:

[1101]

[1102] in:

[1103] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1104] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1105] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1106] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen, preferably fluoro, groups or optionally substituted heterocycles such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted), and

[1107] Y for ULM-g to ULM-i C Is N or CR YC , where R YCis H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl). Each of the heteroaryl groups may be optionally linked / attached to a PTM group (including a ULM' group) via a linker group.

[1108] R from ULM-g to ULM-i 3’ Preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxirane and thiazole (each of which may be optionally substituted), or a group according to the following chemical structure:

[1109]

[1110] in:

[1111] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[1112] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[1113] Each n of ULM-g to ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), wherein each said heterocyclic group is optionally linked / attached to a PTM group (including a ULM' group) via a linker group.

[1114] Preferred R for ULM-g to ULM-i 3’ Substituents also specifically include (and are not limited to the specific compounds disclosed) R 3’ Substituents (including specific compounds disclosed in this specification and the accompanying drawings). These R 3’Each of the substituents may be combined with any number of R 2’ Substituents are used in combination.

[1115] In certain alternative preferred embodiments, the R of ULM-g to ULM-i 2’ is optionally substituted -NR1-X R2’ -alkyl, -NR1-X R2’ -aryl; optionally substituted -NR1-X R2’ -HET, optionally substituted -NR1-X R2’ -aryl-HET or optionally substituted-NR1-X R2’ -HET-aryl, wherein:

[1116] R1 of ULM-g to ULM-i is H or C1-C3 alkyl (preferably H);

[1117] X for ULM-g to ULM-i R2’ is optionally substituted -CH2) n -、-CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CH2CH2O) n - or C3-C6 cycloalkyl; and

[1118] X for ULM-g to ULM-i v is H, halogen or C1-C3 alkyl optionally substituted by one or two hydroxyl groups or up to three halogen groups;

[1119] The alkyl groups of ULM-g to ULM-i are optionally substituted C1-C 10 Alkyl (preferably C1-C6 alkyl) (in certain preferred embodiments, the alkyl group is terminated by a halogen group, typically Cl or Br);

[1120] The aryl group of ULM-g to ULM-i is optionally substituted phenyl or naphthyl (preferably phenyl); and

[1121] HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably with a C1-C3 alkyl group, preferably a methyl group or a halogen group, preferably F or Cl) or a group according to the following chemical structure:

[1122]

[1123] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1124] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1125] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1126] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted);

[1127] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1128] R from ULM-g to ULM-i PROis H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[1129] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[1130] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1).

[1131] Each of these groups may optionally be linked / attached to a PTM group (including a ULM' group) via a linker group.

[1132] In certain alternative preferred embodiments of the present disclosure, R of ULM-g to ULM-i 3’ is 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, optionally substituted-X R3’ -aryl; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or optionally substituted-X R3’ -HET-aryl,

[1133] in:

[1134] R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), aryl or HET group;

[1135] R 1’ is H or C1-C3 alkyl (preferably H);

[1136] V is O, S, or NR 1’ ;

[1137] X R3’ Yes - (CH2) n -、-(CH2CH2O) n -、-CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH- or C3-C6 cycloalkyl, all of which are optionally substituted;

[1138] X v is H, halogen or C1-C3 alkyl optionally substituted by one or two hydroxyl groups or up to three halogen groups;

[1139] Alkyl is an optionally substituted C1-C 10 Alkyl (preferably C1-C6 alkyl) (in certain preferred embodiments, the alkyl group is terminated by a halogen group, typically Cl or Br);

[1140] Aryl is optionally substituted phenyl or naphthyl (preferably phenyl); and

[1141] HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably by C1-C3 alkyl, preferably methyl or halogen group, preferably F or Cl) or a group according to the following chemical structure:

[1142]

[1143] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1144] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1145] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1146] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted);

[1147] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1148] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[1149] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group;

[1150] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

[1151] Each m' of ULM-g to ULM-i is 0 or 1; and

[1152] Each n' of ULM-g to ULM-i is 0 or 1;

[1153] wherein each of said compounds is optionally linked / attached to a PTM group (including a ULM' group), preferably on an alkyl, aryl or Het group, via a linker.

[1154] In an alternative embodiment, the R of ULM-g to ULM-i 3 'Yes-(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET or -(CH2CH2O) n -HET,

[1155] in:

[1156] The aryl group of ULM-g to ULM-i is a phenyl group optionally substituted with one or two substituents, wherein the substituents are preferably selected from -(CH2) n OH, C1-C6 alkyl (which itself is further optionally substituted by CN), halogen (up to three halogen groups), OH, -(CH2) n O(C1-C6)alkyl, amine, mono- or di-(C1-C6)alkyl)amine, wherein the alkyl group on the amine is optionally substituted by 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, or

[1157] The aryl groups of ULM-g to ULM-i are replaced by -(CH2) n OH, -(CH2) n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, wherein the alkyl group on the amine is optionally substituted by 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, CN, NO2, -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6)alkyl, -(V) m’ -(CH2CH2O)n -R PEG Group substituted, where V is O, S or NR 1’ , R 1’ is H or C1-C3 alkyl (preferably H), and R PEG is H or optionally substituted (including optionally substituted by carboxyl) C1-C6 alkyl, or

[1158] The aryl groups of ULM-g to ULM-i are optionally substituted with heterocycles, including heteroaryl groups, selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each preferably with C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl) or a group according to the following chemical structure:

[1159]

[1160] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[1161] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1162] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1163] R from ULM-g to ULM-i UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted);

[1164] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1165] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[1166] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group;

[1167] HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by a C1-C3 alkyl group, preferably a methyl group or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine or a group according to the following chemical structure:

[1168]

[1169] S for ULM-g to ULM-i c It is CHR SSNR URE or O;

[1170] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1171] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[1172] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine (each of which is optionally substituted);

[1173] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups) or an optionally substituted acetylenic group -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[1174] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl, or heterocyclyl;

[1175] R from ULM-g to ULM-i PRO1and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group;

[1176] Each m' of ULM-g to ULM-i is independently 0 or 1; and

[1177] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

[1178] wherein each of said compounds is linked / attached to a PTM group (including a ULM' group), preferably on said aryl or HET group, optionally via a linker group.

[1179] In still further embodiments, preferred compounds include those according to the following chemical structure:

[1180]

[1181] in:

[1182] ULM-i R 1’ It is the group to which OH is metabolized in the patient or subject;

[1183] ULM-i R 2’ is -NH-CH2-aryl-HET (preferably a phenyl group directly attached to a methyl-substituted thiazole);

[1184] ULM-i R 3’ Yes-CHR CR3’ -NH-C(O)-R 3P1 Group or -CHR CR3’ -R 3P2 group;

[1185] ULM-i R CR3’ is C1-C4 alkyl, preferably methyl, isopropyl or tert-butyl;

[1186] ULM-i R 3P1 is C1-C3 alkyl (preferably methyl), optionally substituted oxetane (preferably methyl substituted -(CH2) n OCH3 group, wherein n is 1 or 2 (preferably 2) or groups (the ethyl ether group is preferably substituted at the meta position on the phenyl moiety), morpholino groups (attached to the carbonyl group at the 2 or 3 position);

[1187] ULM-i R 3P2 yes group;

[1188] The aryl group of ULM-i is phenyl;

[1189] HET of ULM-i is an optionally substituted thiazole or isothiazole; and

[1190] ULM-i R HET is H or a halogen group (preferably H);

[1191] or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of said compounds is optionally linked to a PTM group (including a ULM' group) via a linker group.

[1192] In certain aspects, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[1193]

[1194] in:

[1195] R5 and R6 of ULM-j are each independently OH, SH or an optionally substituted alkyl group, or R5, R6 and the carbon atom to which they are attached together form a carbonyl group;

[1196] R7 of ULM-j is H or optionally substituted alkyl;

[1197] E of ULM-j is a bond, C=O, or C=S;

[1198] G of ULM-j is a bond, optionally substituted alkyl, -COOH, or C=J;

[1199] The J of ULM-j is O or N-R8;

[1200] R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

[1201] M of ULM-j is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle or

[1202] R9 and R of ULM-j 10 are each independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted sulfanyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R9, R 10 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[1203] ULM-j R 11 is an optionally substituted heterocycle, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, an optionally substituted aryl group or

[1204] ULM-j R 12 is H or optionally substituted alkyl;

[1205] ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,

[1206] Each R of ULM-j 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

[1207] ULM-j R 15 is H, CN, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;

[1208] Each R of ULM-j 16 is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;

[1209] Each R of ULM-j 25 are independently H or optionally substituted alkyl; or two R 25 The groups may together form oxo or optionally substituted cycloalkyl;

[1210] ULM-j R 23 is H or OH;

[1211] Z1, Z2, Z3 and Z4 of ULM-j are independently C or N; and

[1212] o of ULM-j is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[1213] In certain embodiments, wherein G of ULM-j is C=J, J is O, R7 is H, each R 14 is H and o is 0.

[1214] In certain embodiments, wherein G of ULM-j is C=J, J is O, R7 is H, each R 14 It's H, R 15 is optionally substituted heteroaryl and o is 0. In other cases, E is C=O and M is

[1215] In certain embodiments, where E of ULM-j is C=O, R 11 is an optionally substituted heterocycle or And M is

[1216] In certain embodiments, wherein E of ULM-j is C=O and M is And R 11 yes Each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[1217] In certain embodiments, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1218]

[1219] in:

[1220] The G of ULM-k is C=J, and J is O;

[1221] R7 of ULM-k is H;

[1222] Each R of ULM-k 14 It is H;

[1223] The o of ULM-k is 0;

[1224] R of ULM-k 15 yes and

[1225] R of ULM-k 17 is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

[1226] In other cases, the R of ULM-k 17 is an alkyl group (eg, methyl) or a cycloalkyl group (eg, cyclopropyl).

[1227] In other embodiments, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1228]

[1229] in:

[1230] The G of ULM-k is C=J, and J is O;

[1231] R7 of ULM-k is H;

[1232] Each R of ULM-k 14 It is H;

[1233] o of ULM-k is 0; and

[1234] R of ULM-k 15 Select from the group consisting of:

[1235] The R of ULM-k 30 is H or optionally substituted alkyl.

[1236] In other embodiments, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1237]

[1238] in:

[1239] The E of ULM-k is C=O;

[1240] The M of ULM-k is and

[1241] R of ULM-k 11 Select from the group consisting of:

[1242]

[1243] In still other embodiments, compounds of the following chemical structures:

[1244]

[1245] Wherein E of ULM-k is C=O;

[1246] R of ULM-k 11 yes and

[1247] The M of ULM-k is

[1248] ULM-k's q is 1 or 2;

[1249] R of ULM-k 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or

[1250] R of ULM-k 21 is H or optionally substituted alkyl; and

[1251] R of ULM-k 22 is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[1252] In any of the embodiments described herein, R of ULM-j or ULM-k 11 Select from the group consisting of:

[1253]

[1254]

[1255]

[1256] In certain embodiments, the R of ULM-j or ULM-k 11 Select from the group consisting of:

[1257]

[1258]

[1259] In certain embodiments, the ULM (or ULM' when present) is a group according to the following chemical structure:

[1260]

[1261] in:

[1262] X of ULM-l is O or S;

[1263] Y of ULM-1 is H, methyl or ethyl;

[1264] ULM-1 R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

[1265] M of ULM-1 is an optionally substituted aryl group, an optionally substituted heteroaryl group or

[1266] R9 of ULM-l is H;

[1267] ULM-1 R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted sulfanyl, or cycloalkyl;

[1268] R11 of ULM-1 is an optionally substituted heteroaromatic, an optionally substituted heterocyclic, an optionally substituted aryl or

[1269] ULM-1 R 12 is H or optionally substituted alkyl; and

[1270] ULM-1 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.

[1271] In some embodiments, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1272]

[1273] in:

[1274] Y of ULM-m is H, methyl or ethyl

[1275] R9 of ULM-m is H;

[1276] R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;

[1277] ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle.

[1278] In other preferred embodiments of the present disclosure, ULM and ULM' (when present) are each independently a group according to the following chemical structure:

[1279]

[1280] in:

[1281] ULM-nR 17 is methyl, ethyl or cyclopropyl; and

[1282] ULM-n R9, R 10 and R 11 As defined above. In other cases, R9 is H; and

[1283] ULM-nR 10 is H, alkyl or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[1284] In any aspect or embodiment described herein, the ULM described herein (or ULM', where present) can be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any aspect or embodiment described herein, the ULM described herein (or ULM', where present) can be coupled to the PTM directly through a bond or through a chemical linker.

[1285] In certain aspects of the present disclosure, the ULM portion is selected from the group consisting of:

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302]

[1303]

[1304]

[1305]

[1306]

[1307]

[1308]

[1309] Wherein the VLM can be linked to the PTM via a linker as described herein, optionally via any suitable functional group such as an amine, ester, ether, alkyl or alkoxy group at any suitable position including, for example, an aryl, heteroaryl, phenyl or indolyl phenyl group.

[1310] Exemplary linkers

[1311] In certain embodiments, the compounds described herein include one or more PTMs chemically linked or coupled to one or more ULMs (e.g., at least one of a CLM, VLM, MLM, ILM, or a combination thereof) via a chemical linker (L). In certain embodiments, the linker group L is a structural unit comprising one or more covalently linked units (e.g., -A L 1…(A L ) q -or-(A L ) q -) group, where A L 1 is a group coupled to PTM, and (A L ) q is the group coupled to the ULM.

[1312] In any aspect or embodiment described herein, the linker group L is of formula -(A L ) q - represents a bond or chemical linker group, wherein A L is a chemical moiety, and q is an integer from 1 to 100, and wherein A L Covalently binds to PTMs and ULMs, providing sufficient binding of PTMs to protein targets and ULMs to E3 ubiquitin ligases, leading to target protein ubiquitination.

[1313] In certain embodiments, the linker group L is -(A L ) q -,in:

[1314] (A L ) q is a group connected to at least one of a ULM (such as a CLM or VLM), a PTM moiety, or a combination thereof; q of the linker is an integer greater than or equal to 1;

[1315] Each A L Independently selected from the group consisting of: key, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NRL3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , 0-6 R's can be selected L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted by 0-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 0-8 R L1 and / or R L2 C 5-13 Spiroheterocycloalkyl, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently optionally connected to other groups to form optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and

[1316] R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl)2, N(C1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2、Si(OH)3、Si(C 1-8 Alkyl)3, Si(OH)(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.

[1317] In certain embodiments, 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.

[1318] In certain embodiments, for example, where q of the linker is greater than 2, (A L ) q is a group connected to the ULM, and A L 1 and (A L ) qThe structural units are connected via a linker (L).

[1319] In certain embodiments, for example, wherein q of the linker is 2, (A L ) q is connected to A L 1 and a group connected to the ULM.

[1320] In certain embodiments, for example, where q of the linker is 1, the structure of the linker group L is -A L 1-, and A L 1 is a group connected to the ULM moiety and the PTM moiety.

[1321] In certain embodiments, the unit AL of the linker (L) comprises a group represented by the general structure selected from the group consisting of:

[1322] -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(lower alkoxy)-OCH2-, -NR(CH2) n -(lower alkoxy)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(Heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(Heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocyclyl)-CH2, -NR(CH2CH2)n -(heterocyclyl)-(heterocyclyl)-CH2, -N(R1R2)-(heterocyclyl)-CH2; wherein

[1323] The n of the linker can be 0-10;

[1324] The R of the linker can be H, lower alkyl;

[1325] R1 and R2 of the linker may form a ring by connecting N.

[1326] In any aspect or embodiment described herein, unit A of linker (L) L Includes a group selected from the following:

[1327]

[1328]

[1329]

[1330]

[1331] C1-C6 alkyl, wherein:

[1332] The *N of the heterocycloalkyl group is shared with the PTM; and

[1333] m, n, o, p, q, r and s are each 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.

[1334] In certain embodiments, unit A of linker (L) L A group comprising a general structural representation, said group being selected from the group consisting of:

[1335] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[1336] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[1337] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1338] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1339] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1340] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[1341]

[1342]

[1343]

[1344] in

[1345] 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;

[1346] When the number is zero, there is no NO or OO key

[1347] R of the linker is H, methyl and ethyl;

[1348] The X of the connector is H and F

[1349]

[1350] The m of the joint can be 2, 3, 4, or 5

[1351]

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359] wherein n and m of the linker can each independently be 0, 1, 2, 3, 4, 5, or 6.

[1360] In any aspect or embodiment described herein, unit A of linker (L) L Select from the group consisting of:

[1361]

[1362]

[1363]

[1364] wherein m and n are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

[1365] In any aspect or embodiment described herein, unit A of linker (L) L Select from the group consisting of:

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395] wherein m, n, o, p, q, r, and s are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[1396] In any aspect or embodiment described herein, unit A of linker (L) L Select from the group consisting of:

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408] In further embodiments, the linker (L) comprises a structure selected from, but not limited to, the following structures, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[1409]

[1410] in:

[1411] W L1 and W L2 are each independently absent, a 4-8 membered ring having 0-4 heteroatoms optionally substituted by RQ, each R Q are independently H, halogen, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, or 2 R Q The groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[1412] Y L1 Each is independently a bond, an optionally substituted linear or branched C1-C6 alkyl group, and optionally one or more C atoms are replaced by O; or an optionally substituted linear or branched C1-C6 alkoxy group;

[1413] n and m are independently 0-10; and

[1414] Indicates the point of connection to the PTM or ULM portion.

[1415] In further embodiments, the linker (L) comprises a structure selected from, but not limited to, the following structures, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[1416]

[1417] in:

[1418] W L1 and W L2 Each independently is absent, aryl, heteroaryl, cyclic, heterocyclic, C 1-6 Alkyl and optionally one or more C atoms are replaced by O or N, C 1-6 Olefins and optionally one or more C atoms are replaced by O, C 1-6 Alkyne and optionally one or more C atoms are replaced by O, bicyclic, biaryl, biheteroaryl or biheterocyclic, each of which is optionally replaced by R Q Replace, each R Q are independently H, halogen, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight chain or branched C1-C6 alkyl, optionally substituted straight chain or branched C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with 1 or more -F), OH, NH2, NR Y1 R Y2 , CN, or 2 R Q The groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[1419] Y L1 Each independently is a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (straight chain, branched, optionally substituted) and optionally one or more C atoms are replaced by O; optionally substituted straight chain or branched C1-C6 alkoxy, 3-6 membered alicyclic or aromatic ring containing 0-4 heteroatoms;

[1420] Q L is an optionally bridged 3-6 membered alicyclic or aromatic ring containing 0-4 heteroatoms, which is optionally bridged by 0-6 R Q Replace, each R Q are independently H, optionally substituted straight or branched chain C 1-6Alkyl (eg, optionally substituted with one or more halogen or C 1-6 alkoxy substituted), or 2 R Q The groups and the atoms to which they are attached together form a 3-8 membered ring system containing 0-2 heteroatoms;

[1421] R YL1 、R YL2 are each independently H, OH, an optionally substituted linear or branched C 1-6 Alkyl (eg, optionally substituted with one or more halogen or C 1-6 alkoxy substituted), or R 1 、R 2 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms;

[1422] n and m are independently 0-10; and

[1423] Indicates the point of connection to the PTM or ULM portion.

[1424] In further embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 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 In some embodiments, the joint is an alkyl group, a phenyl group, a benzyl group, a alkylene ...

[1425] In any embodiment of the compounds described herein, the linker group can be any suitable moiety as described herein. In one embodiment, the linker is an unsubstituted or substituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units.

[1426] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50Alkyl (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 50 alkyl) wherein each carbon is optionally substituted with a heteroatom selected from N, S, P, or Si atoms with an appropriate number of hydrogens, substitutions, or both to complete the valences, provided that there is no heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently attached or adjacently positioned).

[1427] In any aspect or embodiment described herein, the linker (L) comprises from 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 ethylene glycol units, wherein a carbon or oxygen is optionally substituted with a heteroatom selected from N, S, P, or Si atoms with an appropriate number of hydrogens to complete the valences. For example, in any aspect or embodiment described herein, the linker (L) has a chemical structure selected from:

[1428]

[1429]

[1430] , wherein the carbon or oxygen may be replaced by a heteroatom selected from N, S, P or Si atoms with an appropriate number of hydrogens to complete the valence, and m, n, o, p, q, r and s are 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.

[1431] In another embodiment, the present disclosure relates to a compound comprising a PTM group as described above, which binds to a target protein or polypeptide (e.g., Kirsten rat sarcoma protein (KRas or KRAS) and / or a gain-of-function KRAS mutant), which is ubiquitinated by a ubiquitin ligase and chemically linked to a ULM group directly or through a linker moiety L, or alternatively the PTM is a ULM' group that is also a ubiquitin ligase binding moiety, which may be the same or different from the ULM group as described above and is directly linked to the ULM group directly or through a linker moiety; and L is a linker moiety as described above, which may be present or absent, and which chemically (covalently) links the ULM to the PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

[1432] 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:

[1433]

[1434] X is selected from the group consisting of O, N, S, S(O) and SO2; n is an integer from 1 to 5; R L1 is hydrogen or an alkyl group, is a mono- or bicyclic aryl or heteroaryl group optionally substituted by 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; is a mono- or bicyclic alkyl or heterocyclic alkyl group, which is optionally substituted with 1-3 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.

[1435] Although the ULM group and the PTM group can be covalently linked to the linker group through any group that is suitable and stable for the linker chemistry, in preferred aspects of the present disclosure, the linker is independently covalently bonded to the ULM group and the PTM group, preferably through an amide, ester, thioester, keto, carbamate (urethane), carbon, or ether, each of which can be inserted anywhere on the ULM group and the PTM group to provide maximum binding of the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain aspects where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself). In certain preferred aspects, the linker can be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, an aryl, or heterocyclic group on the ULM and / or PTM group.

[1436] Exemplary PTMs

[1437] In preferred aspects of the present disclosure, the PTM group is a group that binds to a target protein. The targets of the PTM group are numerous and are selected from proteins expressed in cells, such that at least a portion of the sequence is found in the cell and can bind to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length that can bind to the PTM group according to the present disclosure. As further described herein, any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi, is a target for ubiquitination mediated by the compounds according to the present disclosure. Preferably, the target protein is a eukaryotic protein.

[1438] PTM groups according to the present disclosure include, for example, any portion that specifically binds to a protein (binds to a target protein), and include non-limiting examples of the following small molecule target protein portions: KRas inhibitors, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among others. The following compositions illustrate some members of the small molecule target protein binding portion. Such small molecule target protein binding portions also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target target proteins, such as KRas and / or mutant KRas, including gain-of-function KRas mutants, such as KRas G12C These binding moieties are preferably linked to a ubiquitin ligase binding moiety via a linker so as to present the target protein (bound to the protein target moiety), such as KRas and / or a gain-of-function KRas mutant, in proximity to the ubiquitin ligase for ubiquitination and degradation.

[1439] The present disclosure can be used to treat a number of disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and the patient would benefit from the degradation and / or inhibition of the protein.

[1440] On the other hand, this specification provides therapeutic compositions, which include an effective amount of a compound as described herein or a salt thereof, and a pharmaceutically acceptable carrier, additive or adjuvant, and optionally another bioactivator. The therapeutic composition regulates protein degradation in a patient or subject, such as an animal, such as a human, and can be used to treat or improve a disease state or condition regulated by degraded protein. In certain embodiments, the therapeutic composition as described herein can be used to achieve degradation of target protein, to treat or improve disease, such as cancer (including, for example, pancreatic cancer, colon cancer, lung cancer, non-small cell lung cancer, or a combination thereof). In some other embodiments, the disease includes or is 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.

[1441] In an alternative aspect, the present disclosure relates to a method for treating a disease state of a subject in need thereof or improving the symptoms of a disease or condition by modulating the disease state or condition by degrading a protein or polypeptide, the method comprising: administering to the patient or subject an effective amount, e.g., a therapeutically effective amount of at least one compound as described above, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally another bioactive agent, wherein the composition is effective for treating or improving the disease, condition or symptom of the subject. The methods according to the present disclosure can be used to treat a variety of disease states or conditions, including cancer (including, for example, pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary 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 as described herein. The disease state or condition can be a disease caused by a microbial agent or other exogenous agent such as a virus, bacteria, fungus, protozoa or other microorganism, or can be a disease state caused by overexpression of a protein that causes a disease state and / or condition.

[1442] In another aspect, the present description provides methods of identifying degradation of a target protein in a biological system using compounds according to the present disclosure.

[1443] The term "target protein" is used to describe a protein or polypeptide that is a target for binding to a compound according to the present disclosure and degradation by a ubiquitin ligase as described below. For example, in any aspect or embodiment described herein, a PTM is a small molecule comprising a KRas protein targeting moiety. 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 the target protein. These binding moieties are connected to at least one ULM group (e.g., VLM, CLM, ILM, and / or MLM) via at least one linker group L.

[1444] Target proteins that can be bound to a protein target portion and degraded by a ligase that is bound to a ubiquitin ligase binding portion include any protein or peptide, including fragments thereof, analogs thereof, and / or homologs thereof. Target proteins include proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport, and signal transduction. For example, in any aspect or embodiment described herein, the PTM is a KRas protein binding portion.

[1445] These various protein targets, such as the KRas protein, can be used in screens to identify compound moieties that bind to the protein, and by incorporating such moieties into compounds according to the disclosure, the activity level of the protein can be altered for therapeutic end results.

[1446] The term "protein target moiety" or PTM is used to describe a small molecule that binds to a target protein or other target protein or polypeptide and places the protein or polypeptide in / presents it near a ubiquitin ligase, making it possible to degrade the protein or polypeptide by a ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include KRas inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting proteins containing human BET bromodomains, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aromatic hydrocarbon receptors (AHR). The following compositions illustrate some members of small molecule target proteins. Exemplary protein target moieties according to the present disclosure include KRas inhibitors, haloalkyl halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting proteins containing human BET bromodomains, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aromatic hydrocarbon receptors (AHR).

[1447] The compositions described herein exemplify some members of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the target protein.

[1448] 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 binds to a mutant KRas, e.g., a gain-of-function mutant KRas (e.g., KRas G12C In any aspect or embodiment described herein, the PTM has a chemical structure represented by:

[1449]

[1450]

[1451] in:

[1452] is aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

[1453] X PTM is C or N;

[1454] W PTMSelected 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), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl);

[1455] R PTM1A It 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 (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted (eg, optionally substituted with at least one alkyl group, such as the carbon atom may be optionally substituted with an alkyl group), optionally substituted (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, such as * carbon may be optionally substituted with an alkyl group), wherein N* is the N atom of a heterocycloalkyl group (e.g., a C4-C8 heterocycloalkyl group) of Linker (L);

[1456] R PTM1B It 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 (eg, optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted Optionally substituted

[1457] R PTM9 and R PTM10 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, or optionally substituted aliphatic amide;

[1458] R PTM2 is H, (C=O)R PTM2 ', optionally substituted straight or branched chain alkyl;

[1459] R PTM2' is an optionally substituted linear or branched alkyl, an optionally substituted alkene, -N(R PTM8 )2 or -C(OH)2;

[1460] R PTM3is alkyl, alkoxy, phenyl or naphthalene, each independently substituted by OH, H or halogen;

[1461] R PTM4A is OH, H, halogen, or optionally substituted linear or branched C1-C6 alkyl;

[1462] R PTM4B is OH, H, halogen, or optionally substituted linear or branched C1-C6 alkyl;

[1463] R PTM5 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 alkyl (e.g., optionally substituted straight or branched C1-C6 alkyl), OH, and alkoxy;

[1464] R PTM8 is H or alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl);

[1465] t is 0, 1, 2, 3, 4, 5, 6 (such as 0, 1, 2, 3); and

[1466] represents the attachment site of at least one of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM' or a combination thereof.

[1467] In any aspect or embodiment described herein, the PTM has a chemical structure represented by:

[1468]

[1469]

[1470]

[1471]

[1472]

[1473] in:

[1474] X PTM1 is NH or O;

[1475] R PTM6 is aryl, heteroaryl, wherein N* is the N atom of the heterocycloalkyl group (e.g., C4-C8 heterocycloalkyl) of the linker (L);

[1476] R PTM7 is H, aryl, O-aryl, heteroaryl, O-heteroaryl,

[1477] t is 0, 1, 2, 3, 4, 5, 6 (e.g., 1, 2, or 3);

[1478] R PTM9 is H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, optionally substituted aliphatic amide, optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group);

[1479] can be a single bond or a double bond; and

[1480] represents the attachment site of at least one of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM' or a combination thereof.

[1481] In any aspect or embodiment described herein, the PTM is selected from:

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494] In any aspect or embodiment described herein, the PTM is: (i) a PTM of a compound selected from Tables 4, 6, 8, 10, and 12; or (ii) a PTM of Table 1.

[1495] Therapeutic compositions

[1496] Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein in combination with one or more compounds additionally described herein (all in effective amounts) and a pharmaceutically effective amount of a carrier, additive, or excipient represent another aspect of the present disclosure.

[1497] The present disclosure includes, where applicable, compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. Acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned basic compounds that can be used according to this aspect are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, bitartrates, succinates, maleates, fumarates, gluconates, sucroses, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)], and the like.

[1498] 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 for preparing pharmaceutically acceptable base salts (acidic in nature) of the compounds of the present invention are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium); ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine); and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines, etc.

[1499] According to the present disclosure, the compounds described herein can be administered in single doses or divided doses by oral, parenteral or topical routes. The range of administration of the active compound can be from continuous (intravenous drip) to oral administration several times a day (e.g., QID), and can include other administration routes such as oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include a penetration enhancer), buccal, sublingual and suppository administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form will depend on the pharmacokinetics of the selected specific agent and the severity of the patient's disease. Compounds according to the present disclosure can also be used as sprays, mists or aerosols for intranasal, intratracheal or intrapulmonary administration. Therefore, the present disclosure also relates to pharmaceutical compositions, which include an effective amount of a compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. Compounds according to the present disclosure can be administered in an immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but are also administered in suppositories, transdermal or other topical forms. Intramuscular injection of liposome forms can also be used to control or sustain the release of the compound at the site of injection.

[1500] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in a controlled release formulation. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[1501] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[1502] The sterile injectable forms of the compositions described herein can be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable excipients and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, such as in natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[1503] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in the form of capsules, available diluents include lactose and dried corn starch. When an oral aqueous suspension is desired, the active ingredient is mixed with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[1504] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[1505] The pharmaceutical compositions described herein can also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be performed in the form of a rectal suppository formulation (see above) or a suitable enema formulation. Topically acceptable transdermal patches can also be used.

[1506] For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred aspects of the present disclosure, the compound can be coated on a stent that will be surgically implanted in the patient to suppress or reduce the possibility of blockage in the patient's stent.

[1507] Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[1508] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for oph...

Claims

1. A bifunctional compound having the following chemical structure: ULM-L-PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, in: ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase; PTM is a small molecule comprising a Kirsten rat sarcoma protein (KRas) targeting moiety; and L is a bond or chemical linking moiety connecting the ULM and the PTM.

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

3. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by: in: is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X PTM is C or N; W PTM 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), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl); R PTM1A YesNR 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 -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 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 (e.g., optionally substituted with at least one alkyl group, such as the first carbon may be optionally substituted with an alkyl group), Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the carbon atom may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group), optionally substituted (e.g., optionally substituted with at least one alkyl group, Such as * carbon may be optionally substituted by alkyl), wherein N* is the N atom of the heterocycloalkyl of the linker (L); R PTM1B YesNR 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 (For example, optionally substituted with at least one alkyl group, such as * The carbon may be optionally substituted by an alkyl group), optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted R PTM9 and R PTM10 Each is independently H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, or optionally substituted aliphatic amide; R PTM2 is H, (C=O)R PTM2 ', optionally substituted straight or branched chain alkyl; R PTM2' is an optionally substituted straight or branched alkyl, an optionally substituted alkene, -N(R PTM8 )2 or -C(OH)2; R PTM3 is alkyl, alkoxy, phenyl or naphthalene, each independently substituted by OH, H, or halogen; R PTM4A is OH, H or halogen, optionally substituted straight or branched C1-C6 alkyl; R PTM4B is OH, H, -CH2CN, halogen, or optionally substituted linear or branched C1-C6 alkyl; R PTM5 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 alkyl (e.g., optionally substituted straight or branched C1-C6 alkyl), OH, and alkoxy; R PTM8 is H or alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl or C4 alkyl); t is 0, 1, 2, 3, 4, 5, 6; and Represents the attachment site of at least one of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM' or a combination thereof.

4. The bifunctional compound according to any one of claims 1 to 3, wherein the PTM is represented by: in: X PTM1 is NH or O; R PTM6 is an aryl group, a heteroaryl group, wherein N* is the N atom of the heterocycloalkyl group (e.g., C4-C8 heterocycloalkyl group) of the linker (L); R PTM7 is H, aryl, O-aryl, heteroaryl, O-heteroaryl, R PTM9 is H, optionally substituted C1-C6 alkyl, optionally substituted aliphatic amine, optionally substituted aliphatic amide, optionally substituted (e.g., optionally substituted with at least one alkyl group, such as the * carbon may be optionally substituted with an alkyl group); can be a single bond or a double bond; and Represents the attachment site of at least one of a linker, ULM, ULM', CLM, CLM', VLM, VLM', ILM, ILM', MLM, MLM' or a combination thereof.

5. The bifunctional compound according to any one of claims 1 to 4, wherein the PTM is represented by the following chemical structure:

6. The bifunctional compound according to any one of claims 1 to 5, wherein the ULM is a Von Hippel-Lindau (VHL) ligase binding moiety (VLM) having a chemical structure represented by: in: X 1 , X 2 are independently selected from the following group: bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2; R Y3 , R Y4 Each is independently selected from the following group: H, a linear or branched C optionally substituted by one or more halogens 1-6 Alkyl, optionally substituted with 0-3 R P C 1-6 Alkoxy; R P is 0, 1, 2 or 3 groups independently selected from the following groups: H, halogen, -OH, C 1-3 Alkyl, C=O; W 3 is selected from optionally substituted T, 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 3 C=O、R 1 , R 1a , R 1b ; R 1 , R 1a , R 1b Each is independently selected from the group consisting of: H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halogen 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 is selected from optionally substituted alkyl, -(CH2) n - group, wherein each of the methylene groups is optionally substituted by one or two substituents selected from the following groups: halogen, methyl, optionally substituted alkoxy, linear or branched C1-C6 alkyl optionally substituted by 1 or more halogens, C(O)NR 1 R 1a or NR 1 R 1a , or R 1 and R 1a are linked to form an optionally substituted heterocyclic group or an -OH group or an optionally substituted amino acid side chain; and n is 0-6, W 4 yes R 14a , R 14b are each independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl; W 5 is selected from the group consisting of optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl; R 15 Selected from the following group: H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b NR 14a COR 14b 、SO2NR 14a R 14b NR 14a S02R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; And wherein the dashed line represents the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM' or both to the ULM.

7. The bifunctional compound according to any one of claims 1 to 5, wherein the ULM is a Von Hippel-Lindau (VHL) ligase binding moiety (VLM) having a chemical structure represented by: in: W 3 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl or R9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group; R 11 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, R 12 is selected from the group consisting of: H or optionally substituted alkyl; R 13 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl; R 14a , R 14b are each independently selected from the group consisting of H, haloalkyl or optionally substituted alkyl; W 5 is selected from the group consisting of optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl; R 15 Selected from the following group: H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b NR 14a COR 14b 、SO2NR 14a R 14b NR 14a S02R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; Each R 16 independently selected from the group consisting of halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R 18 is independently selected from the group consisting of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and p is 0, 1, 2, 3 or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM' or both to the ULM.

8. The bifunctional compound according to any one of claims 1 to 7, wherein the ULM has a chemical structure selected from the following group: in: R1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl; R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl; R 15 is selected from the group consisting of H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; X is C, CH2 or C=O R3 is absent or is an optionally substituted 5- or 6-membered heteroaryl; and The dashed line indicates the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety coupling at least one PTM or ULM' or both to the ULM.

9. A composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. A composition for treating a disease or condition in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to any one of claims 1-8, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or condition.

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