Polycyclic compounds and methods for targeted degradation of rapidly accelerated fibrosarcoma polypeptides

Abstract

The present invention relates to polycyclic compounds and methods for targeted degradation of rapidly accelerated fibrosarcoma polypeptides. The present disclosure relates to bifunctional compounds, ULM-L-PTM, which are useful as modulators of rapidly accelerated fibrosarcoma. In particular, the disclosure relates to bifunctional compounds containing on one end a Von Hippel-Lindau, human cerebellar protein, apoptosis inhibitor protein, or a mouse double minute homolog 2 ligand that binds to the corresponding E3 ubiquitin ligase, and on the other end a moiety that binds to the target protein RAF, 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 wide range of pharmacological activities associated with degradation / inhibition of a target protein.

Description

[0001] This application is a divisional application of Chinese patent application No. 201980073600.1, filed on September 7, 2019, entitled “Polycyclic compounds and methods for targeted degradation of rapidly accelerated fibrosarcoma polypeptides”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This disclosure claims the benefit of and priority to U.S. Provisional Application No. 62 / 728,581, filed on September 7, 2018, and is a continuation-in-part of U.S. Patent Application No. 15 / 853,166, filed on December 22, 2017, which was published as U.S. Patent Application Publication No. 2018 / 0179183 A1 on June 28, 2018, which claims priority to U.S. Provisional Application No. 62 / 438,803, filed on December 23, 2016, and U.S. Provisional Application No. 62 / 582,698, filed on November 7, 2017, all of which are incorporated herein by reference in their entirety.

[0004] Incorporated by reference

[0005] U.S. patent application serial number 15 / 230,354, filed on August 5, 2016; and U.S. patent application serial number 15 / 206,497, filed on July 11, 2016; and U.S. patent application serial number 15 / 209,648, filed on July 13, 2016; and U.S. patent application serial number 62 / 406,888, filed on October 11, 2016; and U.S. patent application serial number 14 / 686,640, filed on April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. patent application Ser. No. 14 / 792,414, filed on July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. patent application Ser. No. 14 / 371,956, filed on July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and U.S. patent application Ser. No. 15 / 074,820, filed on March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639, are each incorporated herein by reference in their entireties. In addition, all references cited herein are incorporated herein by reference in their entireties.

[0006] Statement Regarding Federally Funded Research

[0007] This invention was made with government support under Grant No. NIH R35CA197589 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0008] 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 with respect to rapidly accelerated fibrosarcoma (RAF) proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0009] Most small molecule drugs bind enzymes or receptors in a tight and well-defined pocket. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surface and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination, and therefore, due to their specificity for certain protein substrates, are more attractive therapeutic targets than general proteasome inhibitors. The development of E3 ligase ligands has proven challenging, in part due to the fact that they must destroy protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutlin, other compounds targeting E3 ligases have been reported, but this field is still underdeveloped. For example, since the discovery of Nutlin, the first small molecule E3 ligase inhibitor of mouse double minute 2 homolog (MDM2), additional compounds targeting MDM2 (ie, human double minute 2 or HDM2) E3 ligase have been reported (J. Di et al., Current Cancer Drug Targets (2011), 11(8), 987-994).

[0010] The tumor suppressor gene p53 plays an important role in cell growth arrest and apoptosis in response to DNA damage or stress (A. Vazquez et al., Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 is considered to be one of the major pathways for tumor cell survival (AJ Levine et al., Nature (2000), 408, 307-310). Among cancer patients, approximately 50% are found to have p53 mutations ((M. Hollstein et al., Science (1991), 233, 49-53), while in patients with wild-type p53, MDM2 is often found to downregulate p53 through protein interaction between p53 and MDM2 (P. Chene et al., Nat. Rev. Cancer (2003), 3, 102-109). Under normal cellular conditions in the absence of oncogenic stress signals, MDM2 keeps p53 at a low concentration. In response to DNA damage or cellular stress, p53 levels increase, and due to a feedback loop from the p53 / MDM2 autoregulatory system, this also leads to an increase in MDM2. In other words, p53 regulates MDM2 at the transcriptional level, and MDM2 regulates p53 at its activity level (AJ Levine et al., Genes Dev. (1993) 7, 1126-1132).

[0011] Several mechanisms can explain the down-regulation of p53 by MDM2. First, MDM2 binds to the N-terminal domain of p53 and blocks the expression of p53 response genes (J. Momand et al., Cell (1992), 69, 1237-1245). Secondly, MDM2 transports p53 from the nucleus to the cytoplasm to promote protein degradation (J. Roth et al., EMBO J. (1998), 17, 554-564). Finally, MDM2 has the intrinsic E3 ligase activity of conjugating ubiquitin to p53 to be degraded by the ubiquitin-dependent 26s proteasome system (UPS) (Y. Haupt et al., Nature (1997) 387, 296-299). In this way, because MDM2 plays the role of E3 ligase, recruiting MDM2 to disease-causing proteins and realizing their ubiquitination and degradation is a highly concerned method for drug discovery.

[0012] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, the substrate-recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2, and Rbx1. VHL's primary substrate is hypoxia-inducible factor 1 (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine erythropoietin in response to low oxygen levels. The first small-molecule ligand of VHL that targets the substrate-recognition subunit of the E3 ligase was generated, and a crystal structure was obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0013] Human cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Human cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullin regulator 1 (ROC1). This complex ubiquitinates numerous other proteins. Through mechanisms not yet fully elucidated, human cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates numerous developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of human cereblon, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0014] Inhibitor 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 have IAP homologs. IAPs contain an E3 ligase-specific domain and a baculovirus IAP repeat (BIR) domain that recognizes substrates and promotes their ubiquitination. IAPs promote ubiquitination and can directly bind to and inhibit caspases. Caspases are proteases that initiate apoptosis (e.g., caspase-3, caspase-7, and caspase-9). Therefore, by binding to caspases, IAPs inhibit cell death. However, pro-apoptotic stimuli can lead to the release of the mitochondrial proteins DIABLO (also known as second mitochondrial-derived activator of caspases, or SMAC) and HTRA2 (also known as Omi). The binding of DIABLO and HTRA2 appears to block IAP activity.

[0015] 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.

[0016] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), are used to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, this disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that are useful as targeted ubiquitination modulators of a variety of polypeptides and other proteins that, following targeted ubiquitination, are degraded and / or otherwise inhibited by the bifunctional compounds.

[0017] There is a continuing need in the art for effective treatment of diseases associated with overexpression or aggregation of rapidly accelerated fibrosarcoma (RAF) or overactivation of RAF (e.g., constitutively active RAF). For example, current BRaf inhibitors (e.g., vemurafenib and dabrafenib) can target V600 mutant BRaf. Therefore, there is a continuing need for diseases or conditions (e.g., melanoma, lung cancer, pancreatic cancer, and / or colorectal cancer) with different BRaf mutations that are insensitive to currently available agents. In addition, resistance mutations may arise in response to BRaf / MEK inhibitor treatment. For example, p61 splice variants may appear in melanoma patients treated with BRaf / MEK inhibitor therapy, leaving these patients without clinical options. Currently available agents also bind to wild-type BRaf and cause its paradoxical activation, leading to clinical complications. In addition, the low-activity class III BRAF mutation family, which signals through heterodimerization with CRaf, accounts for 40% of BRAF mutations in non-small cell lung cancer (NSCLC) and occasionally appears in other cancers and cannot be targeted by any currently approved or clinical-stage BRAF inhibitors. Class I BRAF mutants (V600E, V600K, V600D) have high kinase activity, are independent of Ras and dimerization, and are sensitive to vemurafenib. Class II BRAF mutants have high to moderate kinase activity, are independent of Ras and dimerization, and are insensitive to vemurafenib. Class III BRAF mutants have substantial to no kinase activity, are independent of Ras and dimerization, and are insensitive to vemurafenib.

[0018] Therefore, nonspecific effects and the inability to target and modulate RAF remain obstacles to the development of effective treatments. Therefore, small molecule therapeutics that effectively target RAF (e.g., effectively inhibit and / or degrade mutant forms of BRaf while sparing wild-type BRaf) and that exploit or enhance the substrate specificity of VHL, human cerebellum, MDM2, and IAP would be very useful. Summary of the Invention

[0019] The present disclosure describes bifunctional compounds and methods of use thereof for recruiting endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, the present disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that are suitable for use as targeted ubiquitination modulators of a variety of polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds as described herein after targeted ubiquitination. The advantages of the compounds provided herein are that a broad spectrum of pharmacological activity can be present consistent with the degradation / inhibition of targeted polypeptides from almost any protein class or family. In addition, the present disclosure provides methods of using an effective amount of a compound as described herein to treat or ameliorate disease conditions (e.g., cancer (e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma), cardiofacial skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD (macula, electrocardiogram abnormalities, wide-set eyes, pulmonary stenosis, genital abnormalities, growth retardation, deafness) syndrome).

[0020] 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 is placed in proximity to the ubiquitin ligase to achieve degradation (and inhibition) of the protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) can be a VHL E3 ubiquitin ligase (VLM) binding moiety, or a human cerebellum 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 depicted as:

[0021]

[0022] The corresponding positions and numbers of PTM and ULM moieties (e.g., VLM, CLM, MLM, or ILM) as shown herein are provided for example only and are not intended to limit the compounds in any way. As will be appreciated by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and position of the various functional moieties can vary as desired.

[0023] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as:

[0024]

[0025] 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, or a VHL-Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a human cerebellum E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM).

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

[0027]

[0028] 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 Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase; CLM is a human cerebellum E3 ubiquitin ligase binding moiety that binds to human cerebellum; MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM is an IAP binding moiety that binds to IAP.

[0029] 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)-).

[0030] In certain embodiments, the compounds as described herein comprise a plurality of independently selected ULMs, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof.

[0031] In certain embodiments, the ILM comprises chemical moieties, such as those described herein.

[0032] In further embodiments, the VLM may be hydroxyproline or a derivative thereof. Additionally, other contemplated VLMs are contained in U.S. Patent Application Publication No. 2014 / 03022523, which, as noted above, is incorporated herein in its entirety.

[0033] 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 phthalimide group or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other contemplated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein in its entirety.

[0034] In certain embodiments, the MLM can be a nutlin or a derivative thereof. Additionally, other contemplated MLMs are included in U.S. patent application Ser. No. 15 / 206,497, filed July 11, 2016, which is incorporated herein in its entirety as described above. In certain additional embodiments, the MLM of the bifunctional compound comprises a chemical moiety such as a substituted imidazoline, a substituted spiro-indolone, 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.

[0035] In further embodiments, the MLM comprises the above core structure, wherein adjacent bisaryl substitutions are positioned in a cis or trans configuration.

[0036] In certain embodiments, "L" is a bond. In other embodiments, the linker "L" is a linker having a linear number of non-hydrogen atoms in the range of 1 to 20. The linker "L" may include, 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 include 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 substitution, single or multiple fluorines may be included.

[0037] 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.

[0038] In certain embodiments, CLM is a derivative of piperidine-2,6-dione, wherein piperidine-2,6-dione may be substituted at the 3-position, and the 3-substitution may be a bicyclic heteroaromatic having a CN bond or a CC bond. Examples of CLM may be, but are not limited to, pomalidomide, lenalidomide, and thalidomide, and derivatives thereof.

[0039] On the other hand, the present 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 protein degradation 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 degraded protein. 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. In yet another aspect, the disclosure provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, the bifunctional compound comprising an ILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and a MLM, preferably connected by a linker moiety, as described elsewhere herein, wherein VLM / ILM / CLM / MLM is coupled to a PTM via a linker to target a protein bound to the PTM for degradation. Similarly, a PTM can be coupled to a VLM or CLM or MLM or ILM via a linker to target a protein or polypeptide for degradation. When a target protein is placed in proximity to an E3 ubiquitin ligase, degradation of the target protein will occur, resulting in degradation / inhibition of the action of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for disease states or conditions that are modulated by the target protein by reducing the level of the protein in the patient's cells.

[0040] In another aspect, the present disclosure provides a method for treating or improving a disease, disorder, or symptom thereof in a subject or patient (e.g., an animal, such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is capable of effectively treating or improving the disease, disorder, or symptom thereof in the subject.

[0041] In another aspect, the present description provides methods of identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0042] The aforementioned general practical areas are given for illustrative purposes only and are not intended to limit the scope of the present disclosure and the appended claims. Based on the claims, description, and examples, one of ordinary skill in the art will understand the additional objects and advantages associated with the compositions, methods, and methods of the present disclosure. For example, various aspects and embodiments of the present disclosure may be utilized in numerous combinations, all of which are explicitly contemplated by this specification. These additional aspects and embodiments are explicitly included within the scope of the present disclosure. Publications and other materials herein that are used to illustrate the background of the present disclosure and to provide additional details about practice in certain circumstances are incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The accompanying drawings are only for the purpose of illustrating the embodiments of the present disclosure and should not be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate exemplary embodiments of the present disclosure, wherein:

[0044] Figure 1A and Figure 1B . Illustration of the general principles of the bifunctional compounds disclosed herein. (A) An exemplary bifunctional compound 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. (B) Functional uses of the bifunctional compounds described herein are illustrated. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein 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 (dark circles) to a lysine on the target protein, with this attachment being achieved via an isopeptide bond. The polyubiquitinated protein is then targeted (far right) for degradation by the cell's proteasome machinery.

[0045] Figure 2A . Table 1A. Exemplary protein targeting moieties and compounds of the present disclosure.

[0046] Figure 2B . Table 1B. Exemplary protein targeting moieties and compounds of the present disclosure.

[0047] Figure 2C . Table 1C. Exemplary protein targeting moieties and compounds of the present disclosure.

[0048] Figure 2D . Table ID. Exemplary protein targeting moieties and compounds of the present disclosure.

[0049] Figure 3A Table 2A. Data for exemplary protein targeting moieties and compounds of the present disclosure.

[0050] Figure 3B .Table 2B. Data for exemplary protein targeting moieties and compounds of the present disclosure.

[0051] Figure 3C .Table 2C. Data for exemplary protein targeting moieties and compounds of the present disclosure.

[0052] Figure 3D .Table 2D. Data for exemplary protein targeting moieties and compounds of the present disclosure.

[0053] Figure 4 . General principle description of the bifunctional compounds disclosed herein.

[0054] Figure 5 Exemplary bifunctional compounds of the present disclosure induce mutant-selective degradation of BRAF.

[0055] Figure 6A 、 6B and 6C. Exemplary bifunctional compounds of the present disclosure induce degradation of mutant BRAF, inhibit cell proliferation, and inhibit MAPK signaling while preserving wild-type BRAF.

[0056] Figure 7 Exemplary bifunctional compounds of the present disclosure induce degradation of vemurafenib-resistant mutant p61.

[0057] Figure 8A and Figure 8B Exemplary bifunctional compounds of the present disclosure induce degradation of mutant BRAF in vivo (a) and reduce tumor volume (B).

[0058] Figure 9A and Figure 9B What mechanism underlies the selectivity of exemplary bifunctional compounds?

[0059] Figure 10 Wild-type BRAF is unable to recruit Cullin 2 (the active E3 ligase). DETAILED DESCRIPTION

[0060] The following is a detailed description provided to help those skilled in the art practice the present disclosure. Those skilled in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0061] The present invention describes compositions and methods that relate to the surprising and unexpected discovery that E3 ubiquitin ligase proteins (e.g., inhibitor of apoptosis protein (IAP), Hippel-Lindau E3 ubiquitin ligase (VHL), human cerebellum E3 ubiquitin ligase, or mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinate target proteins upon proximity to the target protein via a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase targeting moiety ("ULM") coupled to a protein target binding moiety ("PTM") that will cause ubiquitination of a selected target protein, thereby resulting in degradation of the target protein by the proteasome (see Figure 1). The present disclosure also provides libraries of compositions and uses thereof.

[0062] In certain aspects, the present disclosure provides compounds comprising a ligand such as a small molecule ligand (i.e., a molecular weight of less than 2,000, 1,000, 500, or 200 Daltons) that is capable of binding to a ubiquitin ligase such as IAP, VHL, MDM2, or human cerebellum protein. The compound further comprises a portion capable of binding to a target protein in such a way that the target protein is placed near the ubiquitin ligase to achieve degradation (and / or inhibition) of the protein. In addition to the above, a small molecule can also 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.

[0063] Unless defined otherwise, 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 particular embodiments only and are not intended to be limiting of the disclosure.

[0064] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., 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 within the stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges, which may independently be included in smaller ranges, are also encompassed within the disclosure, subject to any specifically excluded limitations in the stated range. Where the stated range includes one or both of the limits, ranges excluding either of these limits are also included in the disclosure.

[0065] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning as applied by persons of ordinary skill in the art in the context of its use in describing the present disclosure.

[0066] 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.

[0067] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" elements so combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open language such as "comprising," may refer to A alone (optionally including elements in addition to B) in one embodiment; to B alone (optionally including elements in addition to A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0068] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating the items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including more than one of a number of elements or a list of elements, and optionally, additionally unlisted items. Only when the contrary term is clearly indicated, such as "only one" or "exactly one", or, when used in the claims, "consisting of..." refers to exactly one element of a number of elements or a list of elements. In general, when preceded by an exclusive term such as "either", "one of", "only one" or "exactly one", as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both").

[0069] 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, "consisting of." Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0070] As used herein in the specification and claims, referring to a list of one or more elements, the phrase "at least one" 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 and every 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 in addition to the elements specifically identified within the list of elements to which the phrase "at least one" refers, elements, whether related or unrelated to those specifically identified, may optionally be present. 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 mean at least one, optionally including more than one A, with no B present (and optionally including elements other than B); in another embodiment, at least one, optionally including more than one B, with no A present (and optionally including elements other than A); in yet another embodiment, at least one, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0071] It should also be understood that in certain methods described herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are recited unless the context dictates otherwise.

[0072] The term "co-administration" or "combination therapy" refers to concurrent administration (administration of two or more therapeutic agents at the same time) and timed administration (administration of one or more therapeutic agents at a different time than administration of other therapeutic agents or agents), as long as the therapeutic agents are present in the patient simultaneously, preferably in effective amounts, to some extent. In certain preferred aspects, one or more compounds of the invention described herein are co-administered in combination with at least one other biologically active agent (especially including anticancer agents). In particularly preferred aspects, co-administration of the compounds produces synergistic and / or therapeutic (including anticancer) activity.

[0073] Unless otherwise indicated, as used herein, the term "compound" refers to any specific compound disclosed herein and includes its 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 prodrug forms). Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0074] In its use in this context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to prodrug forms of the compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds herein, many substituents and variables associated therewith are described, among others. It will be understood by those of ordinary skill 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 within the context of the compounds shown and the well-known rules for valence interaction.

[0075] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins in order to target them for degradation. For example, IAPs are E3 ubiquitin ligase proteins that, alone or in combination with E2 ubiquitin conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins and subsequently target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to target proteins. Typically, ubiquitin ligases involve polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can instead be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0076] The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domesticated animal, to whom treatment, including prophylactic treatment, is provided with a composition according to the present disclosure. For treatment of those infections, conditions, or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domesticated animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. In general, in this disclosure, unless otherwise specified or implied by the context in which the term is used, the term patient refers to a human patient.

[0077] The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0078] Compounds and compositions

[0079] In one aspect, the present disclosure provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM"), which is an IAP E3 ubiquitin ligase binding moiety ("ILM"), a human cerebellum 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 coupled to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure:

[0080] (A)PTM-L-ULM

[0081] Wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of the moieties in the compounds shown herein are provided for example 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.

[0082] 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), cerebellum (i.e., CLM), and VHL (i.e., VLM). In addition, 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 human cerebellum binding moieties.

[0083] 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 an ILM or VLM or CLM or MLM coupled (e.g., covalently, 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 joined or coupled via a chemical linker (L). ILM binds to IAP E3 ubiquitin ligase, VLM binds to VHL, CLM binds to human cerebellum protein E3 ubiquitin ligase, MLM binds to MDM2 E3 ubiquitin ligase, and PTM recognizes the target protein, and the interaction of each portion with its target is beneficial for degrading the target protein by placing the target protein near the ubiquitin ligase protein. Exemplary bifunctional compounds can be depicted as:

[0084] (B) PTM-ILM

[0085] (C) PTM—CLM

[0086] (D) PTM—VLM

[0087] (E) PTM-MLM

[0088] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be depicted as:

[0089] (F) PTM-L-ILM

[0090] (G) PTM—L—CLM

[0091] (H) PTM—L—VLM

[0092] (I) PTM-L-MLM

[0093] 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 human cerebellum protein E3 ubiquitin ligase binding moiety, VLM is the VHL binding moiety, and MLM is the MDM2 E3 ubiquitin ligase binding moiety.

[0094] In certain embodiments, a ULM (eg, ILM, CLM, VLM, or MLM) exhibits activity or an IC of less than about 200 μM. 50 Binds to an E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase, human cerebellum E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase). 50 It can be determined according to any method known in the art, such as fluorescence polarization analysis.

[0095] In certain additional embodiments, the bifunctional compounds described herein exhibit IC 50 An activity of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0096] 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, human cerebellin, and / or MDM2), or a combination thereof. In any aspect or embodiment described herein, the PTMs and ULMs (e.g., ILMs, VLMs, CLMs, and / or MLMs) can be coupled directly or via one or more chemical linkers, or a combination thereof. In further embodiments in which the compound has multiple ULMs, the ULMs can be for the same E3 ubiquitin ligase, or each corresponding ULM can specifically bind to a different E3 ubiquitin ligase. In further embodiments in which the 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.

[0097] In certain embodiments where the compound comprises multiple ULMs, the ULMs are identical. In other embodiments where the compound comprises multiple ULMs (e.g., ULMs, ULM's, etc.), at least one PTM is coupled to the ULM directly, via a chemical linker (L), or both. In certain other embodiments, the compound comprising multiple ULMs also comprises multiple PTMs. In other embodiments, the PTMs are identical or, optionally, different. In other embodiments where the PTMs are different, each PTM may bind to the same protein target or specifically bind to different protein targets.

[0098] In certain embodiments, a compound may comprise multiple ULMs and / or multiple ULMs'. In further embodiments where the compound comprises at least two different ULMs, the multiple ULMs and / or multiple ULMs' further comprise at least one PTM coupled to the ULM or ULM' directly or via a chemical linker, or both. In any embodiment described herein, a compound comprising at least two different ILMs may further comprise multiple PTMs. In further embodiments, the PTMs are the same 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. In further embodiments, the PTM itself is a ULM (or ULM'), such as an ILM, VLM, CLM, MLM, ILM', VLM', CLM', and / or MLM'.

[0099] In further embodiments, the present description provides compounds as described herein, including enantiomers, diastereomers, solvates, and polymorphs thereof, including pharmaceutically acceptable salt forms, such as acid and base salt forms.

[0100] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0101] The term "alkyl" in this context shall mean a straight-chain, branched or cyclic fully saturated hydrocarbon or alkyl group, preferably a C1-C 10 , more preferably C1-C6 or C1-C3 alkyl, it can be optionally substituted.The example of alkyl is especially methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl.In certain embodiments, alkyl is blocked with halogen group (At, Br, Cl, F or I).In certain preferred embodiments, compound according to the present disclosure can be used for being covalently bound to dehalogenase.These compounds generally contain the side chain (usually connected by polyethylene glycol group) of alkyl blocking, and the far end of described alkyl has halogen substituent (usually chlorine or bromine), thereby makes the compound containing this type of part be covalently bound to protein.

[0102] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0103] The term "alkynyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0104] The term "alkylene" when used herein refers to an optionally substituted -(CH2) n-group (n is generally 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), and may be substituted with one or more halo groups (preferably 1 to 3 halo groups) or one or two hydroxyl groups, O-(C1 to C6 alkyl) or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a carbamate or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (a polyethylene glycol chain of 1 to 10, preferably 1 to 6, typically 1 to 4 ethylene glycol units), which is substituted (preferably, but not exclusively, at the distal end of the polyethylene glycol chain); an alkyl chain substituted with a single halo group (preferably a chloro group). In other embodiments, the alkylene (typically 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.

[0105] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A carbon atom range including CO means that the carbon is absent and replaced with H. Thus, a carbon atom range of CO-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for CO, H replaces the carbon.

[0106] The term "substituted" or "optionally substituted" shall independently (i.e., when more than one substituent is present, each substituent is independent of the other substituents) mean one or more substituents (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure, and which may themselves be further substituted) at a carbon (or nitrogen) position anywhere on the molecule within the context, and include hydroxy, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2 or 3 halogens, especially alkyl, especially methyl such as trifluoromethyl), alkyl (preferably C1-C1-C2), ...1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-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 (such that the attachment is on the alkylene, rather than at the ester function, the ester function is preferably substituted with C1-C6 alkyl or aryl), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five or six membered cyclic alkylene amines, also including C1-C6 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) group (which may be optionally further substituted with a polyethylene glycol chain, to which an alkyl group containing a single halogen, preferably chlorine, substituent is further bonded), hydrazine, amido, which is preferably substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl) as substituents. Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, wherein R1 and R2 are each as described elsewhere herein, and 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 (which may be substituted by any one or more of the above substituents) is attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety). As identified above, an alkylene group -(CH2) m -or-(CH2) n-Groups or other chains (e.g., ethylene glycol chains) can be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl, which can be optionally substituted by one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F) or the side chains of amino acids as described elsewhere herein and optionally substituted amides (preferably formamides substituted as described above) or carbamate groups (often with one or two C0-C6 alkyl substituents, which groups can be further substituted). In certain embodiments, the alkylene group (typically a single methylene group) is substituted by one or two optionally substituted C1-C6 alkyls, preferably C1-C4 alkyls, most typically methyl or O-methyl or the side chains of amino acids as described elsewhere herein. In the present disclosure, the moiety in the molecule can be optionally substituted by up to five substituents, preferably up to three substituents. Most often, in the present disclosure, the substituted moiety is substituted by one or two substituents.

[0107] The term "substituted" (each substituent being independent of any other substituent) in the context in which it is used shall also mean C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, formamide, sulfone (including sulfonamide), keto, carboxyl, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, carbamate -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 amines, which may be optionally substituted with one or two hydroxy groups). Within the context, unless otherwise stated, each of these groups contains 1 to 6 carbon atoms. In certain embodiments, preferred substituents will 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 groups), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. Within 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 groups or optionally substituted heterocyclyl groups as described elsewhere herein. As disclosed elsewhere herein, alkylene groups may also be substituted, preferably with optionally substituted C1-C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), the side chain of an amino acid group as described elsewhere herein, an amide group as described above, or a carbamate group OC(O)-NR1R2 group, wherein R1 and R2 are as described elsewhere herein, but many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably not more than 3 substituents, preferably 1 or 2 substituents. It should be noted that in cases where compounds at a particular position of the molecule require substitution (primarily due to valency) but no substitution is indicated, the substituent is interpreted or understood to be H unless the context of the substitution suggests otherwise.

[0108] In this 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 is capable of being bound to the compounds according to the present disclosure at any available stable position on the ring or as otherwise indicated in the presented chemical structure. In this context, other examples of aryl groups may include heterocyclic aromatic ring systems, "heteroaryl" 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, benzofurazane, etc., which may be optionally substituted as described above. Heteroaryl groups that may be mentioned include 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, phenanthidine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanthene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyridazine. pyrimidine; 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, etc., all of which may be optionally substituted.

[0109] The term "substituted aryl" refers to an aromatic carbocyclic group comprising 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 comprise 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 with 1 or 2 hydroxyl or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6alkyl, 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 preferably being substituted with a linker group attached to the PTM group, including a ULM 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 isoxazoles), optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzimidazoles, optionally substituted oxaimidazoles or methyloxaimidazoles, optionally substituted diazolyls including methyldiazolyls, optionally substituted triazolyls, optionally substituted pyridyls including halo- (preferably F) or methyl substituted pyridyls or oxapyridyls (wherein the pyridyl group is attached to the phenyl group through an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3 or 4-azaindolizines), optionally substituted quinolines, and combinations thereof.

[0110] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, however, these general substituents have the same meanings as those defined herein.

[0111] The term "heteroaryl" or "hetaryl" may refer to, but is in no way limited to, optionally substituted quinoline (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2-azaindolizine, 3-azaindolizine or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzofuroxazole, benzothiazolyl ... oxazolidinone, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably substituted with methyl), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted with methyl and / or thiol), 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-pyridine, 3-pyridine or 4-pyridine), or a group conforming to the following chemical structure:

[0112]

[0113] in:

[0114] S c It is CHR SS NR URE or O;

[0115] R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0116] R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);

[0117] R UREis 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 an optionally substituted heterocycle such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0118] Y C Is N or CR YC , where R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl).

[0119] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing an aryl or heteroaryl group, respectively, and an alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring system meeting the above definitions.

[0120] As used herein, the term "aralkyl" refers to an aryl group as defined above attached to an alkyl group as defined above. The aralkyl group is attached to the parent moiety via the alkyl group, wherein the alkyl group has one to six carbon atoms. The aryl group in the aralkyl group may be substituted as defined above.

[0121] The term "heterocycle" refers to a ring radical containing at least one heteroatom (e.g., 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 as described above.

[0122] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl , isothiazolidinyl, isothiazolyl, isoxazolidinyl, 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, oxane, oxetanyl, oxathiolanyl, thiazane and the like.

[0123] The heterocyclic group may be optionally substituted by a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclooxy, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, alkyl substituted with -SO-, -SOaryl, -SO-heteroaryl, -SO2-alkyl, alkyl substituted with -SO2-, -SO2-aryl, oxo (═O), and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidinium, imidazoline, piperidine, piperazine, indoline, N-morpholinyl, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen heterocycles. The term "heterocycle" also includes bicyclic groups in which any one of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, etc.).

[0124] 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, such as 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 with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthiol, aryl, nitro, thiol, or sulfonic acid, and these general substituents have the same meanings as the corresponding groups defined in this legend.

[0125] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group wherein at least one ring carbon atom in 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 in 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 sulfonic acid, and the meanings of these general substituents are the same as those of the corresponding groups defined in this legend.

[0126] The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic, and includes aryl, alkyl, alkenyl and alkynyl groups.

[0127] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0128] The term "lower alkyl" refers to methyl, ethyl or propyl

[0129] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0130] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, and A can be independently covalently coupled to a linker and / or a linker having one or more PTM, ULM, ILM, or ILM' groups attached thereto.

[0131] Exemplary CLM

[0132] New imide compounds

[0133] In one aspect, the present disclosure provides compounds that can be used to bind and / or inhibit human cerebellum protein. In certain embodiments, the compound is selected from the following chemical structures:

[0134]

[0135] in:

[0136] W of formula (a) to (e) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4)] is independently selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl (e.g., optionally substituted 3-6 membered cycloalkyl, optionally substituted cyclopropyl, or optionally substituted cyclobutyl), optionally substituted heterocycloalkyl, and N-alkyl;

[0137] W3 is selected from C or N;

[0138] X of formulae (a) to (e) is independently selected from absent, O, S and CH2;

[0139] Y of formulas (a) to (e) is independently selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0140] Z of formulae (a) to (e) is independently selected from absent, O, S, or CH2, except that X and Z cannot both be absent or cannot both be CH2;

[0141] G and G' of formula (a) to (e) are independently selected from H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", -(CH2) n′ -OP(=O)(OC 1-6 Alkyl)(OH), -(CH2) n′ -OP(=O)(OC 1-6 alkyl)2, -(CH2) n′ -OP(=O)(OH)2、-CH2OCOO(CH2CH2O) n″ CH3, CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0142] n" is an integer from 8 to 35 (e.g., 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, or 35);

[0143] Q1-Q4 of formulae (a) to (e) each independently represents a carbon C substituted by a group independently selected from H, R, N or N-oxide;

[0144] A of formulae (a) to (e) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

[0145] R in formulas (a) to (e) includes, but is not limited to, H, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", halogen, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), unsubstituted or substituted straight or branched chain alkyl (e.g., C1-C6 straight or branched chain alkyl, optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy may be substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 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;

[0146] Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6;

[0147] R′ and R″ of formula (a) to (e) are independently selected from H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, —C(═O)R, optionally substituted heterocyclyl;

[0148] n and n' of formula (a) to formula (e) are each independently an integer of 1-10 (eg, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0149] represents a single bond or a double bond; and

[0150] The bonds of formulae (a) to (e) represent stereospecific ((R) or (S)) or non-stereospecific bonds.

[0151] Exemplary CLM

[0152] In any of the compounds described herein, the CLM comprises a chemical structure selected from:

[0153]

[0154]

[0155] in:

[0156] W of formula (a) to (e) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), and (a4)] is independently selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl (e.g., optionally substituted 3-6 membered cycloalkyl, optionally substituted cyclopropyl, or optionally substituted cyclobutyl), optionally substituted heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), and N-alkyl;

[0157] W3 is selected from C or N;

[0158] X of formulae (a) to (e) is independently selected from absent, O, S and CH2;

[0159] Y of formulas (a) to (e) is independently selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0160] Z of formulae (a) to (e) is independently selected from absent, O, S, and CH2, except that X and Z cannot both be absent or cannot both be CH2;

[0161] G and G' of formula (a) to (e) are independently selected from H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", -(CH2) n′ -OP(=O)(OC 1-6 Alkyl)(OH), -(CH2) n′ -OP(=O)(OC 1-6 alkyl)2, -(CH2) n′ -OP(=O)(OH)2、-CH2OCOO(CH2CH2O) n″ CH3, CH2-heterocyclyl optionally substituted by R' and benzyl optionally substituted by R'; -

[0162] n″ is an integer from 8 to 35 (e.g., 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, or 35);

[0163] Q1-Q4 of formulae (a) to (e) each independently represents a carbon C substituted by a group independently selected from H, R, N or N-oxide;

[0164] A of formulae (a) to (e) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

[0165] R in formulas (a) to (e) includes but is not limited to H, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", halogen, optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), optionally substituted -aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), optionally substituted straight or branched alkyl (e.g., For example, C1-C6 straight or branched chain alkyl, which is optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy or hexyloxy; wherein the alkoxy may be substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 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, wherein at least one R (e.g., O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted substituted C3-C7 heterocyclyl), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), heteroaryl (e.g., C5-C7 heteroaryl), amine, amide, or carboxyl) is modified to be covalently bound to a PTM, a chemical linker group (L), a ULM, a CLM′ (e.g., a CLM′ is an additional CLM having the same or different structure as the first CLM), or a combination thereof.

[0166] Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6;

[0167] R′ and R″ of formula (a) to (e) are independently selected from a bond, H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, —C(═O)R, optionally substituted heterocyclyl;

[0168] n' and n in formula (a) to formula (e) are each independently an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0169] The bonds of formulae (a) to (e) represent stereospecific ((R) or (S)) or non-stereospecific bonds.

[0170] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of:

[0171]

[0172] Formula (g)

[0173] in:

[0174] W of formula (g) is independently selected from CH2, C=O, NH and N-alkyl;

[0175] A of formula (g) is independently selected from H, methyl, alkyl (e.g., a or C1-C6 alkyl (straight chain, branched, optionally substituted));

[0176] R of formula (g) is independently selected from H, OH, NH2, halogen, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), optionally substituted -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), optionally substituted aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl);

[0177] n of formula (g) represents an integer from 1 to 4 (e.g., 1, 2, 3, or 4), wherein at least one R (e.g., at least one of the following: OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl) is modified to be covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM′), or a combination thereof; and

[0178] Formula (g) represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0179] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, and Rn of formulas (a) to (g) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), (a4), and (G)] can be independently covalently coupled to a linker and / or a linker attached to one or more PTM, ULM, CLM, or CLM' groups.

[0180] In any aspect or embodiment described herein, the CLM includes 1 to 4 R groups on Q1, Q2, Q3, Q4, or a combination thereof, wherein each R is an independently selected functional group or atom, e.g., OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, cyano, or carboxyl, and optionally, one of which is modified to be covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM′), or a combination thereof.

[0181] In some embodiments, a CLM is represented by the following structure, where the dashed line indicates the linker attachment point:

[0182]

[0183] More specifically, non-limiting examples of CLMs include those shown below as well as those "hybrid" molecules that arise from a combination of one or more of the different features shown in the molecules below.

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] In any of the compounds described herein, the CLM comprises a chemical structure selected from:

[0195]

[0196]

[0197]

[0198]

[0199] in:

[0200] W is independently selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and N-alkyl;

[0201] Q1, Q2, Q3, Q4, Q5 each independently represent a carbon C or N substituted by a group independently selected from H, R', N or N-oxide;

[0202] R 1 Selected from absent, H, OH, CN, C1-C3 alkyl, C=O;

[0203] R 2 Selected from absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2;

[0204] 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);

[0205] R 4 is selected from H, alkyl, substituted alkyl;

[0206] R 5 and R 6 Each is independently H, halogen, C(=O)R′, CN, OH, CF3;

[0207] X is C, CH, C═O or N;

[0208] X1 is C=O, N, CH or CH2;

[0209] R' is selected from H, OH, halogen, amine, cyano, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., C1-C3 alkoxy), NR 2 R 3 、C(=O)OR 2 , optionally substituted phenyl;

[0210] n is 0-4;

[0211] is a single bond or a double bond; and

[0212] The CLM is covalently bound to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0213] In any aspect or embodiment described herein, CLM or CLM' is substituted via an R group of formula (h) to (ab) (e.g., 1 、R 2 、R 3 、R 4 or R'), W, X, or a Q group (eg, Q1, Q2, Q3, Q4, or Q5) is covalently bonded to a PTM, a chemical linker group (L), ULM, CLM, CLM', or a combination thereof.

[0214] In any of the embodiments described herein, CLM or CLM' is substituted by W, X, R, R 1 、R 2 、R 3 、R 4 、R 5 , R', Q1, Q2, Q3, Q4 and Q5 are covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM' or a combination thereof.

[0215] 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 attached to one or more PTM, ULM, ULM', CLM, or CLM' groups.

[0216] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds that arise from combining one or more of the different features of the following compounds:

[0217]

[0218]

[0219]

[0220] in:

[0221] W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0222] R 1 Selected from absent, H, CH, CN, C1-C3 alkyl;

[0223] R 2 is H or C1-C3 alkyl;

[0224] R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

[0225] R 4 is methyl or ethyl;

[0226] R 5 is H or halogen;

[0227] R 6 is H or halogen;

[0228] The R of CLM is H;

[0229] R' is H or the point of attachment of a PTM, PTM', a chemical linker group (L), a ULM, a CLM, or a CLM',

[0230] Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;

[0231] Is a single bond or a double bond;

[0232] n is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); and

[0233] R includes H, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’R", halogen, optionally substituted heterocyclyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 aryl), optionally substituted straight or branched chain alkyl (e.g., C1-C6 straight or branched chain alkyl, optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy or hexyloxy; wherein the alkoxy may be substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl, optionally substituted 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.

[0234] In any aspect or embodiment described herein, at least one R among Q1, Q2, Q3, Q4, Q5, or a combination thereof (e.g., at least one of the following: OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl) is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM′ (e.g., CLM′ is an additional CLM having the same or different structure as the first CLM), or a combination thereof.

[0235] In any of the embodiments described herein, W, R 1 、R 2 , Q1, Q2, Q3, Q4 and R can be independently covalently coupled to a linker and / or a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0236] In any of the embodiments described herein, R of formula (ac) to (an) 1 、R 2 , Q1, Q2, Q3, Q4R can be independently covalently coupled to a linker and / or a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0237] In any of the embodiments described herein, Q1, Q2, Q3, Q4R of formula (ac) to (an) can be independently covalently coupled to a linker and / or a linker attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0238] In any aspect or embodiment described herein, R of formula (ac) to (an) is modified to be covalently bonded 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.

[0239] In any aspect or embodiment described herein, the CLM is selected from:

[0240]

[0241]

[0242] Where R' is a halogen, and R 1 As described in any aspect or embodiment described herein.

[0243] In some cases, the CLM can be an imide that binds to human cerebellum protein E3 ligase. These imide and linker attachment points can be, but are not limited to, the following structures:

[0244]

[0245] wherein R' is a halogen.

[0246] Exemplary VLM

[0247] In certain embodiments of the compounds described herein, the ULM is a VLM and comprises the chemical structure of ULM-a:

[0248]

[0249] in:

[0250] Dashed lines indicate attachment of at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM' or VLM' or CLM' or ILM' or MLM'), or a chemical linker moiety coupling at least one PTM, ULM' or VLM' or CLM' or ILM' or MLM' to the other end of the linker;

[0251] Formula ULM-a X 1 、X 2 Each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2;

[0252] R of formula ULM-a Y3 、R Y4 are each independently selected from H, optionally substituted linear or branched C 1-6 Alkyl (eg, optionally substituted with one or more halogens), optionally substituted C 1-6 Alkoxy (eg, optionally with 0-3 R P group substitution);

[0253] R of formula ULM-a P is 0, 1, 2 or 3 groups, each independently selected from H, halogen, -OH, C 1-3 Alkyl, C=O;

[0254] W of ULM-a 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-diheteroaryl, optionally substituted -T-heterocycle, optionally substituted -T-diheterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle;

[0255] Formula ULM-a X 3 C=O、R 1 、R 1a 、R 1b ;

[0256] R 1 、R 1a 、R 1b Each is independently selected from H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halo or -OH groups, R Y3 C=O、R Y3 C=S、R Y3 SO, R Y3 SO2、N(R Y3 R Y4 )C=O、N(R Y3 R Y4 )C=S、N(R Y3 R Y4 )SO and N(R Y3 R Y4 )SO2;

[0257] T of formula ULM-a is selected from optionally substituted alkyl, -(CH2) n - group, wherein each of the methylene groups is optionally substituted by one or two groups selected from the group consisting of halogen, methyl, optionally substituted alkoxy, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH),(CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, linear or branched C1-C6, C(O)NR optionally substituted by one or more halogens or OH 1 R 1a or NR 1 R 1a , or R 1 and R 1a joined to form an optionally substituted heterocycle, or an -OH group, or an optionally substituted amino acid side chain;

[0258] each m′ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);

[0259] W of ULM-a 4 is optionally substituted -NR 1 -T-aryl, wherein the aryl group may be optionally substituted with an optionally substituted 5-6 membered heteroaryl, an optionally substituted aryl or an optionally substituted alkoxy, an optionally substituted -NR 1 -T-heteroaryl or optionally substituted-NR1 -T-heterocyclic substitution, wherein -NR 1 With X 2 covalently bonded, and R 1 is H or CH 3 , preferably H; and

[0260] n is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0261] In any of the embodiments described herein, T is selected from optionally substituted alkyl, -(CH2) n - group, wherein each of the methylene groups is optionally substituted by one or two groups selected from the group consisting of halogen, methyl, optionally substituted alkoxy, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH),(CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, 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 join to form an optionally substituted heterocycle, or an -OH group or an optionally substituted amino acid side chain; each m' is independently an integer from 1 to 4 (e.g., 1, 2, 3 or 4), and n is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0262] In any aspect or embodiment described herein, W of Formula ULM-a 4 for

[0263]

[0264] in:

[0265] W 5 is an optionally substituted phenyl, an optionally substituted naphthyl or an optionally substituted 5-10 membered heteroaryl (e.g., W 5(optionally substituted with one or more [e.g. 1, 2, 3, 4 or 5] halo, CN, optionally substituted straight or branched C1-C12 alkyl optionally having one or more (e.g. 1, 2, 3, 4 or more) carbon atoms replaced by oxygen atoms, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy);

[0266] R 14a 、R 14b are each independently selected from H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH),(CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, or an optionally substituted straight or branched chain alkyl group in which one or more carbon atoms are optionally replaced by oxygen;

[0267] each m′ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);

[0268] R 1 is H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halogen or -OH groups;

[0269] W 6 is an optionally substituted 8-14 membered bicyclic heterocycle (e.g., and

[0270] R 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 alkoxy, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

[0271] In any aspect or embodiment described herein, W of Formula ULM-a 5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl (e.g. W 5 (optionally substituted with one or more [e.g. 1, 2, 3, 4 or 5] halo, CN, optionally substituted straight or branched C1-C12 alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy or hydroxy),

[0272] R of formula ULM-a 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

[0273] In the aspects or embodiments described herein, W for use in the present disclosure 4 Substituents also specifically include (and are not limited to the specific compounds disclosed) W 4 Substituents, which are found in the identified compounds disclosed herein. These W 4 Each of the substituents may be combined with any number of W also disclosed herein. 3 Substituents are used in combination.

[0274] In aspects or embodiments described herein, ULM-a is optionally replaced by 0-3 R P Each R P are independently H, halogen, -OH, C1-3 alkyl, or C=O.

[0275] In aspects or 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.

[0276] and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

[0277] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0278]

[0279] in:

[0280] W of ULM-b 3 is selected from optionally substituted aryl, optionally substituted heteroaryl or

[0281] 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;

[0282] R of formula ULM-b 11 is selected from optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0283] R of formula ULM-b 12 is selected from H or optionally substituted alkyl;

[0284] R of formula ULM-b 13 is selected from 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;

[0285] R of formula ULM-b 14a 、R 14b are each independently selected from H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH),(CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2)m’ OH, or an optionally substituted straight or branched chain alkyl group in which one or more carbons are optionally replaced by oxygen;

[0286] R 1 is H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halogen or -OH groups;

[0287] each m′ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);

[0288] W of ULM-b 5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl,

[0289] 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, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

[0290] Each R of the formula ULM-b 16 independently selected from H, CN, halo, optionally substituted alkyl optionally having one or more carbon atoms replaced by oxygen atoms (e.g., optionally substituted by CN or OH), optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

[0291] o of formula ULM-b is 0, 1, 2, 3 or 4;

[0292] R of formula ULM-b 18 are independently selected from H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and

[0293] p of formula ULM-b 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.

[0294] 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.

[0295] In certain embodiments, R of Formula ULM-b 17 Selected from methyl, ethyl, isopropyl and cyclopropyl.

[0296] In certain additional embodiments, R of Formula ULM-b 15 Selected from:

[0297]

[0298] In certain embodiments, R of Formula ULM-b 11 Selected from:

[0299]

[0300]

[0301] In certain embodiments, the ULM has a chemical structure selected from the group consisting of:

[0302]

[0303] in:

[0304] 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;

[0305] R of formula ULM-c, ULM-d and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH,(CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH or cyclopropyl;

[0306] each m′ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);

[0307] R of formula ULM-c, ULM-d and ULM-e 15 is selected from H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;

[0308] X of formula ULM-c, ULM-d and ULM-e is C, CH2 or C=O;

[0309] R3 of formula ULM-c, ULM-d and ULM-e is absent, a bond or an optionally substituted 5- or 6-membered heteroaryl; and

[0310] Therein, the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

[0311] In certain embodiments, the ULM comprises a group according to the following chemical structure:

[0312]

[0313] in:

[0314] R of ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH,(CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH or cyclopropyl;

[0315] each m′ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);

[0316] R9 of formula ULM-f is H;

[0317] R of ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0318] R of ULM-f 11 yes or optionally substituted heteroaryl;

[0319] p of the formula ULM-f is 0, 1, 2, 3 or 4;

[0320] Each R of the formula ULM-f 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;

[0321] R of ULM-f 12 It is H, C=O;

[0322] 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,

[0323] R of ULM-f 15 is selected from H, halogen, Cl, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted cycloheteroalkyl;

[0324]

[0325] The dashed lines of formula ULM-f indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

[0326] In certain embodiments, the ULM is selected from the following structures:

[0327]

[0328]

[0329] where n is 0 or 1.

[0330] In certain embodiments, the ULM is selected from the following structures:

[0331]

[0332]

[0333]

[0334]

[0335] 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 lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to ULM-a.

[0336] 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 so that they become part of a prodrug.

[0337] In certain embodiments, the hydroxyl group on the pyrrolidine ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9, respectively, comprises an ester-linked prodrug moiety.

[0338] In any aspect or embodiment described herein, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0339]

[0340] in:

[0341] 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) n -WCOCW-(C0-C6)alkyl containing an epoxide moiety WCOCW, 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) nOC(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) n NHC(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);

[0342] 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);

[0343] ULM-g R S is C1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclic group or -(CH2) M NR1R2 group;

[0344] 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);

[0345] 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 -(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 -XR2′ -heterocyclic group; optionally substituted;

[0346] 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’ -heterocyclyl, 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’ -heterocyclyl, optionally substituted -X R3’ -alkyl; optionally substituted -X R3′ -aryl; optionally substituted -X R3′ -heteroaryl; optionally substituted -X R3′ -heterocyclic group; optionally substituted;

[0347] 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 group;

[0348] V of ULM-g is O, S or NR1;

[0349] R1 of ULM-g is the same as above;

[0350] ULM-g R 1 and R 1′ Each independently is H or C1-C3 alkyl;

[0351] ULM-gXR2’ and X R3’ each independently 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 X v is H, halogen or optionally substituted C1-C3 alkyl;

[0352] Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0353] Each m′ of ULM-g is independently 0 or 1;

[0354] Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0355] Each n′ of ULM-g is independently 0 or 1;

[0356] Each u of ULM-g is independently 0 or 1;

[0357] Each v of ULM-g is independently 0 or 1;

[0358] Each w of ULM-g is independently 0 or 1; and

[0359] 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 bound to the PTM group through a linker group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of X, X and X' are optionally modified to be covalently bound to each other directly or through a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0360] In any aspect or embodiment described herein, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0361]

[0362] in:

[0363] ULM-h R 1’ ,R 2’and R 3 Each of ' 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

[0364] When the PTM is not ULM', the R of ULM-h 1’ 、R 2’ and R 3’ Any one or more of is optionally modified to incorporate a linker group that further covalently binds to the PTM group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of are optionally modified to be covalently bound to each other directly or through a linker group, or

[0365] or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0366] In any aspect or embodiment described herein, the ULM and any ULM' present are each independently according to the chemical structure:

[0367]

[0368] in:

[0369] 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 incorporate a linker group that further covalently binds to the PTM group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of are optionally modified to be covalently bound to each other directly or through a linker group, or

[0370] or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0371] In other aspects of the present invention, 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) nH, 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. 1’ When it is or contains a carboxylic acid group, the hydroxyl or amine group, hydroxyl group, carboxylic acid group or amine group (each of which may be optionally substituted) may be further chemically modified to provide a covalent linker group to which the PTM group (including the ULM) is bonded;

[0372] 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;

[0373] R from ULM-g to ULM-i 2’ Preferably, optionally substituted -NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocyclic ring, wherein R 1 is H or CH3, preferably H and T are optionally substituted -(CH2) n - group, wherein each of the methylene groups may be optionally substituted with 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 to 6 (e.g., 0, 1, 2, or 3, such as 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.

[0374] 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 optionally linked to the PTM group via a linker group attached to the PTM group (including the ULM' group), a halogen (preferably F or Cl), an amine, a mono- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, a C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or a CN group (each of which may be at the ortho, meta, and tertiary positions of the phenyl ring). substituted in the ortho, meta and / or para position of the phenyl ring, preferably in the para position), optionally substituted phenyl (the phenyl group itself is optionally linked to the PTM via a linker group, including a ULM' group) and / or at least one of a F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN group (in the ortho, meta and / or para position of the phenyl ring, preferably in the para position), optionally substituted naphthyl, optionally substituted heteroaryl, preferably optionally substituted isoxazole (including isoxazole substituted by methyl), optionally substituted optionally substituted oxazole (including oxazole substituted with methyl), optionally substituted thiazole (including thiazole substituted with methyl), optionally substituted isothiazole (including isothiazole substituted with methyl), optionally substituted pyrrole (including pyrrole substituted with methyl), optionally substituted imidazole (including methylimidazole), optionally substituted benzimidazole or methoxybenzimidazole, optionally substituted oxaimidazole or methyloxaimidazole, optionally substituted diazole group (including methyldiazole group), optionally substituted triazole group (including substituted with methyl), an optionally substituted pyridine group (including a pyridine group or an oxapyridine group substituted with a halo (preferably F) or methyl group, wherein the pyridine group is attached to the phenyl group through an oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2-azaindolizine, 3-azaindolizine or 4-azaindolizine), an optionally substituted quinoline, an optionally substituted group according to the following chemical structure:

[0375]

[0376] in:

[0377] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0378] R from ULM-g to ULM-i HETis H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0379] 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);

[0380] 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 groups, preferably fluoro groups, or optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocycle, preferably for example piperidine, morpholine, pyrrolidine, tetrahydrofuran);

[0381] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0382] 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

[0383] 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 (when substituted, each of said groups is preferably substituted with methyl or halogen (F, Br, Cl), each of which may be optionally linked to a PTM group (including a ULM' group) via a linker group).

[0384] In certain preferred aspects, ULM-g to ULM-i

[0385] Group,

[0386] Among them, R PRO and n are the same as above.

[0387] About R of 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 oxamidazole, or a group according to the following chemical structure:

[0388]

[0389] in:

[0390] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0391] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R of ULM-g to ULM-i a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0392] 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);

[0393] 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 groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0394] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halo groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl), each of which may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0395] R from ULM-g to ULM-i 2’ Preferred heterocyclic groups include tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiazane, each of which may be optionally substituted, or a group according to the following chemical structure:

[0396]

[0397] Preferably, Group,

[0398] in:

[0399] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl;

[0400] 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

[0401] 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 may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0402] 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 found in the identified compounds disclosed herein (including specific compounds disclosed in this specification and the accompanying drawings). These R 2′ Each of the substituents may be combined with any number of R 3′ Substituents are used in combination.

[0403] R from ULM-g to ULM-i 3’ Preferably, it is optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle. In a preferred embodiment, R 1 is H or C1-C3 alkyl, preferably H or CH3, T is optionally substituted -(CH2) n - group, wherein each of the methylene groups may be optionally substituted by one or two substituents, preferably selected from halogen, 1-C6 alkyl (straight chain, branched, optionally substituted) or the side chain of an amino acid as described elsewhere herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, for example 0, 1, 2 or 3 (such as 0 or 1). Alternatively, T may also be -(CH2O) n -group, -(OCH2) n -group, -(CH2CH2O) n -group, -(OCH2CH2) n - groups, each of which is optionally substituted.

[0404] R from ULM-g to ULM-i 3’Preferred aryl groups include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is optionally linked to the PTM group (including the ULM' group) via a linker group and / or substituted by halogen (preferably F or Cl), amine, mono- or di-alkylamine (preferably dimethylamine), amide (preferably -(CH2) m -NR1C(O)R2 group, wherein m, R1 and R2 are the same as above), halo (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 group or -(CH2) m NR1R2 groups, each of which may be substituted in the ortho, meta and / or para positions of the phenyl ring, preferably the para position), 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 a linker group to which a F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN or a PTM group (including a ULM' group) is attached, wherein the substitution occurs in the ortho, meta and / or para positions of the phenyl ring, preferably the para position), optionally substituted groups include naphthyl as described above, optionally substituted heteroaryl groups (preferably optionally substituted isoxazole including methyl substituted isoxazole, optionally substituted oxazole including methyl substituted oxazole, optionally substituted thiazole including methyl substituted thiazole, optionally substituted Substituted pyrroles include methyl-substituted pyrroles, optionally substituted imidazoles include methylimidazole, benzylimidazole or methoxybenzylimidazole, oxaimidazole or methyloxaimidazole, optionally substituted diazolyl includes methyldiazolyl, optionally substituted triazolyl includes methyl-substituted triazolyl, pyridyl includes halogen- (preferably F) or methyl-substituted pyridyl or oxapyridyl (wherein the pyridine group is linked to the phenyl group through oxygen) or optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or thiazane. Each of the aryl, heteroaryl or heterocyclic groups can be optionally linked to the PTM group (including the ULM' group) via a linker group.

[0405] 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 substituted with methyl), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted with methyl and / or thiol), optionally substituted isothiazole, optionally substituted triazole (preferably substituted with 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-pyridine, 3-pyridine or 4-pyridine) or a group according to the following chemical structure:

[0406]

[0407] in:

[0408] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0409] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0410] 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);

[0411] R from ULM-g to ULM-iURE 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 groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0412] 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 by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -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 to a PTM group (including a ULM' group) via a linker group.

[0413] R from ULM-g to ULM-i 3’ Preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane and thiazane, each of which may be optionally substituted, or a group according to the following chemical structure:

[0414] Preferably, Group,

[0415] in:

[0416] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0417] 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

[0418] Each n in ULM-g to ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), wherein each of the heterocyclic groups may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0419] 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 found in the identified compounds disclosed herein (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.

[0420] In certain alternative preferred embodiments, 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-heteroaryl,

[0421] in:

[0422] R1 of ULM-g to ULM-i is H or C1-C3 alkyl (preferably H);

[0423] 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

[0424] 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;

[0425] The alkyl groups of ULM-g to ULM-i are optionally substituted C1-C 10 an alkyl (preferably a C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen group (typically Cl or Br));

[0426] Aryl of ULM-g to ULM-i is optionally substituted phenyl or naphthyl (preferably phenyl); and

[0427] HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably substituted by 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:

[0428]

[0429] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0430] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0431] 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);

[0432] 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 groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0433] 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 by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0434] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0435] 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

[0436] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1).

[0437] Each of these groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

[0438] In certain alternative 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 -XR3′ -HET group, optionally substituted -X R3′ -aryl-HET group or optionally substituted -X R3′ -HET-aryl,

[0439] in:

[0440] R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), optionally substituted aryl or HET group;

[0441] R 1’ is H or C1-C3 alkyl (preferably H);

[0442] V is O, S, or NR 1’ ;

[0443] 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;

[0444] X v is H, halogen or C1-C3 alkyl optionally substituted by one or two hydroxyl groups or up to three halogen groups;

[0445] Alkyl is an optionally substituted C1-C 10 an alkyl (preferably a C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen group (typically Cl or Br));

[0446] Aryl is optionally substituted phenyl or naphthyl (preferably phenyl); and

[0447] HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, 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:

[0448]

[0449] S for ULM-g to ULM-i c It is CHRSS NR URE or O;

[0450] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0451] 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);

[0452] 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 optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0453] 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 by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0454] R from ULM-g to ULM-i PROis H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0455] 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;

[0456] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

[0457] Each m' of ULM-g to ULM-i is 0 or 1; and

[0458] Each n' of ULM-g to ULM-i is 0 or 1;

[0459] Each of the compounds is preferably linked to a PTM group (including a ULM' group) via a linker group, preferably on an alkyl, aryl or Het group.

[0460] In an alternative embodiment, R of ULM-g to ULM-i 3 'Yes-(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET or -(CH2CH2O) n -HET,

[0461] in:

[0462] 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-C6alkyl)amine, wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, or

[0463] 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 with 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, CN, NO2, optionally substituted -(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

[0464] The aryl groups of ULM-g to ULM-i are optionally substituted with heterocycles, including heteroaryls selected from oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each preferably substituted with C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), or a group according to the following chemical structure:

[0465]

[0466] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0467] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where Ra is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0468] 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);

[0469] 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 optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0470] 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 by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0471] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or halo, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0472] 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;

[0473] HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, 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:

[0474]

[0475] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0476] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0477] 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);

[0478] 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 optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0479] 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 by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0480] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl;

[0481] 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;

[0482] Each m' of ULM-g to ULM-i is independently 0 or 1; and

[0483] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

[0484] Each of the compounds is preferably linked to a PTM group (including a ULM' group) on the alkyl or HET group, optionally via a linker group.

[0485] In further embodiments, preferred compounds include compounds according to the following chemical structure:

[0486]

[0487] in:

[0488] ULM-i R 1’ is OH or a group that metabolizes or undergoes OH in the patient;

[0489] ULM-i R 2′ is -NH-CH2-aryl-HET (preferably a phenyl group directly attached to a methyl-substituted thiazole);

[0490] ULM-i R 3’ Yes-CHR CR3’ -NH-C(O)-R 3P1 Group or -CHR CR3’ -R 3P2 group;

[0491] ULM-i R CR3’is C1-C4 alkyl, preferably methyl, isopropyl or tert-butyl;

[0492] ULM-i R 3P1 is a C1-C3 alkyl group (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted, -(CH2) n OCH3 group, wherein n is 1 or 2 (preferably 2), or groups (the ethyl ether group is preferably substituted on the phenyl portion), morpholino groups (attached to the carbonyl group at the 2- or 3-position;

[0493] ULM-i R 3P2 yes group;

[0494] The aryl group of ULM-i is phenyl;

[0495] HET of ULM-i is an optionally substituted thiazole or isothiazole; and

[0496] ULM-i R HET is H or a halogen group (preferably H);

[0497] 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.

[0498] In certain aspects, the bifunctional compound comprises a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[0499]

[0500] in:

[0501] each R5 and R6 of ULM-j is independently OH, SH or an optionally substituted alkyl group, or R5, R6 and the carbon atom to which they are attached form a carbonyl group;

[0502] R7 of ULM-j is H or optionally substituted alkyl;

[0503] E of ULM-j is a bond, C=O, or C=S;

[0504] G of ULM-j is a bond, optionally substituted alkyl, -COOH, or C=J;

[0505] The J of ULM-j is O or N-R8;

[0506] R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

[0507] M of ULM-j is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group or

[0508] Each R9 and R of ULM-j 10 are independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[0509] ULM-j R 11 is an optionally substituted heterocycle, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl or, or

[0510] ULM-j R 12 is H or optionally substituted alkyl;

[0511] 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,

[0512] Each R of ULM-j 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;

[0513] ULM-j R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;

[0514] Each R of ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;

[0515] Each R of ULM-j 25 are independently H or optionally substituted alkyl; or two R 25 The groups may be taken together to form oxo or optionally substituted cycloalkyl;

[0516] ULM-j R 23 is H or OH;

[0517] Z1, Z2, Z3 and Z4 of ULM-j are independently C or N; and

[0518] o of ULM-j is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0519] 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.

[0520] 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

[0521] In certain embodiments, wherein E of ULM-j is C=O, R 11 is an optionally substituted heterocycle or And M is

[0522] In certain embodiments, wherein E of ULM-j is C=O and M is And R 11 yes Each R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0523] In certain embodiments, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0524]

[0525] in:

[0526] The G of ULM-k is C=J, and J is O;

[0527] R7 of ULM-k is H;

[0528] Each R of ULM-k 14 It is H;

[0529] The o of ULM-k is 0;

[0530] R of ULM-k 15 yes and

[0531] R of ULM-k 17 is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[0532] In other cases, the R of ULM-k 17 is an alkyl group (eg, methyl) or a cycloalkyl group (eg, cyclopropyl).

[0533] In other embodiments, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0534]

[0535] in:

[0536] The G of ULM-k is C=J, and J is O;

[0537] R7 of ULM-k is H;

[0538] Each R of ULM-k 14 It is H;

[0539] o of ULM-k is 0; and

[0540] R of ULM-k 15 Selected from:

[0541]

[0542] The R of ULM-k 30 is H or optionally substituted alkyl.

[0543] In other embodiments, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0544]

[0545] in:

[0546] The E of ULM-k is C=O;

[0547] The M of ULM-k is and

[0548] R of ULM-k 11 Selected from:

[0549]

[0550] In yet other embodiments, the compound has the chemical structure,

[0551] Wherein E of ULM-k is C=O;

[0552] R of ULM-k 11 yes and

[0553] The M of ULM-k is

[0554] ULM-k's q is 1 or 2;

[0555] R of ULM-k 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or

[0556] R of ULM-k 21 is H or optionally substituted alkyl; and

[0557] R of ULM-k 22 is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[0558] In any of the embodiments described herein, R of ULM-j or ULM-k 11 Selected from:

[0559]

[0560]

[0561] In certain embodiments, R of ULM-j or ULM-k 11 Selected from:

[0562]

[0563]

[0564] In certain embodiments, the ULM (or ULM' where present) is a group according to the following chemical structure:

[0565]

[0566] in:

[0567] X of ULM-l is O or S;

[0568] Y of ULM-1 is H, methyl or ethyl;

[0569] ULM-1 R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

[0570] M of ULM-1 is an optionally substituted aryl group, an optionally substituted heteroaryl group or

[0571] R9 of ULM-l is H;

[0572] ULM-1 R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl;

[0573] R11 of ULM-1 is optionally substituted heteroaromatic, optionally substituted heterocyclic, optionally substituted aryl or;

[0574] ULM-1 R 12 is H or optionally substituted alkyl; and

[0575] ULM-1 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.

[0576] In some embodiments, ULM and any ULM' present are each independently a group according to the following chemical structure:

[0577]

[0578] in:

[0579] Y of ULM-m is H, methyl or ethyl;

[0580] R9 of ULM-m is H;

[0581] R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;

[0582] ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle.

[0583] In other embodiments of the present disclosure, the ULM and any ULM' present are each independently a group according to the following chemical structure:

[0584]

[0585] ULM-n

[0586] in:

[0587] ULM-nR 17 is methyl, ethyl or cyclopropyl; and

[0588] ULM-n R9, R10 and R 11 As defined above. In other cases, R9 is H; and

[0589] ULM-nR 10 is H, alkyl or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[0590] In any aspect or embodiment described herein, the ULM as described herein (or ULM' as present) can be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. In addition, in any aspect or embodiment described herein, the ULM as described herein (or ULM' as present) can be directly coupled to the PTM via a bond or chemical linker.

[0591] In certain aspects of the present disclosure, the ULM moiety is selected from:

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615] Wherein the VLM can be linked to the PTM via a linker as described herein at any suitable position, including, for example, an aryl, heteroaryl, phenyl or phenyl group of an indole group, optionally via any suitable functional group, such as an amine, ester, ether, alkyl or alkoxy group.

[0616] Exemplary ILM

[0617] AVPI tetrapeptide fragment

[0618] 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 chemical structures represented by formula (I), (II), (III), (IV), and (V):

[0619]

[0620]

[0621] in:

[0622] R of formula (I), (II), (III), (IV) and (V) 1 Selected from H or alkyl;

[0623] R of formula (I), (II), (III), (IV) and (V) 2 Selected from H or alkyl;

[0624] R of formula (I), (II), (III), (IV) and (V) 3 is selected from H, alkyl, cycloalkyl and heterocycloalkyl;

[0625] 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 taken together to form a pyrrolidine or piperidine ring, which is further optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which may then be further fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;

[0626] R of formula (I), (II), (III), (IV) and (V) 3 and R 5 taken together to form a 5-8 membered ring, which is further optionally fused to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;

[0627] R of formula (I), (II), (III), (IV) and (V) 7 Selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C(O)-R 4 , aralkyl, heteroaryl, heteroaryl-C(O)-R 4 , heteroaryl-R 4 , heteroaryl-naphthalene, heteroarylalkyl or C(O)NH-R 4 , each further optionally substituted by 1-3 groups selected from halogen, alkyl, haloalkyl, hydroxy, alkoxy, cyano, (hetero)cycloalkyl, (hetero)aryl, -C(O)NH-R 4 or -C(O)-R 4 substituted with a substituent; and

[0628] R 4 Selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, and further optionally substituted by 1-3 substituents as described above.

[0629] As shown above, P1, P2, P3 and P4 of formula (II) are related to A, V, P and I of the AVPI tetrapeptide fragment or its non-natural mimetic, respectively. 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.

[0630] 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:

[0631]

[0632] in:

[0633] R1 of formula (VI) is independently selected from H, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 1O -cycloalkyl;

[0634] R2 of formula (VI) is independently selected from H, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl or C3-C 1O -cycloalkyl;

[0635] 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;

[0636] Each Z of formula (VI) is independently selected from H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F or -CH2OH;

[0637] R4 of formula (VI) is independently selected from C1-C 16 Straight or branched alkyl, C1-C 16 -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;

[0638] 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;

[0639] 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 -cycloalkynyl, -OC(O)-(CH2) 0-6 -phenyl, -OC(O)-(CH2) 1-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;

[0640] het of formula (VI) is independently selected from a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system comprising 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;

[0641] R of formula (VI) 10 Selected from H, -CH3, -CF3, -CH2OH or -CH2Cl;

[0642] 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 R11 and R 12 Together with nitrogen, it forms het, and

[0643] As shown in formula (VII), U of formula (VI) is independently:

[0644]

[0645] in:

[0646] Each n in formula (VII) is independently selected from 0 to 5;

[0647] X of formula (VII) is selected from -CH and N;

[0648] 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 substituted with a heteroatom selected from O, S or N, and wherein each alkyl group is independently unsubstituted or substituted;

[0649] R of formula (VII) d Selected from Re-Q-(R f ) P (R g ) q and Ar1-D-Ar2;

[0650] 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;

[0651] p and q of formula (VII) are independently selected from 0 or 1;

[0652] R of formula (VII) e Selected from C 1-8 -alkyl and alkylidene, and each ring is unsubstituted or substituted;

[0653] Q is selected from N, O, S, S(O) and S(O)2;

[0654] Ar1 and Ar2 of formula (VII) are independently selected from substituted or unsubstituted aryl and het;

[0655] R of formula (VII) f and R g Compounds are independently selected from H, -C1-10-alkyl, C 1-10-Alkaryl, -OH, -OC 1-10 -alkyl, -(CH2) 0-6 -C 3-7 -cycloalkyl, -O-(CH2) 0-6 -aryl, phenyl, aryl, phenyl-phenyl, -(CH2) 1-6 -het、-O-(CH2) 1-6 -het、-OR 13 、-C(0)-R 13 、-C(O)-N(R 13 )(R 14 )、-N(R 13 )(R 14 ),-SR 13 、-S(O)-R 13 、-S(O)2-R 13 、-S(O)2-NR 13 R 14 、-NR 13 -S(O)2-R 14 、-SC t-10 -alkyl, aryl-C 1-4 -alkyl or het-C 1-4 -alkyl, wherein alkyl, cycloalkyl, het and aryl are unsubstituted or substituted, -SO2-C 1-2 -alkyl, -SO2-C 1-2 -alkylphenyl, -OC 1-4 -alkyl, or any R g and R f together forming a ring selected from het or aryl;

[0656] 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-dioxane or C 1-7 -alkyl-OH; wherein alkyl, alkylene or arylene is unsubstituted or substituted with 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 );

[0657] 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);

[0658] R6, R7R8 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 R6, R7, R8 and R9 are optionally taken together to form a ring system;

[0659] 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;

[0660] wherein R of formula (VII) 13 and R 14 The alkyl substituents are unsubstituted or substituted and, when substituted, are selected from C 1-10 -alkyl, halogen, OH, -OC 1-6 -alkyl, -SC 1-6 -alkyl and one or more substituents of -CF3; and R 13 and R 14 The substituted phenyl or aryl groups are replaced by one or more 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 is substituted by a substituent; or a pharmaceutically acceptable salt or hydrate thereof.

[0661] 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:

[0662]

[0663] wherein each of A1 and A2 of formula (VIII) is independently selected from optionally substituted monocyclic fused rings, aryl and heteroaryl; and

[0664] R of formula (VIII) is selected from H or Me.

[0665] In one 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).

[0666] In a specific embodiment, the ILM is selected from

[0667]

[0668] In any of the compounds described herein, the ILM may have a 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:

[0669]

[0670] where R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl, most preferably selected from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, and R of formula (IX) 2 Selected from -OPh or H.

[0671] 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:

[0672]

[0673] in:

[0674] R in formula (X) 1 Selected from H, -CH2OH, --CH2CH2OH, --CH2NH2, , --CH2CH2NH2;

[0675] X of formula (X) is selected from S or CH2;

[0676] R in formula (X)2 Selected from:

[0677]

[0678] R in formula (X) 3 and R 4 Independently selected from H or Me

[0679] 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:

[0680]

[0681] wherein R in formula (XI) 1 is selected from H or Me, and R of formula (XI) 2 Select H or

[0682]

[0683] In any of the compounds described herein, the ILM may have a 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:

[0684]

[0685] in:

[0686] R in formula (XII) 1 Selected from:

[0687]

[0688] and

[0689] R in formula (XII) 2 Selected from:

[0690]

[0691] In any of the compounds described herein, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0692]

[0693] In any of the compounds described herein, the ILM may have the structure of Formula (XIII), which is based on the IAP ligands summarized in Flygare, JA et al., Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010), or non-natural mimetics thereof:

[0694]

[0695] in:

[0696] Z of formula (XIII) is absent or is O;

[0697] R in formula (XIII) 1 Selected from:

[0698]

[0699] R 10 is selected from H, alkyl or aryl;

[0700] X is selected from CH2 and O; and

[0701] It is a nitrogen-containing heteroaryl group.

[0702] In any of the compounds described herein, the ILM may have the structure of Formula (XIV), which is based on the IAP ligands summarized in Flygare, JA et al., Small-molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20(2), 251-67 (2010), or non-natural mimetics thereof:

[0703]

[0704] in:

[0705] Z of formula (XIV) is absent or O;

[0706] R in formula (XIV) 3 and R 4 independently selected from H or Me;

[0707] R in formula (XIV) 1 Selected from:

[0708]

[0709] R 10 is selected from H, alkyl or aryl;

[0710] X is selected from CH2 and O; and

[0711] It is a nitrogen-containing heteroaryl group.

[0712] In any of the compounds described herein, the ILM is selected from:

[0713]

[0714] They are derivatives of the ligands disclosed in US Patent Publication No. 2008 / 0269140 and US Patent No. 7,244,851.

[0715] 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:

[0716]

[0717] in:

[0718] Z of formula (XV) is absent or O;

[0719] R in formula (XV) 1 Selected from:

[0720]

[0721] R 10 is selected from H, alkyl or aryl;

[0722] X is selected from CH2 and O; and

[0723] is a nitrogen-containing heteroaryl group; and

[0724] R 2 Formula (XV) is selected from H, alkyl or acyl;

[0725] In one embodiment, the ILM has the following structure:

[0726]

[0727] 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:

[0728]

[0729] in:

[0730] 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;

[0731] Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl group; more preferably a 5-membered nitrogen-containing heteroaryl group, and most preferably thiazole; and

[0732] Ar of formula (XVI) is an aryl group or a heteroaryl group.

[0733] 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 thiazole amideisosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or a non-natural mimetic thereof:

[0734]

[0735] in:

[0736] R of formula (XVII) 1 Selected from Te group halogen (such as fluorine), cyano,

[0737] X of formula (XVII) is selected from O or CH2.

[0738] 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 amideisosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or a non-natural mimetic thereof:

[0739]

[0740] wherein R of formula (XVIII) is selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl or halogen (in variable substitution positions).

[0741] 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 thiazole amideisosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or a non-natural mimetic thereof:

[0742]

[0743] in It is a 6-membered nitrogen heteroaryl.

[0744] In a certain embodiment, the ILM of the composition is selected from:

[0745] In certain embodiments, the ILM of the composition is selected from:

[0746]

[0747] 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:

[0748]

[0749] wherein X of formula (XX) is selected from CH2, O, NH or S.

[0750] 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:

[0751]

[0752] in:

[0753] R in formula (XXI) 2 Selected from:

[0754] R in formula (XXI)5 Selected from: and

[0755] W of formula (XXI) is selected from CH or N; and

[0756] R 6 is independently a monocyclic or bicyclic fused aryl or heteroaryl group.

[0757] In certain embodiments, the ILM of the compound is selected from:

[0758]

[0759] In any of the compounds described herein, the ILM may have a structure of Formula (XXII) or (XXIV), which are derived from IAP ligands 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 non-natural mimetics thereof, and the chemical linker of the linker group L is as shown:

[0760]

[0761] in:

[0762] R of formula (XXII), (XXIII) or (XXIV) 1 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl or optionally substituted aryl;

[0763] R of formula (XXII), (XXIII) or (XXIV) 2 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl or optionally substituted aryl;

[0764] Or alternatively,

[0765] R of formula (XXII), (XXIII) or (XXIV) 1 and R 2are independently selected from optionally substituted thioalkyl, wherein the substituent attached to the S atom of the thioalkyl is optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2) v COR 20 、-CH2CHR 21 COR 22 or -CH2R 23 ,

[0766] in:

[0767] v is an integer from 1 to 3;

[0768] -(CH2) v COR 20 and -CH2R 23 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0769] -CH2CHR 21 COR 2 R 21 Selected from NR 24 R 25 ;

[0770] -CH2R 23的 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0771] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0772] NR 24 R 25 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted aralkyl, optionally substituted heterocyclic group, -CH2(OCH2CH2O) m CH3, or a polyamine chain such as spermine or spermidine;

[0773] OR 26 R 26 is selected from optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2; and

[0774] m is an integer from 1 to 8;

[0775] R of formula (XXII), (XXIII) or (XXIV)3 and R 4 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroaralkyl, or optionally substituted heterocycloalkyl, wherein the substituent is alkyl, halogen, or OH;

[0776] R of formula (XXII), (XXIII) or (XXIV) 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.

[0777] In a specific embodiment, the ILM according to formula (XXII) to (XXIV):

[0778] R 7 and R 8 selected from H or Me;

[0779] R 5 and R 6 Selected from:

[0780]

[0781] R 3 and R 4 Selected from:

[0782]

[0783] In any of the compounds described herein, the ILM may have a structure of Formula (XXV), (XXVI), (XXVII), or (XXVIII), which are derived from the IAP ligands 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 non-natural mimetics thereof, and the chemical linker of the linker group L is as shown:

[0784]

[0785] in:

[0786] R of formula (XXV) to (XXVIII) 2is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl or optionally substituted aryl;

[0787] or alternatively;

[0788] R of formula (XXV) and (XXVIII) 1 and R 2 independently selected from H, optionally substituted thioalkyl-CR 60 R 61 SR 70 , where R 60 and R 61 is 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 ;

[0789] in:

[0790] v is an integer from 1 to 3;

[0791] -(CH2) v COR 20 and -CH2CHR 21 COR 22 R 20 and R 22 Independently selected from OH, NR 24 R 25 OR 26 ;

[0792] -CH2CHR 21 COR 22的R21 Selected from NR 24 R 25 ;

[0793] -CH2R 23 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein optional substituents include alkyl and halogen;

[0794] NR 24 R 25 R 24 is selected from hydrogen or optionally substituted alkyl;

[0795] NR 24 R 25 R 25is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted aralkyl, optionally substituted heterocyclic group, -CH2CH2(OCH2CH2) m CH3, or polyamine chain -[CH2CH2(CH2)NH]CH2CH2(CH2) r NH2, such as spermine or spermidine,

[0796] Where =0-2, =1-3, =0-2;

[0797] OR 26 R 26 is optionally substituted alkyl, wherein the optional substituent is OH, halogen or NH2;

[0798] m is an integer from 1 to 8;

[0799] R of formula (XXV) to (XXVIII) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; and

[0800] R of formula (XXV) to (XXVIII) 31 is selected from optionally further substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably selected from:

[0801]

[0802] In any of the compounds described herein, the ILM may have a structure of Formula (XXIX) or (XXX), which are derived from an IAP ligand described in WO Publication No. 2013 / 071039, or a non-natural mimetic thereof:

[0803]

[0804] in:

[0805] R of formula (XXIX) and (XXX) 43 and R 44 are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, further optionally substituted cycloalkylalkyl, and

[0806] R of formula (XXIX) and (XXX) 6 and R 8 are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl.

[0807] Each X of formula (XXIX) and (XXX) is independently selected from:

[0808]

[0809]

[0810] Each Z of formula (XXIX) and (XXX) is selected from Each of these represents the point of attachment to the compound; and

[0811] Each Y is selected from:

[0812]

[0813]

[0814] in:

[0815] represents the point of attachment to the -C=O portion of the compound;

[0816] represents the point of attachment to the amino portion of the compound;

[0817] represents the first point of attachment to Z;

[0818] represents the second point of attachment to Z; and

[0819] A is selected from -C(O)R 3 or

[0820] or a tautomeric form of any of the foregoing, wherein:

[0821] -C(O)R 3 R 3 Selected from OH, NHCN, NHS02R 10 NHOR 11 or N(R 12 )(R 13 );

[0822] NHSO2R 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;

[0823] N(R 12 )(R 13 ) of R 12 and R 13 Each of which is independently selected from hydrogen, -C 11-C4 alkyl, -(C1-C4 alkylene)-NH-(C1-C4 alkyl), benzyl, -(C1-C4 alkylene)-C(O)OH,

[0824] -(C1-C4 alkylene)-C(O)CH3, -CH(benzyl)-COOH, -C1-C4 alkoxy, and

[0825] -(C1-C4 alkylene)-O-(C1-C4 hydroxyalkyl); or N(R 12 )(R 13 ) of R 12 and R 13 Together with the nitrogen atom to which they are normally bound, they form a saturated heterocyclic group which optionally contains one further heteroatom selected from N, O and S, and wherein the saturated heterocyclic ring is optionally substituted by methyl.

[0826] In any of the compounds described herein, the ILM may have the structure of Formula (XXXI), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039, or a non-natural mimetic thereof:

[0827]

[0828] in:

[0829] W in formula (XXXI) 1 Selected from O, S, NR A or C(R 8a )(R 8b );

[0830] W in formula (XXXI) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); The premise is W 1 and W 2 Neither O nor S;

[0831] R in formula (XXXI) 1 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);

[0832] When X 1 Selected from O, NR A , S, S(O) or S(O)2, then X 2 C(R 2a R 2b);

[0833] or:

[0834] X in formula (XXXI) 1 Selected from CR 2c R 2d , X 2 CR 2a R 2b , and R 2c and R 2a together to form a bond;

[0835] or:

[0836] X in formula (XXXI) 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;

[0837] or:

[0838] X in formula (XXXI) 1 is 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);

[0839] 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;

[0840] CR 2c R 2d and CR 2a R 2b的 R 2a 、R 2b 、R 2c 、R 2dindependently 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 ;

[0841] -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 ;

[0842] NR D R E的 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);

[0843] m of formula (XXXI) is selected from 0, 1 or 2;

[0844] -U- of formula (XXXI) 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-;

[0845] R in formula (XXXI) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0846] R in formula (XXXI) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0847] -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);

[0848] or:

[0849] R in formula (XXXI) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0850] or:

[0851] R in formula (XXXI) 3 Combined with the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0852] R in formula (XXXI) 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;

[0853] Each of the following R 7 :-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 , 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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

[0854] R 7 p is selected from 0, 1 or 2;

[0855] 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;

[0856] or:

[0857] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0858] or:

[0859] R 8a and R 8d 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 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;

[0860] or:

[0861] 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0862] or:

[0863] 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0864] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, isospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 Replacement; and

[0865] 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 by halogen, -OH or C1-C3 alkyl.

[0866] In any of the compounds described herein, the ILM may have the structure of Formula (XXXII), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039, or a non-natural mimetic thereof:

[0867]

[0868] in:

[0869] W in formula (XXXII) 1 O, S, NR A or C(R 8a )(R 8b );

[0870] W in formula (XXXII) 2 O, S, NR A or C(R 8c )(R 8d ); The premise is W 1 and W 2 Neither O nor S;

[0871] R in formula (XXXII) 1 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);

[0872] When X in formula (XXXII) 1 NR A When X 2 C=O or CR 2c R2d , and X 3 CR 2a R 2b ;

[0873] or:

[0874] When X in formula (XXXII) 1 When selected from S, S(O) or S(O)2, then X 2 CR 2c R 2d , and X 3 CR 2a R 2b ;

[0875] or:

[0876] When X 1 When formula (XXXII) is O, then X 2 CR 2c R 2d and NR A , and X 3 CR 2a R 2b ;

[0877] or:

[0878] When X in formula (XXXII) 1 When it is CH3, then X 2 Selected from O, NR A , S, S(O) or S(O)2, and X 3 CR 2a R 2b ;

[0879] When X in formula (XXXII) 1 CR 2e R 2f , and X2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X of formula (XXXII) 3 CR 2a R 2b ;

[0880] or:

[0881] X in formula (XXXII) 1 and X 3 are CH2, and X of formula (XXXII) 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);

[0882] or:

[0883] X in formula (XXXII) 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 CR 2a R 2b ;

[0884] or:

[0885] X in formula (XXXII) 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 (XXXII) 1 CR 2e R 2f ;

[0886] 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;

[0887] CR 2c R 2d , CR 2a R 2b and CR 2e R 2f R 2a 、R 2b 、R 2c 、R 2d 、R2e 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 ;

[0888] -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 ;

[0889] NR D R E的 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);

[0890] m of formula (XXXII) is selected from 0, 1 or 2;

[0891] -U- of formula (XXXII) 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-;

[0892] R in formula (XXXII) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0893] R in formula (XXXII) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0894] -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);

[0895] or:

[0896] R in formula (XXXII) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0897] or:

[0898] R in formula (XXXII) 3 Combined with the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0899] R in formula (XXXII) 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;

[0900] Each of the following R7 :-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 , 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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

[0901] R 7 p is selected from 0, 1 or 2;

[0902] C(R 8a )(R 8b ) and C(R 8c )(R 8d ) of R 8a 、R 8b 、R 8c and R 8dIndependently selected from H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, and substituted or unsubstituted aryl;

[0903] or:

[0904] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0905] or:

[0906] R 8a and R 8d 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 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;

[0907] or:

[0908] 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0909] or:

[0910] 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0911] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, isospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 Replacement; and

[0912] 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 by halogen, -OH or C1-C3 alkyl.

[0913] In any of the compounds described herein, the ILM may have a structure of Formula (XXXIII), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039, or a non-natural mimetic thereof:

[0914]

[0915] in:

[0916] W in formula (XXXIII) 1 Selected from O, S, NR A or C(R 8a )(R 8b );

[0917] W in formula (XXXIII) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); The premise is W 1 and W 2 Neither O nor S;

[0918] R in formula (XXXIII) 1 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);

[0919] When X in formula (XXXIII) 1 Selected from NR A , S, S(O) or S(O)2, then X in formula (XXXIII)2 CR 2c R 2d , and X of formula (XXXIII) 3 CR 2a R 2b ;

[0920] or:

[0921] When X in formula (XXXIII) 1 When X is O, then X in formula (XXXIII) 2 Selected from O, NR A , S, S(O) or S(O)2, and X of formula (XXXIII) 3 CR 2a R 2b ;

[0922] or:

[0923] When X in formula (XXXIII) 1 CR 2e R 2f , and X of formula (XXXIII) 2 CR 2c R 2d , and R 2e and R 2c together form a bond, and X of formula (XXXIII) 3 CR 2a R 2b ;

[0924] or:

[0925] X in formula (XXXIII) 1 and X 2 is independently selected from C and N, and is 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 (XXXIII) 3 CR 2a R 2b ;

[0926] or:

[0927] X in formula (XXXIII) 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 CR 2e R 2f ;

[0928] NR A R a is H, C1-C6 alkyl, -C(=O)C1-C2 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0929] 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 ;

[0930] -C(=O)R B R B is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6 alkyl-(substituted or unsubstituted C3-C6 cycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted C2-C5 heterocycloalkyl), -C1-C6 alkyl-(substituted or unsubstituted aryl), -C1-C6 alkyl-(substituted or unsubstituted heteroaryl), or -NR D R E ;

[0931] NR D R E的 RD 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);

[0932] m of formula (XXXIII) is 0, 1 or 2;

[0933] -U- in formula (XXXIII) 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-;

[0934] R in formula (XXXIII) 3 is a C1-C3 alkyl group or a C1-C3 fluoroalkyl group;

[0935] R in formula (XXXIII) 4 NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0936] -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);

[0937] or:

[0938] R in formula (XXXIII) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0939] or:

[0940] R in formula (XXXIII) 3 Combined with the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0941] R in formula (XXXIII) 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;

[0942] Each of the following R 7 :-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 , 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 10cycloalkyl), -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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

[0943] R 7 p is 0, 1, or 2;

[0944] 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;

[0945] or:

[0946] R 8a and R 8d As defined above, and R 8b and R 8c together to form a bond;

[0947] or:

[0948] R 8a and R 8d 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 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;

[0949] or:

[0950] R 8c and R 8d As defined above, and R 8a and R8b Together with the atoms to which they are attached, they form a substituted or unsubstituted saturated or partially saturated 3-7 membered spiro or isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0951] or:

[0952] 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[0953] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, isospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 Replacement; and

[0954] 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 by halogen, -OH or C1-C3 alkyl.

[0955] In any of the compounds described herein, the ILM may have the structure of Formula (XXXIV), which is derived from an IAP ligand described in WO Publication No. 2013 / 071039, or a non-natural mimetic thereof:

[0956]

[0957] in:

[0958] W of formula (XXXIV) 1 Selected from O, S, NR A or C(R 8a)(R 8b );

[0959] W of formula (XXXIV) 2 Selected from O, S, NR A or C(R 8c )(R 8d ); The premise is W 1 and W 2 Neither O nor S;

[0960] W of formula (XXXIV) 3 Selected from O, S, NR A or C(R 8e )(R 8f ), provided that the ring includes W 1 、W 2 and W 3 does not contain two adjacent oxygen or sulfur atoms;

[0961] R in formula (XXXIV) 1 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);

[0962] When X in formula (XXXIV) 1 When X is O, then X in formula (XXXIV) 2 Selected from CR 2c R 2d and NR A , and X of formula (XXXIV) 3 CR 2a R 2b ;

[0963] or:

[0964] When X in formula (XXXIV) 1 When CH2, X in formula (XXIV) 2 Selected from O, NR A , S, S(O) or S(O)2, and X of formula (XXXIV) 3 CR 2a R 2b ;

[0965] or:

[0966] When X in formula (XXXIV) 1 CR 2e R 2f, and X of formula (XXXIV) 2 CR 2c R 2d , and R 2e and R 2c together form a bond, and X of formula (XXXIV) 3 CR 2a R 2b ;

[0967] or:

[0968] X in formula (XXXIV) 1 and X 3 are CH2, and X of formula (XXXIV) 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);

[0969] or:

[0970] X in formula (XXXIV) 1 and X 2 is independently selected from C and N, and is 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 (XXXIV) 3 CR 2a R 2b ;

[0971] or:

[0972] X in formula (XXXIV) 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 CR 2e R 2f ;

[0973] 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;

[0974] 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 ;

[0975] -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 ;

[0976] NR D R E的 R D and R Eindependently 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);

[0977] m of formula (XXXIV) is selected from 0, 1 or 2;

[0978] -U- of formula (XXXIV) 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-;

[0979] R in formula (XXXIV) 3 Selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

[0980] R in formula (XXXIV) 4 Selected from -NHR 5 、-N(R 5 )2、-N+(R 5 )3 or -OR 5 ;

[0981] -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);

[0982] or:

[0983] R in formula (XXXIV) 3 and R 5 Together with the atoms to which they are attached, they form a substituted or unsubstituted 5-7 membered ring;

[0984] or:

[0985] R in formula (XXXIV) 3 Combined with the nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;

[0986] R in formula (XXXIV) 6 Selected from -NHC(=O)R7 、-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;

[0987] Each of the following R 7 :-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 , 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 10cycloalkyl), -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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

[0988] R 7 p is selected from 0, 1 or 2;

[0989] 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;

[0990] or:

[0991] 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 to form a bond;

[0992] or:

[0993] C(R 8a )(R 8b )、C(R 8c )(R 8d ) and C(R 8e )(R8f ) of R 8a 、R 8b 、R 8d and R 8f As defined above, and R 8c and R 8e together to form a bond;

[0994] or:

[0995] 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 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;

[0996] or:

[0997] 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 with the atoms to which they are attached, 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;

[0998] or:

[0999] C(R 8c )(R 8d ) and C(R 8e )(R 8f ) of R 8c 、R 8d 、R8e 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[1000] or:

[1001] R 8a 、R 8b 、R 8e and R 8f C(R 8a )(R 8b ) and C(R 8e )(R 8f ) is 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[1002] or:

[1003] R 8a 、R 8b 、R 8c and R 8d C(R 8a )(R 8b ) and C(R 8c )(R 8d ) is 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 isospiro ring containing 1-3 heteroatoms selected from S, O and N;

[1004] or:

[1005] wherein each substituted alkyl, heteroalkyl, fused ring, spiro ring, isospiro ring, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is replaced by 1-3 R 9 Replacement; and

[1006] R 8a 、R 8b 、R 8c 、R 8d 、R 8e and R 8f 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 by halogen, -OH or C1-C3 alkyl.

[1007] In any of the compounds described herein, the ILM may have the structure of Formula (XXXV), (XXXVI), or (XXXVII), 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, ACS Chem. Biol., 8(4), 725-32 (2013), or a non-natural mimetic thereof:

[1008]

[1009] in:

[1010] R of formula (XXXV) and (XXXVII) 2 independently selected from H or ME;

[1011] R in formula (XXXV) 3 and R 4 independently selected from H or ME;

[1012] X of formula (XXXV) and (XXXVII) is independently selected from O or S; and

[1013] R of formula (XXXV) and (XXXVII) 1 Selected from:

[1014]

[1015] In one embodiment, the ILM has a structure according to Formula (XXXVIII):

[1016]

[1017] Formula (XXXVIII) wherein R 3 and R 4 independently selected from H or ME;

[1018] is a 5-membered heterocyclic ring selected from the following:

[1019]

[1020] In one embodiment, the compound of formula (XXXVIII)

[1021] In a specific embodiment, the ILM has the structure and is attached to the linker group L as shown below:

[1022]

[1023] In any of the compounds described herein, the ILM may have the structure of Formula (XXXIX) or (XL), 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:

[1024]

[1025] in:

[1026] R of formula (XXXIX) and (XL) 1 Selected from:

[1027]

[1028] R of formula (XXXIX) and (XL) 2 selected from H or Me;

[1029] R of formula (XXXIX) and (XL) 3 Selected from:

[1030]

[1031] X is selected from H, halogen, methyl, methoxy, hydroxy, nitro or trifluoromethyl.

[1032] In any of the compounds described herein, the ILM can have a structure as shown in Formula (XLI) or (XLII) and be chemically linked to a linker as shown, or a non-natural mimetic thereof:

[1033]

[1034]

[1035] In any of the compounds described herein, the ILM may have the structure of Formula (XLIII), 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:

[1036]

[1037] in:

[1038] R1 of formula (XLIII) is selected from:

[1039]

[1040] X is selected from H, fluoro, methyl or methoxy.

[1041] In one embodiment, the ILM is represented by the following structure:

[1042]

[1043] In a specific embodiment, the ILM is selected from the following structures, and the chemical connection between the ILM and the linker group L is as follows:

[1044]

[1045] In any compound described herein, the ILM is selected from 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:

[1046]

[1047] In a specific embodiment, the ILM is selected from the following structures, and the chemical connection between the ILM and the linker group L is as follows:

[1048]

[1049] In any of the compounds described herein, the ILM may have the structure of Formula (XLIV), which is 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:

[1050]

[1051] wherein X of formula (XLIV) is one or two substituents independently selected from H, halogen or cyano.

[1052] In any of the compounds described herein, the ILM can have a structure as shown in Formula (XLV) or (XLVI) and be chemically linked to a linker group L, or a non-natural mimetic thereof, as shown:

[1053]

[1054] wherein X of formula (XLV) and (XLVI) is one or two substituents independently selected from H, halogen, or cyano; and L of formula (XLV) and (XLVI) is a linker group as described herein.

[1055] In any of the compounds described herein, the ILM may have the structure of Formula (XLVII), which is based on the IAP ligands described in Ardecky, RJ et al., Design, sysnthesis and evaluation of inhibitor of apoptosis (IAP) antagonists that are highly selective for the BIR2 domain of XIAP, Bioorg. Med. Chem., 23(14), 4253-7 (2013), or non-natural mimetics thereof:

[1056]

[1057] in:

[1058] Formula (XLVII) is a natural or unnatural amino acid; and

[1059] R of formula (XLVII) 2 Selected from:

[1060] In any of the compounds described herein, the ILM can have a structure as shown in Formula (XLVIII) or (XLIX) and be chemically linked to a linker group L, or a non-natural mimetic thereof, as shown in the formula:

[1061]

[1062] Formula (XLVIII) and (XLIX) The amino acid is a natural or unnatural amino acid; and

[1063] L of formula (XLVIII) and (XLIX) is a linker group as described herein.

[1064] In any of the compounds described herein, the ILM may have a structure selected from the following, which is based on 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:

[1065]

[1066] In any of the compounds described herein, the ILM has a structure according to formula (L), 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:

[1067]

[1068] wherein R of formula (L) is selected from:

[1069]

[1070] R1 is selected from H or Me;

[1071] R2 is selected from alkyl or cycloalkyl;

[1072] X is 1-2 substituents independently selected from halogen, hydroxy, methoxy, nitro and trifluoromethyl

[1073] Z is O or NH;

[1074] HET is a monocyclic or fused bicyclic heteroaryl; and

[1075] --- of formula (L) is an optional double bond.

[1076] In a specific embodiment, the ILM of the compound has a chemical structure selected from the group consisting of:

[1077]

[1078]

[1079] Exemplary MLM

[1080] In certain additional 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 thiazolimidazolines, substituted pyrrolopyrrolidones, and substituted isoquinolinones.

[1081] In further embodiments, the MLM comprises the above core structure, wherein adjacent bisaryl substitutions are positioned in a cis or trans configuration.

[1082] In other embodiments, the MLM comprises 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.

[1083] In certain preferred embodiments, MLM is a derivative of a substituted imidazoline as shown in formula (A-1), or a thiazolimidazolidine as shown in formula (A-2), or a spiroindolinone as shown in formula (A-3), or a pyrrolidine as shown in formula (A-4), or a piperidinone / morpholinone as shown in formula (A-5), or an isoquinolinone as shown in formula (A-6), or a pyrrolopyrimidine / imidazopyridine as shown in formula (A-7), or a pyrrolopyrrolidone / imidazopyrrolidone as shown in formula (A-8).

[1084]

[1085]

[1086] Wherein, the above formula (A-1) to formula (A-8):

[1087] X in formula (A-1) to formula (A-8) is selected from carbon, oxygen, sulfur, sulfoxide, sulfone and NR a ;

[1088] R a are independently H or an alkyl group having 1 to 6 carbon atoms;

[1089] Y and Z of formula (A-1) to formula (A-8) are independently carbon or nitrogen;

[1090] 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;

[1091] R1 and R2 of formula (A-1) to formula (A-8) are independently selected from 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:

[1092] Halogen, -CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, and dialkylamine having 2 to 6 carbons;

[1093] R3 and R4 of formula (A-1) to formula (A-8) are independently selected from H, methyl and C1 to C6 alkyl;

[1094] R5 of formula (A-1) to formula (A-8) is selected from 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:

[1095] Halogen, -CN, C1 to C6 alkyl, C3 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons, amide having 2 to 6 carbons, dialkylamine having 2 to 6 carbons, alkyl ether (C2 to C6), alkyl ketone (C3 to C6), morpholino, alkyl ester (C3 to C6), alkyl cyanide (C3 to C6);

[1096] R6 in formula (A-1) to formula (A-8) is H or -C(=O)R b ,in

[1097] R in formula (A-1) to formula (A-8) b Selected from alkyl, cycloalkyl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, 4-morpholinyl, 1-(3-oxopiperazinyl), 1-piperidinyl, 4-NR c 4-morpholinyl c -1-piperidinyl and 3-R c -1-piperidinyl, wherein

[1098] R in formula (A-1) to formula (A-8) c is selected from alkyl, fluoro-substituted alkyl, cyanoalkyl, hydroxy-substituted alkyl, cycloalkyl, alkoxyalkyl, amidealkyl, alkylsulfone, alkylsulfoxide, alkylamide, aryl, heteroaryl, monosubstituted, disubstituted or trisubstituted aryl or heteroaryl, CH2CH2R d and CH2CH2CH2R d ,in

[1099] R in formula (A-1) to formula (A-8) dSelected from alkoxy, alkylsulfone, alkylsulfoxide, N-substituted carboxamide, -NHC(O)-alkyl, -NH-SO2-alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

[1100] R7 of formula (A-1) to formula (A-8) is selected from H, C1 to C6 alkyl, cycloalkyl, fluorine-substituted alkyl, cyano-substituted alkyl, 5-membered or 6-membered heteroaryl or aryl, substituted 5-membered or 6-membered heteroaryl or aryl;

[1101] R8 in formula (A-1) to formula (A-8) is selected from -R e -C(O)-R f 、-R e -alkoxy, -R e -aryl, -R e -heteroaryl and -R e -C(O)-R f -C(O)-R g ,in:

[1102] R in formula (A-1) to formula (A-8) e is an alkylene group having 1 to 6 carbons or a bond;

[1103] R in formula (A-1) to formula (A-8) f is a substituted 4- to 7-membered heterocycle;

[1104] R in formula (A-1) to formula (A-8) g is selected from aryl, heteroaryl, substituted aryl or heteroaryl, and 4- to 7-membered heterocyclic rings;

[1105] R9 of formula (A-1) to formula (A-8) is selected from a mono-, di- or tri-substituent on the fused bicyclic aromatic ring in formula (A-3), wherein the substituents are independently selected from halogen, unsubstituted or Cl- or F-substituted olefins, alkynes, and alkyls;

[1106] R in formula (A-1) to formula (A-8) 10 Selected from aryl or heteroaryl, wherein the heteroaryl may contain one or two heteroatoms, such as sulfur or nitrogen, the aryl or heteroaryl may be monocyclic or bicyclic, the aryl or heteroaryl may be unsubstituted or substituted with one to three substituents, the substituents including halogen, F, Cl, -CN, alkene, alkyne, C1 to C6 alkyl, C1 to C6 cycloalkyl, -OH, alkoxy having 1 to 6 carbons, fluorine-substituted alkoxy having 1 to 6 carbons, sulfoxide having 1 to 6 carbons, sulfone having 1 to 6 carbons, ketone having 2 to 6 carbons;

[1107] R in formula (A-1) to formula (A-8) 11 Yes -C(O)-N(R h )(Ri ), where R h and R i Selected from:

[1108] H; optionally substituted straight-chain 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; fluorine-substituted alkyl carboxylic acid; optionally substituted cycloalkyl, 3-hydroxycyclobutane, 4-hydroxycyclohexane, aryl-substituted cycloalkyl; heteroaryl-substituted cycloalkyl; or Rh and Ri are taken together to form a ring;

[1109] R in formula (A-1) to formula (A-8) 12 and R 13 R12 and R13 are independently selected from H, lower alkyl (C1 to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6), cycloalkyl (4, 5 and 6 membered rings), substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5-membered and 6-membered aryl and heteroaryl, R12 and R13 can be linked to form 5-membered and 6-membered rings with or without substitution on the ring;

[1110] R in formula (A-1) to formula (A-8) 14 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;

[1111] R in formula (A-1) to formula (A-8) 15 For CN;

[1112] R in formula (A-1) to formula (A-8) 16C1-6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl in which one or more hydrogens are replaced by fluorine, alkyl or cycloalkyl in which one CH2 is replaced by S(=O), -S or -S(=O)2, alkyl or cycloalkyl in which the terminal CH3 is replaced by S(=O)2(alkyl)(alkyl), -C(=O)N(alkyl)(alkyl), -N(alkyl)S(=O)2(alkyl), -C(=O)2(alkyl), -O(alkyl), alkyl or cycloalkyl in which hydrogen is replaced by hydroxy substituted C1-6 alkyl or alkyl-cycloalkyl, a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally containing a -(C=0)- group, or a 5- to 6-membered aryl or heteroaryl group, 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 unsubstituted or substituted with 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;

[1113] R in formula (A-1) to formula (A-8) 17 Selected from (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 wherein one or more hydrogens are replaced by fluorine, C1-6 alkyl wherein one carbon is replaced by S(O), S(O)(O), C1-6 alkoxyalkyl wherein one or more hydrogens are replaced by fluorine, C1-6 alkyl wherein a hydrogen is replaced by cyano, 5-membered 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;

[1114] R in formula (A-1) to formula (A-8) 18 Selected from substituted aryl, heteroaryl, alkyl, cycloalkyl, the substituents are preferably -N(C1-4alkyl)(cycloalkyl), -N(C1-4alkyl)alkyl-cycloalkyl and -N(C1-4alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];

[1115] R in formula (A-1) to formula (A-8) 19 Selected from 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, alkyl sulfone, and the halogen substitution may be monosubstituted, disubstituted or trisubstituted;

[1116] R in formula (A-1) to formula (A-8) 20and 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 heterocycles which can be further substituted;

[1117] R in formula (A-1) to formula (A-8) 22 is selected from H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, trans-amide, sulfonamide, trans-sulfonamide, N-acylurea, nitrogen-containing 5-membered heterocyclic ring, wherein the 5-membered heterocyclic ring may be further substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl, CN and alkyl sulfone;

[1118] 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, fluorinated C1-6 alkyl, CN, alkoxy, alkylsulfone, amide and sulfonamide;

[1119] R in formula (A-1) to formula (A-8) 24 Selected from -CH2-(C1-6 alkyl), -CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl may be substituted by halogen, alkoxy, hydroxylated alkyl, cyano-substituted alkyl, cycloalkyl and substituted cycloalkyl;

[1120] R in formula (A-1) to formula (A-8) 25 is selected from C1-6 alkyl, C1-6 alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl, substituted aryl or heteroaryl, 5-membered, 6-membered and 7-membered nitrogen-containing saturated heterocyclic rings, 5,6-fused and 6,6-fused nitrogen-containing saturated heterocyclic rings, which may be substituted by C1-6 alkyl, fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl;

[1121] R in formula (A-1) to formula (A-8) 26 Selected from C1-6 alkyl, C3-6 cycloalkyl, wherein the alkyl or cycloalkyl may be -OH, alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl, -NH2, -NH-alkyl, NH-C(O)alkyl, -NH-S(O)2-alkyl and -S(O)2-alkyl;

[1122] R in formula (A-1) to formula (A-8) 27 is selected from 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 monosubstituted, disubstituted and trisubstituted;

[1123] R in formula (A-1) to formula (A-8) 28 is selected from aryl, 5-membered 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-substituents, including halogen, -CN, alkylsulfone and fluorine-substituted alkyl; and

[1124] R in formula (A-1) to formula (A-8) 1” is selected from the group consisting of alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl and alkoxy-substituted cycloalkyl.

[1125] In certain embodiments, R of Formula (A-1) to Formula (A-8) f and R g The heterocycle in is substituted pyrrolidine, substituted piperidine, or substituted piperazine.

[1126] More specifically, non-limiting examples of MLMs include those shown below as well as those "hybrid" molecules that arise from a combination of one or more of the different features shown in the molecules below.

[1127] Using the MLMs in formulas 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.

[1128] In certain embodiments, the present disclosure provides a bifunctional molecule comprising a structure selected from the group consisting of:

[1129]

[1130]

[1131] 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 、R11 、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).

[1132] In certain embodiments, the present 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 A-1-1, A-1-2, A-1-3, and A-1-4:

[1133]

[1134] in:

[1135] 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 F, Cl, Br, I, acetylene, CN, CF3 and NO2;

[1136] R3′ is selected from -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3 and -OCH(CH3)2;

[1137] R4' of formula A-1-1 to A-1-4 is selected from H, halogen, -CH3, -CF3, -OCH3, -C(CH3)3, -CH(CH3)2, -cyclopropyl, -CN, -C(CH3)2OH, -C(CH3)2OCH2CH3, -C(CH3)2CH2OH, -C(CH3)2CH2OCH2CH3, -C(CH3)2CH2OCH2CH2OH, -C (CH3)2CH2OCH2CH3, -C(CH3)2CN, -C(CH3)2C(O)CH3, -C(CH3)2C(O)NHCH3, -C(CH3)2C(O)N(CH3)2, -SCH3, -SCH2CH3, -S(O)2CH3, -S(O2)CH2CH3, -NHC(CH3)3, -N(CH3)2, pyrrolidinyl and 4-morpholinyl;

[1138] R5' of formula A-1-1 to A-1-4 is selected from halogen, -cyclopropyl, -S(O)2CH3, -S(O)2CH2CH3, 1-pyrrolidinyl, -NH2, -N(CH3)2, and -NHC(CH3)3; and

[1139] R6' of formulae A-1-1 to A-1-4 is selected from the structures given below, wherein the linker attachment point is represented by "*".

[1140] In addition to R6' being the linker attachment point, R4' can also serve as a linker attachment position. In the case where R4' is the linker attachment site, the linker will be attached to the terminal atom of the R4' group shown above.

[1141] In certain embodiments, the linker attachment position of Formulae A-1-1 to A-1-4 is at least one or both of R4' or R6'.

[1142] In certain embodiments, R6' of formula A-1-1 to A-1-4 is independently selected from H,

[1143]

[1144] Where "*" indicates the attachment point of the linker.

[1145] In certain embodiments, the linker of formula A-4-1 to A-4-6 is attached to at least one of R1 ', R2', R3', R4', R5', R6', or a combination thereof.

[1146] In certain embodiments, the present 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 A-4-1, A-4-2, A-4-3, A-4-4, A-4-5, and A-4-6:

[1147]

[1148] in:

[1149] R7′ of formula 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, or 4) halogens;

[1150] 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 following: 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, monosubstituted, disubstituted, or trisubstituted;

[1151] R9' of formulas A-4-1 to A-4-6 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted cycloalkenyl;

[1152] Z of formula A-4-1 to A-4-6 is selected from H, -OCH3, -OCH2CH3 and halogen;

[1153] R10′ and R11′ of formula A-4-1 to A-4-6 are each independently selected from H, (CH2) n -R′、(CH2) n -NR′R″、(CH2) n -NR′COR″、(CH2) n -NR′SO2R″、(CH2) n -COOH, (CH2) n -COOR′, (CH) n -CONR′R″、(CH2) n -OR′、(CH2) n -SR′、(CH2) n -SOR′、(CH2) n -CH(OH)-R′、(CH2)n -COR′、(CH2) n -SO2R'、(CH2) n -SONR′R″、(CH2) n -SO2NR′R″、(CH2CH2O) m -(CH2) n -R′、(CH2CH2O) m -(CH2) n -OH、(CH2CH2O) m -(CH2) n -OR′、(CH2CH2O) m -(CH2) n -NR′R″、(CH2CH2O) m -(CH2) n -NR′COR″、(CH2CH2O) m (CH2) n -NR′SO2R″、(CH2CH2O) m (CH2) n -COOH、(CH2CH2O) m (CH2) n -COOR′、(CH2CH2O) m -(CH2) n -CONR′R″、(CH2CH2O) m -(CH2) n -SO2R′、(CH2CH2O) m -(CH2) n -COR′、(CH2CH2O) m -(CH2) n -SONR′R″、(CH2CH2O) m -(CH2) n -SO2NR′R″、(CH2) p -(CH2CH2O) m -(CH2) n R′、(CH2)p-(CH2CH2O) m -(CH2) n -OH、(CH2) p -(CH2CH2O) m -(CH2)n-OR′、(CH2) p -(CH2CH2O) m -(CH2) n -NR′R″、(CH2) p -(CH2CH2O) m-(CH2) n -NR′COR″、(CH2) p -(CH2CH2O)m-(CH2) n -NR′SO2R″、(CH2) p -(CH2CH2O) m -(CH2) n -COOH, (CH2) p -(CH2CH2O) m -(CH2) n -COOR′, (CH2) p -(CH2CH2O) m -(CH2) n -CONR′R″, (CH2)p-(CH2CH2O) m -(CH2) n -SO2R′、(CH2) p -(CH2CH2O) m -(CH2) n -COR′、(CH2) p -(CH2CH2O) m -(CH2) n -SONR′R″、(CH2) p -(CH2CH2O) m -(CH2) n -SO2NR′R″, aryl-(CH2) n -COOH and heteroaryl-alkyl-CO-alkyl-NR'R"m, wherein the alkyl group may be substituted with OR', and heteroaryl-(CH2) n - heterocycle, wherein the heterocycle 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, chloroalkyl and heteroaryl;

[1154] m, n and p are independently 0 to 6;

[1155] R12′ of formula A-4-1 to A-4-6 is selected from —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);

[1156] R1" of formulae A-4-1 to A-4-6 is selected from H, alkyl, aryl-substituted alkyl, alkoxy-substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy-substituted cycloalkyl.

[1157] In any aspect or embodiment described herein, the alkyl, alkoxy, etc. may be lower alkyl or lower alkoxy.

[1158] In certain embodiments, the linker attachment position of Formulas A-4-1 to A-4-6 is at least one of Z, R8′, R9′, R10′, R11′, R12″, or R1″.

[1159] The methods for designing chimeric molecules as shown in A-1-1 to A-1-4, A-4-1 to A-4-6 can be applied to MLMs having formulas A-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent-exposed region in the MLM can be connected to a linker "L" to be attached to a target protein ligand "PTM" to construct a PROTAC.

[1160] Exemplary MDM2 binding moieties include, but are not limited to, the following:

[1161] 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: Enroute to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or in addition to) the following compounds nutlin-3, nutlin-2 and nutlin-1 (derivatized), and all derivatives and analogs thereof:

[1162]

[1163] (derivatization, wherein a linker group L or a -(L-MLM) group is attached, for example, at a methoxy group or as a hydroxyl group);

[1164]

[1165] (derivatized, wherein a linker group L or a -(L-MLM) group is attached, for example, at a methoxy or hydroxyl group);

[1166]

[1167] (derivatization, wherein the linker group L or -(L-MLM) group is attached, for example, via a methoxy group or as a hydroxyl group); and

[1168] 2. trans-4-iodo-4′-boryl-chalcone

[1169]

[1170] (derivatized, wherein the linker group L or linker group L or -(L-MLM) group is attached, for example, via a hydroxyl group).

[1171] Exemplary linkers

[1172] In certain embodiments, the compounds described herein comprise 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 covalent linkages (e.g., -A L 1… (A L ) q -or-(A L ) q -), wherein A1 is a group coupled to PTM, and (A L ) q is the group coupled to the ULM.

[1173] In any aspect or embodiment described herein, the linker (L) connection or coupling of the ULM (e.g., VLM, ILM, CLM, or MLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, any subsequent heteroatom (if present) is separated by at least one single carbon atom (e.g., -CH2-), such as from an acetal or amino group. For another example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[1174] In any aspect or embodiment described herein, the linker group L is a bond or is of the formula -(A L ) q41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 , 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100), and wherein L is covalently bound to a PTM and a ULM and provides sufficient binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase, thereby resulting in ubiquitination of the target protein.

[1175] In any aspect or embodiment described herein, the linker group L is -(A L ) q -,in:

[1176] (A l ) q is a group linked to at least one of a ULM moiety, a PTM moiety (e.g., CLM or VLM), or a combination thereof;

[1177] q of the linker is an integer greater than or equal to 1; (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 , 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100);

[1178] Each A L independently selected from a bond, CR L1 R L2 、O、S、SO、SO2、NRL3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 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 is optionally linked to other groups to form an optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and

[1179] 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, C3-11 Heterocyclic group, OC 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

[1180] In any aspect or embodiment described herein, 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.

[1181] In any aspect or embodiment described herein, for example, when q of the linker is greater than 2, (A L ) q Yes to A L 1 and (A L ) q A group wherein unit A L The PTM was coupled to the ULM.

[1182] In any aspect or embodiment described herein, for example, when q of the linker is 2, (A L ) q To connect to A L 1 and ULM groups.

[1183] In any aspect or embodiment described herein, for example, when 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.

[1184] In any aspect or embodiment described herein, the linker (L) comprises a group represented by a general structure selected from:

[1185] -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-(heterocycle)-CH2, -NR(CH2CH2) n -(heterocycle)-(heterocycle)-CH2, -N(R1R2)-(heterocycle)-CH2; wherein:

[1186] n of the linker can be 0 to 10;

[1187] The R of the linker can be H, lower alkyl;

[1188] R1 and R2 of the linker may form a ring via the attached N.

[1189] In any aspect or embodiment described herein, the linker (L) comprises a group represented by a general structure selected from:

[1190] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[1191] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[1192] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1193] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1194] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[1195] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[1196]

[1197]

[1198] in

[1199] each m, n, o, p, q, and r of the linker is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

[1200] When the number is zero, there is no NO or OO key

[1201] R of the linker is H, methyl and ethyl;

[1202] The X of the linker is H and F

[1203]

[1204] The m of the linker can be 2, 3, 4, 5

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[1214] In any aspect or embodiment described herein, the linker (L) is selected from:

[1215]

[1216]

[1217]

[1218] wherein each n and m is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[1219] In any aspect or embodiment described herein, the linker (L) is selected from:

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230] In any aspect or embodiment described herein, the linker (L) is selected from:

[1231]

[1232]

[1233]

[1234]

[1235] In any aspect or embodiment described herein, the linker (L) is selected from:

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261] , wherein m, n, o, p, q, r, s are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[1262] In any aspect or embodiment described herein, the linker (L) is selected from:

[1263]

[1264]

[1265]

[1266]

[1267]

[1268]

[1269]

[1270]

[1271]

[1272] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[1273]

[1274] in:

[1275] W L1 and W L2 Each independently does not exist, is a 4-8 membered ring having 0-4 heteroatoms, optionally replaced by R Q Replace, 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;

[1276] 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;

[1277] n is 0-10; and

[1278] Indicates the point of attachment to the PTM or ULM portion.

[1279] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[1280]

[1281] in:

[1282] W L1 and W L2 Each independently does not exist and is an aryl, heteroaryl, ring, heterocycle, C 1-6 Alkyl and optionally one or more C atoms are replaced by O, 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 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;

[1283] Y L1 Each independently is a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C=O, C=S, SO, SO2, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms are replaced by O; optionally substituted linear or branched C1-C6 alkoxy;

[1284] Q L is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally surrounded by 0-6 R Q Replace, each R Q are independently H, optionally substituted linear or branched C1-6 Alkyl (eg, optionally substituted with one or more halo or C 1-6 alkoxy substituted), or 2 R Q The groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms;

[1285] 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 halo 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;

[1286] n is 0-10; and

[1287] Indicates the point of attachment to the PTM or ULM portion.

[1288] In other 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, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 8, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc. ethylene glycol units), about 1 to about 50 ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, about 1 to about 8 ethylene glycol units and 1 to 6 ethylene glycol units, about 2 to 4 ethylene glycol units; or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene or heterocyclyl group. In certain embodiments, the linker can be asymmetric or symmetric.

[1289] 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 a substituted or unsubstituted 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.

[1290] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 100Alkyl (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 、C 50 、C 51 、C 52 、C 53 、C 54 、C 55 、C 56 、C 57 、C 58 、C 59 、C 60 、C 61 、C 62 、C 63 、C 64 、C 65 、C 66 、C 67 、C 68 ​​​​​​​​​​​74 、C 75 、C 76 、C 77 、C 78 、C 79 、C 80 、C 81 、C 82 、C 83 、C 84 、C 85 、C 86 、C 87 、C 88 、C 89 、C 90 、C 91 、C 92 、C 93 、C 94 、C 95 、C 96 、C 97 、C 98 、C 99 or C 100 alkyl), wherein each carbon is optionally substituted with: (1) a heteroatom selected from N, S, P, or Si atoms with an appropriate number of hydrogens, substituents, or both to complete the valence, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonding (e.g., no heteroatoms are covalent linkers or adjacently positioned).

[1291] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 100 Alkyl (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C30 、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 、C 50 、C 51 、C 52 、C 53 、C 54 、C 55 、C 56 、C 57 、C 58 、C 59 、C 60 、C 61 、C 62 、C 63 、C 64 、C 65 、C 66 、C 67 、C 68 、C 69 、C 70 、C 71 、C 72 、C 73 、C 74 、C 75 、C 76 、C 77 、C 78 、C 79 、C 80 、C 81 、C 82 、C 83 、C 84 、C 85 、C 86 、C 87 、C 88 、C 89 、C 90 、C 91 、C 92 、C 93 、C 94 、C 95 、C 96、C 97 、C 98 、C 99 or C 100 alkyl), wherein:

[1292] Each carbon is optionally substituted with the following groups: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 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 is optionally linked to other groups to form an optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and

[1293] R L1 、R L2 、R L3 、RL4 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 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 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, NH SO2NH(C1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

[1294] In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonding (eg, no heteroatoms are covalently linked or adjacently positioned).

[1295] 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 alkylene glycol units, wherein a carbon or oxygen may be substituted with a heteroatom selected from N, S, P, or Si atoms, with an appropriate number of hydrogen atoms to complete the valence. For example, in any aspect or embodiment described herein, the linker (L) has a chemical structure selected from:

[1296]

[1297]

[1298] , 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.

[1299] In any aspect or embodiment described herein, the present disclosure relates to a compound comprising a PTM group as described above that is bound to a target protein or polypeptide (e.g., RAF), the PTM group being ubiquitinated by a ubiquitin ligase and being chemically linked directly or through a linker moiety L to a ULM group, or the PTM is alternatively a ULM' group, which is also a ubiquitin ligase binding moiety that can be the same or different from the ULM group as described above and is directly linked to the ULM group or through a linker moiety to the ULM group; and L is a linker moiety as described above that can be present or absent and that chemically (covalently) links the ULM to the PTM; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[1300] In any aspect or embodiment described herein, the linker group L is a group comprising one or more covalently linked structural units independently selected from:

[1301]

[1302] X is selected from O, N, S, S(O) and SO2; n is an integer from 1 to 5, 5; R L1 is hydrogen or an alkyl group, is a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; is a monocyclic or bicyclic cycloalkyl or heterocyclic group optionally substituted by 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy or cyano; and the phenyl ring fragment may be optionally substituted by 1, 2 or 3 substituents selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxy and cyano. In one embodiment, the linker group L comprises up to 10 covalently linked structural units, as described above.

[1303] 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 bound 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 maximize binding of the ULM group on the ubiquitin ligase to 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 attached to an optionally substituted alkyl, alkylene, alkenyl or alkynyl, aryl, or heterocyclic group on the ULM and / or PTM group.

[1304] Exemplary PTMs

[1305] In a preferred aspect of the present disclosure, the PTM group is a group that binds to a target protein. The targets of the PTM group are of various types and are selected from proteins expressed in cells so that at least a portion of the sequence is present in the cell and can bind to the PTM group. The term "protein" includes oligopeptides and polypeptide sequences of sufficient length so that they can bind to the PTM group according to the present disclosure. As described elsewhere herein, any protein in a eukaryotic system or microbial system (including viruses, bacteria or fungi) is a target for ubiquitination mediated by a compound according to the present disclosure. Preferably, the target protein is a eukaryotic protein.

[1306] PTM groups according to the present disclosure include, for example, any portion of the following non-limiting examples that specifically bind to a protein (bind to a target protein) and include small molecule target protein moieties: RAF 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), etc. The compositions described below illustrate some members of the 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 protein of interest. These binding moieties are preferably connected to the ubiquitin ligase binding moiety via a linker so as to present the target protein (to which the protein target moiety binds) in the vicinity of the ubiquitin ligase for ubiquitination and degradation.

[1307] According to the present disclosure, a target protein is any protein that can be bound to a protein target portion or a PTM group and act on or be degraded by a ubiquitin ligase (e.g., RAF). Typically, a target protein can include, for example, a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with a cell integration function (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis), a protein with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death Proteins of interest may include proteins from eukaryotic organisms (e.g., c-RAF, A-RAF, and / or B-RAF) and prokaryotes, including humans as targets for drug therapy, other animals, including domesticated animals, microorganisms for identifying targets for antibiotics and other antimicrobial agents, and plants, and even viruses (e.g., v-RAF and / or v-Mil), among others.

[1308] The present disclosure can be used to treat a variety of disease states and / or conditions, including any disease state and / or condition in which proteins are dysregulated and the patient would benefit from protein degradation.

[1309] On the other hand, the present specification provides therapeutic compositions comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient, and optionally another bioactive agent. The therapeutic composition regulates protein degradation 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 degraded protein. 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, cardiofacial skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome. In certain other embodiments, the disease is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma.

[1310] In an alternative aspect, the present disclosure relates to a method for treating a disease state in a subject in need thereof or ameliorating the symptoms of a disease or condition by degrading a protein or polypeptide that is used to modulate the disease state or condition, 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 an additional bioactive agent, wherein the composition is effective in treating or ameliorating the disease or condition or the symptoms thereof in the subject. The methods according to the present disclosure can be used to treat a variety of disease states or conditions, including cancer, cardiofacial cutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, LEOPARD syndrome, by administering an effective amount of at least one compound as described herein. The disease state or condition can be caused by a microbial agent or other exogenous agent, such as a virus (e.g., a murine retrovirus or an avian retrovirus, such as avian retrovirus MH2), a bacterium, a fungus, a protozoa, or other microorganism, or can be a disease state caused by overexpression of a protein and / or the presence of a constitutively activated protein that results in the disease state and / or condition.

[1311] In another aspect, the present description provides methods of identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[1312] 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 for degradation by a ubiquitin ligase as described below. 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 a protein of interest. These binding moieties are linked to at least one ULM group (e.g., VLM, CLM, ILM, and / or MLM) via at least one linker group L.

[1313] Target proteins that can be bound to a protein target portion and degraded by the ligase to which the ubiquitin ligase binding portion is bound 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, immune, contractile, storage, transport, and signal transduction. More specifically, a variety of drug targets for human therapy represent protein targets to which a protein target portion can be bound and incorporated into the compounds according to the present disclosure.These include proteins that can be used to restore function in a variety of polygenic diseases, including, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, tryptase-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, newokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transporter inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neurotransmitter Peptide Y and receptors, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranyl transferase, TrkA receptor of NGF, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel. Additional target proteins include acetyl-CoA carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase and enolpyruvylshikimate phosphate synthase.

[1314] These protein targets 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 to achieve a therapeutic end result.

[1315] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and places / presents the protein or polypeptide in the vicinity of a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include RAF inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among others. The compositions described below illustrate some members of small molecule target proteins.

[1316] Exemplary protein targeting moieties according to the present disclosure include RAF inhibitors, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[1317] The compositions described below illustrate 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 protein of interest. The references cited below are incorporated herein by reference in their entirety.

[1318] In any aspect or embodiment described herein, the PTM is a small molecule comprising a B-RAF protein targeting moiety.

[1319] In any aspect or embodiment described herein, the PTM targets and / or binds to RAF. For example, in any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structure consisting of PTM-Ia or PTM-Ib:

[1320]

[1321] in:

[1322] The double point bond is an aromatic bond;

[1323] V PTM 、W PTM 、X PTM 、YPTM , Z PTM Is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N , CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C;

[1324] X PTM35 、X PTM36 、X PTM37 and X PTM38 are independently selected from CH and N;

[1325] R PTM1 covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof;

[1326] R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle;

[1327] R PTM2a and R PTM2b It is hydrogen, OH, halogen;

[1328] R PTM3 is absent or is hydrogen, aryl, methyl, ethyl, other alkyl, cycloalkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle;

[1329] R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; and

[1330] R PTM5 Selected from:

[1331]

[1332] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structure consisting of PTM-IIa or PTM-IIb:

[1333]

[1334] in:

[1335] X PTM1 、X PTM2 、X PTM3 、X PTM4 、X PTM5 and X PTM6 are independently selected from CH or N;

[1336] R PTM5a is selected from the group consisting of: a bond, an optionally substituted amine, an optionally substituted amide (e.g., optionally substituted with alkyl, methyl, ethyl, propyl or butyl), H, -NHC(O)R PTM5 ;

[1337] R PTM5 Selected from:

[1338]

[1339] R PTM5b is hydrogen or a linear or branched C1-C4 alkyl group (e.g., methyl or ethyl);

[1340] R PTM6a and R PTM6b Each is independently selected from hydrogen, halogen or optionally substituted straight or branched C1-C6 alkyl;

[1341] R PTM6 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle;

[1342] R PTM6c is hydrogen or a linear or branched C1-C4 alkyl group (e.g., methyl or ethyl);

[1343] R PTM7 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle;

[1344] R PTM8 、R PTM9 or R PTM10are independently selected from absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle;

[1345] R PTM11 is absent, is hydrogen, halogen, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; and

[1346] R PTM8 、R PTM9 or R PTM10 At least one of is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM′, a CLM′, an ILM′, a VLM′, a MLM′, or a combination thereof, or R PTM8 、R PTM9 and R PTM10 Modified to form polycyclic (eg, bicyclic) fused rings with chemical linker groups.

[1347] In certain embodiments, the PTM may comprise a chemical group selected from the group consisting of:

[1348]

[1349]

[1350] where R PTM5 、R PTM6a 、R PTM6b 、R PTM6 、R PTM7 、R PTM8 、R PTM9 、R PTM10 、R PTM11 As described in this article.

[1351] In some embodiments, when R PTM9 When it is the covalent bonding position, R PTM7 and R PTM8 Can be linked together in a certain way via covalent bonds to form a PTM7 and R PTM8 The bicyclic group of the attached ring.

[1352] In other embodiments, when R PTM8 When it is the covalent bonding position, R PTM9 and R PTM10 Can be linked together in a certain way via covalent bonds to form aPTM9 and R PTM10 The bicyclic group of the attached ring.

[1353] In another embodiment, when R PTM10 When it is the covalent bonding position, R PTM8 and R PTM9 Connected together in a certain way through covalent bonds to form a PTM8 and R PTM9 The bicyclic group of the attached ring.

[1354] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structure consisting of PTM-III:

[1355]

[1356] in:

[1357] X PTM7 、X PTM8 、X PTM9 、X PTM10 、X PTM11 、X PTM12 、X PTM13 、X PTM14 、X PTM15 、X PTM16 、X PTM17 、X PTM18 、X PTM19 、X PTM20 are independently CH or N;

[1358] R PTM12 、R PTM13 、R PTM14 、R PTM15 、R PTM16 、R PTM17 、R PTM18 、R PTM19 are independently selected from absent, hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle;

[1359] R PTM20 It is a small group containing fewer than four non-hydrogen atoms;

[1360] R PTM21is selected from trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH3, NHCH3, dimethylamino, or M1-CH2-CH2-M2, wherein M1 is CH2, O, or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; and

[1361] R PTM12 、R PTM13 and R PTM16 At least one of is modified to be covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM' or a combination thereof.

[1362] In some embodiments, when R PTM12 When it is the covalent bonding position, R PTM13 and R PTM14 Can be linked together in a certain way via covalent bonds to form a PTM13 and R PTM14 The bicyclic group of the attached ring; and / or R PTM15 and R PTM16 Connected together in a certain way through covalent bonds to form a PTM15 and R PTM16 The bicyclic group of the attached ring.

[1363] In other embodiments, when R PTM13 When it is the covalent bonding position, R PTM12 and R PTM16 Can be linked together in a certain way via covalent bonds to form a PTM12 and R PTM16 The bicyclic group of the attached ring; and / or R PTM15 and R PTM16 Can be linked together in a certain way via covalent bonds to form a PTM15 and R PTM16 The bicyclic group of the attached ring.

[1364] In another embodiment, when R PTM16 When it is the covalent bonding position, R PTM12 and R PTM13 Connected together in a certain way through covalent bonds to form a PTM12 and R PTM13 The bicyclic group of the attached ring; and / or R PTM13 and R PTM14 Connected together in a certain way through covalent bonds to form a PTM13 and R PTM14 The bicyclic group of the attached ring.

[1365] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structure consisting of PTM-IVa or PTM-IVb:

[1366]

[1367] in:

[1368] X PTM21 、X PTM22 、X PTM23 、X PTM24 、X PTM25 、X PTM26 、X PTM27 、X PTM28 、X PTM29 、X PTM30 、X PTM31 、X PTM32 、X PTM33 、X PTM34 are independently CH or N;

[1369] R PTM22 Selected from:

[1370]

[1371] R PTM25a and R PTM25b Each is independently selected from hydrogen, halogen or C1-C6 alkyl (straight chain, branched, optionally substituted);

[1372] R PTM23 、R PTM24 、R PTM28 、R PTM29 、R PTM30 、R PTM31 、R PTM32 are independently selected from absence, a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight chain, branched chain, optionally substituted), OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl (straight chain, branched chain, optionally substituted), cycloalkyl (optionally substituted), aryl (optionally substituted), or heterocycle (optionally substituted); and

[1373] R PTM25 Absent, is hydrogen, halogen, C1-C6 alkyl (straight chain, branched, optionally substituted), OCH3, NHCH3 or SCH3;

[1374] RPTM26 Absent, is hydrogen, halogen, C1-C6 alkyl (straight chain, branched, optionally substituted), OCH3, NHCH3 or SCH3;

[1375] R PTM27 is selected from the group consisting of: absence, hydrogen, halogen, C1-C6 alkyl (straight chain, branched, optionally substituted), OCH3, NHCH3 or SCH3; and

[1376] R PTM24 、R PTM29 、R PTM32 At least one of is modified to be covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM' or a combination thereof.

[1377] In some embodiments, when R PTM24 When it is the covalent bonding position, R PTM31 and R PTM32 Can be linked together in a certain way via covalent bonds to form a PTM31 and R PTM32 The bicyclic group of the attached ring; or R PTM29 and R PTM30 Can be linked together in a certain way via covalent bonds to form a PTM29 and R PTM30 a bicyclic group of the attached ring;

[1378] In other embodiments, when R PTM29 When it is the covalent bonding position, R PTM24 and R PTM32 Can be linked together in a certain way via covalent bonds to form a PTM24 and R PTM32 The bicyclic group of the attached ring; and / or R PTM31 and R PTM32 Can be linked together in a certain way via covalent bonds to form a PTM31 and R PTM32 a bicyclic group of the attached ring;

[1379] In another embodiment, when R PTM32 When it is the covalent bonding position, R PTM24 and R PTM29 Connected together in a certain way through covalent bonds to form a PTM24 and R PTM29 The bicyclic group of the attached ring; and / or R PTM29 and R PTM30 Connected together in a certain way through covalent bonds to form a PTM29and R PTM30 The bicyclic group of the attached ring.

[1380] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the chemical structure consisting of PTM-Va or PTM-Vb:

[1381]

[1382]

[1383] in:

[1384] X PTM35 、X PTM36 、X PTM37 、X PTM38 and X PTM39 are independently CH or N;

[1385] R PTM33 is halogen or linear or branched C1-C4 haloalkyl;

[1386] R PTM34 、R PTM35 、R PTM36 、R PTM37 and R PTM38 Each is independently selected from hydrogen, halogen or linear or branched C1-C4 alkyl (e.g. methyl, ethyl, propyl or butyl);

[1387] R PTM39 is optionally substituted C4-C7 heterocycloalkyl (e.g., optionally substituted C5 or C6 heterocycloalkyl); and

[1388] Is the point of attachment to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[1389] In any aspect or embodiment described herein, the PTM is selected from the group consisting of chemical structures PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, PTM-8, PTM-9, PTM-10, PTM-11, PTM-12, and PTM-13:

[1390]

[1391]

[1392] In any aspect or embodiment described herein, the ULM is selected from:

[1393]

[1394] where R 14a It is H, methyl or hydroxymethyl.

[1395] In any aspect or embodiment described herein, at least one of the following is included: (i) the PTM is selected from the PTM of compounds 1-873 or 307-873 of the present disclosure; (ii) the chemical linker group (L) is selected from the linker of compounds 1-873 or 307-873 of the present disclosure; (iii) the ULM is selected from the ULM of compounds 1-873 or 307-873 of the present disclosure; (iv) the compound further comprises a prodrug chemical moiety selected from the PTM of compounds 796-873, or (v) a combination thereof.

[1396] In any aspect or embodiment described herein, the ULM is selected from:

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407] Prodrug bifunctional compounds

[1408] In any aspect or embodiment described herein, the bifunctional compound of the present disclosure or its prodrug further comprises a plurality of ethylene glycol units. In any aspect or embodiment described herein, the bifunctional compound of the present disclosure or its prodrug further comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more) polyethylene glycol (PEG) chain. In any aspect or embodiment described herein, the bifunctional compound of the present disclosure or its prodrug further comprises a plurality (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of polyethylene glycol chains having a uniform chain length or a mixture of multiple chain lengths. In any aspect or embodiment described herein, the bifunctional compound or its prodrug further comprises a prodrug moiety selected from exemplary compounds 796-873.

[1409] In any aspect or embodiment described herein, the bifunctional compound of the present disclosure or a prodrug thereof further comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more) polyethylene glycol chain described herein, wherein in a compound selected from exemplary compounds 796-873, each polyethylene glycol chain is covalently attached to the bifunctional compound at the same point of attachment as a PEG chain. In any aspect or embodiment described herein, each PEG chain is covalently attached to the bifunctional compound via a variable (e.g., via a methyl or O) or in place of a variable of a VLM described herein (e.g., R P 、R 14a 、R 14b 、W4、W5、R 1’ 、R 2’ 、R 3’ ), a CLM described herein (eg, G or G'), or a PTM described herein (eg, R PTM6c ) is attached directly or indirectly. For example, in any aspect or embodiment described herein with respect to the VLM, R P 、R 14A 、R 14b or a combination thereof is modified to be covalently linked directly or indirectly (e.g., R P or R 1′ The hydroxyl group of R, R 14a The methyl group, R 14b or W5 is modified to be covalently attached) to a moiety comprising a PEG chain or replaced by a moiety comprising a PEG chain. Additionally, in any aspect or embodiment described herein having a CLM, G, G', or a combination thereof is modified to be covalently attached, directly or indirectly, to a moiety comprising a PEG chain (e.g., a methyl group of G or G' is modified to be covalently attached) or replaced by a moiety comprising a PEG chain.

[1410] In any aspect or embodiment described herein, the bifunctional compounds of the present disclosure, or prodrugs thereof, include at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more)

[1411]

[1412] , wherein r is an integer from 8 to 35 (e.g., 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, or 35). For example, in any aspect or embodiment described herein for a VLM, R P 、R 14A 、R 14b or a combination thereof is modified to be covalently linked directly or indirectly (e.g., R P The hydroxyl group, R 14a The methyl group, R 14b or W5 is modified to be covalently linked) to one of the above structures, or is replaced by one of the above structures. In addition, in any aspect or embodiment described herein for CLM, G, G' or a combination thereof is modified to be directly or indirectly covalently linked to one of the above structures (e.g., the methyl group of G or G' is modified to be covalently linked), or is replaced by one of the above structures. For example, in any aspect or embodiment described herein, each PEG chain can be attached to VLM, CLM or PTM via a chemical group selected from the following:

[1413]

[1414] In any aspect or embodiment described herein, the polyethylene glycol chain of the bifunctional compound or prodrug thereof comprises or is from about 8 ethylene glycol units to about 35 ethylene glycol units (e.g., 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, or 35), from about 10 ethylene glycol units to about 35 ethylene glycol units (e.g., from about 10 to about 35 ethylene glycol units, from about 10 to about 30 ethylene glycol units, about 10 to about 25 ethylene glycol units, about 10 to about 20 ethylene glycol units, about 10 to about 15 ethylene glycol units, about 15 to about 35 ethylene glycol units, about 15 to about 30 ethylene glycol units, about 15 to a...

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: The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to an E3 ubiquitin ligase; The PTM is a small molecule comprising a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; and The L is a bond or a chemical linking moiety connecting the ULM and the PTM.

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

3. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by the chemical structure PTM-Ia or PTM-Ib: in: The double point bond is an aromatic bond; V PTM 、W PTM 、X PTM 、Y PTM 、Z PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, C; X PTM35 , X PTM36 , X PTM37 and X PTM38 are independently selected from CH and N; R PTM1 covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, an ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof; R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; R PTM2a and R PTM2b It is hydrogen, OH, halogen; R PTM3 is absent or is hydrogen, aryl, methyl, ethyl, other alkyl, cycloalkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; and R PTM5 Selected from:

4. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by the chemical structure PTM-IIa or PTM-IIb: in: X PTM1 , X PTM2 , X PTM3 , X PTM4 , X PTM5 and X PTM6 are independently selected from CH or N; R PTM5a is selected from: H, optionally substituted amides (eg, optionally substituted with alkyl, methyl, ethyl, propyl or butyl), optionally substituted amines, -NHC(O)R PTM5 ; R PTM5 Selected from: R PTM5b is hydrogen or a linear or branched C1-C4 alkyl group (e.g., methyl or ethyl); R PTM6a and R PTM6b Each is independently selected from hydrogen, halogen or optionally substituted straight or branched C1-C6 alkyl; R PTM6 is any of the following: absent, hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; R PTM6c is hydrogen or a linear or branched C1-C4 alkyl group (e.g., methyl or ethyl); R PTM7 is absent and is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3 or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; R PTM8 , R PTM9 or R PTM10 is independently selected from absence, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; and R PTM11 is absent, is hydrogen, halogen, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; At least one of R PTM8 , R PTM9 , or R PTM10 Modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', a MLM' or a combination thereof, or R PTM8 , R PTM9 and R PTM10 Modified to form a polycyclic (eg, bicyclic) fused ring with a chemical linker group.

5. The bifunctional compound according to claim 4, wherein: When R PTM9 When it is the covalent bonding site, R PTM7 and R PTM8 are connected together in a certain way via covalent bonds to form a PTM7 and R PTM8 a bicyclic group of the attached ring; or When R PTM8 When it is the covalent bonding site, R PTM9 and R PTM10 are connected together in a certain way via covalent bonds to form a PTM9 and R PTM10 a bicyclic group of the attached ring; or When RRPTM10 is the site of covalent attachment, RPTM8 and RPTM9 are linked together via covalent bonds in a manner to form a bicyclic group having a ring attached to RPTM8 and RPTM9.

6. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by the chemical structure PTM-III: PTM-III in: X PTM7 , X PTM8 , X PTM9 , X PTM10 , X PTM11 , X PTM12 , X PTM13 , X PTM14 , X PTM15 , X PTM16 , X PTM17 , X PTM18 , X PTM19 , X PTM20 are independently CH or N; R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 is independently selected from absence, hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; R PTM20 It is a small group containing fewer than four non-hydrogen atoms; R PTM21 is selected from trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH3, NHCH3, dimethylamino, or M1-CH2-CH2-M2, wherein M1 is CH2, O or NH, and M2 is hydrogen, alkyl, cycloalkyl, aryl or heterocycle; and R PTM12 , R PTM13 and R PTM16 At least one of is modified to be covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, ULM', CLM', ILM', VLM', MLM' or a combination thereof.

7. The compound according to claim 6, wherein: When R PTM12 is the site of covalent bonding, R PTM13 and R PTM14 are connected together in a certain way via covalent bonds to form a PTM13 and R PTM14 The bicyclic group of the attached ring and / or R PTM15 and R PTM16 are connected together in a certain way via covalent bonds to form a PTM15 and R PTM16 a bicyclic group of the attached ring; When R PTM13 When it is the covalent bonding site, R PTM12 and R PTM16 are connected together in a certain way via covalent bonds to form a PTM12 and R PTM16 The bicyclic group of the attached ring and / or R PTM15 and R PTM16 are connected together in a certain way via covalent bonds to form a PTM15 and R PTM16 a bicyclic group of the attached ring; or When R PTM16 When it is the covalent bonding site, R PTM12 and R PTM13 are connected together in a certain way via covalent bonds to form a PTM12 and R PTM13 The bicyclic group of the attached ring and / or R PTM13 and R PTM14 are connected together in a certain way via covalent bonds to form a PTM13 and R PTM14 The attached ring is a bicyclic group.

8. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by the chemical structure PTM-IVa or PTM-IVb: in: X PTM21 , X PTM22 , X PTM23 , X PTM24 , X PTM25 , X PTM26 , X PTM27 , X PTM28 , X PTM29 , X PTM30 , X PTM31 , X PTM32 , X PTM33 , X PTM34 are independently CH or N; R PTM22 Selected from: R PTM25a and R PTM25b Each is independently selected from hydrogen, halogen or C1-C6 alkyl (straight chain, branched, optionally substituted); R PTM23 , R PTM24 , R PTM28 , R PTM29 , R PTM30 , R PTM31 , R PTM32 is independently selected from absence, a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight chain, branched chain, optionally substituted), OCH3, NHCH3, or M1-CH2-CH2-M2, wherein M1 is CH2, O and NH, and M2 is hydrogen, alkyl (straight chain, branched chain, optionally substituted), cycloalkyl (optionally substituted), aryl (optionally substituted), or heterocycle (optionally substituted); and R PTM25 is selected from absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3 or SCH3; R PTM26 is selected from absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3 or SCH3; R PTM27 is selected from the group consisting of absence, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3 or SCH3; and R PTM24 , R PTM29 , R PTM32 At least one of is modified to be covalently bonded to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, ULM', CLM', ILM', VLM', MLM' or a combination thereof.

9. The bifunctional compound according to claim 8, wherein: When R PTM24 is the site of covalent bonding, R PTM31 and R PTM32 are connected together in a certain way via covalent bonds to form a PTM31 and R PTM32 The bicyclic group of the attached ring, or R PTM29 and R PTM30 are connected together in a certain way via covalent bonds to form a PTM29 and R PTM30 a bicyclic group of the attached ring; or When R PTM29 When it is the covalent bonding site, R PTM24 and R PTM32 are connected together in a certain way via covalent bonds to form a PTM24 and R PTM32 The bicyclic group of the attached ring and / or R PTM31 and R PTM32 are connected together in a certain way via covalent bonds to form a PTM31 and R PTM32 a bicyclic group of the attached ring; or When R PTM32 When it is the covalent bonding site, R PTM24 and R PTM29 are connected together in a certain way via covalent bonds to form a PTM24 and R PTM29 The bicyclic group of the attached ring and / or R PTM29 and R PTM30 are connected together in a certain way via covalent bonds to form a PTM29 and R PTM30 The attached ring is a bicyclic group.

10. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by the chemical structure PTM-Va: in: X PTM35 , X PTM36 , X PTM37 , X PTM38 and X PTM39 are independently CH or N; R PTM33 is halogen or straight-chain or branched C1-C4 haloalkyl; R PTM34 , R PTM35 , R PTM36 , R PTM37 and R PTM38 Each is independently selected from hydrogen, halogen or straight or branched C1-C4 alkyl (e.g. methyl, ethyl, propyl or butyl); R PTM39 is optionally substituted C4-C7 heterocycloalkyl (eg, optionally substituted C5 or C6 heterocycloalkyl); and It is the point of attachment to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, ULM', CLM', ILM', VLM', MLM' or a combination thereof.

11. The bifunctional compound of claims 1 to 10, wherein the PTM is selected from PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, PTM-8, PTM-9, PTM-10, PTM-11, PTM-12, and PTM-13:

12. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is selected from: Wherein R 14a It is methyl or hydroxymethyl.

13. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is a Von Hippel-Lindau (VHL) ligase binding moiety (VLM) having a chemical structure represented by: in: X 1 , X 2 Each independently selected from the bond O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2; R Y3 , R Y4 Each independently selected from H, linear or branched C 1-6 Alkyl (optionally substituted by one or more halogens), optionally substituted C 1-6 Alkoxy (eg, optionally with 0-3 R P group substitution); R P is 0, 1, 2 or 3 groups, each independently selected from 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-diheteroaryl, optionally substituted -T-heterocycle, optionally substituted T-diheterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl or optionally substituted -NR 1 -T-heterocycle; Formula ULM-a X 3 C=O、R 1 , R 1a , R 1b ; R 1 , R 1a , R 1b Each is independently selected from H, a linear or branched C1-C6 alkyl group optionally substituted by one or more halo or -OH groups, R Y3 C=O、R Y3 C=S、R Y3 SO, R Y3 SO2、N(R Y3 R Y4 )C=O、N(R Y3 R Y4 )C=S、N(R Y3 R Y4 )SO and N(R Y3 R Y4 )SO2; T is selected from optionally substituted alkyl, -(CH2) n - group, wherein each of the methylene groups is optionally substituted by one or two groups selected from 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 Substituents, or R 1 and R 1a joined to form an optionally substituted heterocycle, or an -OH group or an optionally substituted amino acid side chain; and n is 0 to 6, W 4 yes R 14a , R 14b are each independently selected from H, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, -(CH2) m’ C(=O)(CH2) m’ C(=O)(OH),(CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, or an optionally substituted straight or branched chain alkyl group wherein one or more carbons are optionally replaced by oxygen; R 1 is H, a linear or branched C1-C6 alkyl group optionally substituted by one or more halogen or -OH groups; Each m' is individually an integer from 1 to 4 (eg, 1, 2, 3, or 4); W 5 is selected from optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, W 6 is an optionally substituted 8-14 membered bicyclic heterocycle; R 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 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 The dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

14. The bifunctional compound according to any one of claims 1 to 11, 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 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 optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, R 12 is selected from H or optionally substituted alkyl; R 13 is selected from 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 1 is H, a linear or branched C1-C6 alkyl group optionally substituted by one or more halogen or -OH groups; R 14a , R 14b are each independently selected from H, haloalkyl, optionally substituted alkoxy, (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH, (CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH, optionally substituted hydroxyalkyl, -(CH2) m’ C(=O)(CH2) m’ C(═O)(OH), or an optionally substituted straight or branched chain alkyl group in which one or more carbons are optionally replaced by oxygen; Each m' is individually an integer from 1 to 4 (eg, 1, 2, 3, or 4); W 5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl, R 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 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 H, CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R 18 is independently selected from H, 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 that couples at least one PTM or ULM' or both to the ULM.

15. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM has a chemical structure selected from the group consisting of: 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, (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH,(CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH or cyclopropyl; Each m' is individually an integer from 1 to 4 (eg, 1, 2, 3, or 4); R 15 is selected from 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 a bond or an optionally substituted 5- or 6-membered heteroaryl; and Therein, the dashed lines indicate the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM' or both to the ULM.

16. The bifunctional compound of any one of claims 1 to 11, wherein the ULM comprises a group according to the following chemical structure: in: R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, (CH2) m’ OCOCH2(CH2) m’ OCH2(CH2) m’ CO(CH2) m’ OH,(CH2) m’ OCOCH2(CH2) m’ CO(CH2) m’ OH or cyclopropyl; Each m' is individually an integer from 1 to 4 (eg, 1, 2, 3, or 4); R9 is H; R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 11 yes optionally substituted heteroaryl, p is 0, 1, 2, 3 or 4; and Each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R 12 It is H, C=O R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl or optionally substituted aralkyl, R 15 is selected from H, halogen, Cl, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloheteroalkyl, Dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM' or both to the ULM.

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

18. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is a CLM having a chemical structure represented by: in: W is selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and N-alkyl; W3 is selected from C or N; Each X is independently selected from absent, O, S and CH2; Y is selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z is selected from the group consisting of absent, O, S and CH2; G and G' are independently selected from H, optionally substituted straight or branched alkyl, OH, -(CH2) n’ -OP(=O)(OC 1-6 Alkyl)(OH), -(CH2) n’ -OP(=O)(OC 1-6 Alkyl)2, -(CH2) n’ -OP(=O)(OH)2、-CH2OCOO(CH2CH2O) n” CH3, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R'; n" is an integer from 8 to 35 (e.g., 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, or 35); Q1, Q2, Q3 and Q4 each independently represent a carbon C substituted by a group independently selected from H, R, N or N-oxide; A is independently selected from H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl and F; R includes halogen, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), optionally substituted straight or branched chain alkyl (e.g., C1-C6 straight or branched chain alkyl, which is optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy may be substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 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, wherein at least one R is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM' (e.g., CLM' is an additional CLM having the same or different structure as the first CLM), or a combination thereof; Each of x, y and z is independently 0, 1, 2, 3, 4, 5 or 6; n' and n in formula (a) to formula (f) are each independently an integer of 1-10 (eg, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); R' and R" are independently selected from H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C(=O)R, optionally substituted heterocyclyl; represents a single bond or a double bond; and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

19. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is a CLM having a chemical structure represented by: in: W is independently selected from CH2, C=O, NH and N-alkyl; A is independently selected from H, methyl or optionally substituted alkyl (e.g., C1-C6 alkyl (straight chain, branched, optionally substituted)); R of formula (g) is independently selected from H, O, OH, N, NH, NH2, halogen, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), optionally substituted -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), optionally substituted aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl); n of formula (g) represents an integer from 1 to 4 (e.g., 1, 2, 3, or 4), wherein at least one R (e.g., at least one of the following: O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl) is modified to be covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof; and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

20. The bifunctional compound according to any one of claims 1 to 11, wherein the ULM is a CLM having a chemical structure represented by: in: W is independently selected from CH2, O, CHR, C=O, SO2, NH, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and N-alkyl; Q1, Q2, Q3, Q4, Q5 each independently represent a carbon C or N substituted by a group independently selected from H, R', N or N-oxide; R 1 Selected from absent, H, OH, CN, C1-C3 alkyl, C=O; R 2 Selected from absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2; 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); R 4 is selected from H, alkyl, substituted alkyl; R 5 and R 6 Each is independently H, halogen, C(=O)R', CN, OH, CF3; X is C, CH, C═O or N; X1 is C═O, N, CH or CH2; R' is selected from H, OH, halogen, amine, cyano, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., C1-C3 alkoxy), NR 2 R 3 、C(=O)OR 2 , optionally substituted phenyl; n is 0-4; is a single bond or a double bond; and The CLM is covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

21. The bifunctional compound according to any one of claims 1 to 11, wherein: The ULM is a (MDM2) binding moiety (MLM) having a chemical moiety selected from substituted imidazolines, substituted spiro-indolones, substituted pyrrolidines, substituted piperidones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazopyridines, substituted thiazolidinones, substituted pyrrolopyrrolidones, and substituted isoquinolinones; or The ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) comprising the amino acids alanine (A), valine (V), proline (P) and isoleucine (I) or non-natural mimetics thereof.

22. The bifunctional compound of any one of claims 1 to 11, wherein the ULM is an IAP E3 ubiquitin ligase binding moiety (ILM) comprising an AVP1 tetrapeptide fragment or a derivative thereof.

23. The bifunctional compound of claim 1, wherein at least one of the following is satisfied: (i) the chemical linker group (L) is selected from the linkers of compounds 307-873, (ii) the ULM is selected from the ULMs of compounds 307-873, (iii) the PTM is selected from the PTMs of compounds 307-873, (iv) the compound further comprises a prodrug chemical moiety selected from the PTMs of compounds 796-873, or (v) a combination thereof.

24. The bifunctional compound according to any one of claims 1 to 23, wherein the linker (L) comprises a chemical structural unit represented by the following formula: -(A L ) q -, in: (A L ) q is a group connected to at least one of the CLM, the PTM, or a combination thereof; q is an integer greater than or equal to 1; Each A L independently selected from a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 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 with 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 0-6 R L1 and / or R L2 The aryl group is substituted with 0-6 R L1 and / or R L2 A heteroaryl substituted with a radical, wherein R L1 or R L2 Each independently is optionally connected to other groups to form optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and 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 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

25. The bifunctional compound according to any one of claims 1 to 24, wherein the linker (L) comprises a group represented by a general structure selected from the following: -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-; wherein m, n, o, p, q and r are independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero, there are no N-O or OO bonds, R is selected from H, methyl and ethyl, and X is selected from H and F; 26. The bifunctional compound according to any one of claims 1 to 24, wherein the linker (L) is selected from: wherein m, n, o, p, q, r or s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

27. The bifunctional compound according to any one of claims 1 to 24, wherein the linker (L) is selected from: wherein each n and m is independently selected from 0, 1, 2, 3, 4, 5 or 6.

28. The bifunctional compound according to any one of claims 1 to 24, wherein the linker (L) is selected from:

29. The compound according to any one of claims 1 to 23, wherein the linker (L) comprises the following chemical structure: in: W L1 and W L2 Each independently absent is a 4-8 membered ring with 0-4 heteroatoms, optionally substituted by RQ, each RQ independently being H, halo, OH, CN, CF3, optionally substituted straight or branched C1-C6 alkyl, optionally substituted straight or branched C1-C6 alkoxy, or 2 RQ groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 Each is independently a bond, an optionally substituted straight or branched C1-C6 alkyl group, and optionally one or more C atoms are replaced by O; or an optionally substituted straight or branched C1-C6 alkoxy group; n is 0-10; and Indicates the attachment point to the PTM or ULM portion.

30. The compound according to any one of claims 1 to 23, wherein the linker (L) comprises the following chemical structure: in: W L1 and W L2 Each independently does not exist and is aryl, heteroaryl, ring, heterocycle, C 1-6 alkyl and optionally one or more C atoms are replaced by O, 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 optionally replaced by R Q Replace, each R Q are independently H, halide, 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; Y L1 Each independently is a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C=O, C=S, SO, SO2, optionally substituted straight or branched C1-C6 alkyl and optionally one or more C atoms are replaced by O; optionally substituted straight or branched C1-C6 alkoxy; Q L is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally surrounded by 0-6 R Q Replace, each R Q are independently H, optionally substituted straight or branched chain C 1-6 Alkyl (eg, optionally substituted with one or more halogen or C 1-6 alkoxy substituted), or 2 R Q The groups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 are each independently H, OH, an optionally substituted straight or branched chain 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; n is 0-10; and Indicates the attachment point to the PTM or ULM portion.

31. The bifunctional compound according to claim 29 or 30, wherein the linker (L) is selected from:

32. The bifunctional compound according to any one of claims 1 to 23, wherein the linker (L) comprises an optionally substituted C1-C 100 Alkyl, wherein: Each carbon is optionally substituted with the following groups: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 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 with 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 The aryl group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroaryl substituted with a radical, wherein R L1 or R L2 Each independently is optionally connected to other groups to form optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and 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 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

33. The bifunctional compound according to any one of claims 1 to 24 and 32, wherein the linker is selected from:

34. The bifunctional compound of claim 1, wherein the compound is selected from Table 1A to Table 1C.

35. The bifunctional compound of any one of claims 1 to 34, further comprising at least one polyethylene glycol chain.

36. A composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 35, and a pharmaceutically acceptable carrier.

37. The composition of claim 35, wherein the composition further comprises at least one of an additional bioactive agent or another bifunctional compound according to any one of claims 1 to 34.

38. The composition of claim 36, wherein the additional bioactive agent is an anti-cancer agent.

39. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to any one of claims 1 to 35, wherein the composition is used to treat a disease or condition in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is capable of effectively treating or ameliorating at least one symptom of the disease or condition.

40. The composition of claim 38, wherein the disease or disorder is associated with BRaf accumulation and aggregation.

41. The composition of claim 38 or 39, wherein the disease or condition is cancer; cardiofacial cutaneous syndrome; neurofibromatosis type 1; Costello syndrome; Noonan syndrome; or lentigo associated with RAF accumulation and aggregation, electrocardiographic abnormalities, hypertelorism, pulmonary stenosis, genital anomalies, growth retardation, deafness (LEOPARD) syndrome.

42. The composition of claim 39, wherein the cancer is renal cell carcinoma; pancreatic cancer, colorectal cancer; lung cancer; ovarian cancer; thyroid cancer; pilocytic astrocytoma; prostate cancer; gastric cancer; hepatocellular carcinoma; or melanoma.

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