TAU protein targeting compounds and related methods of use

Abstract

The present invention provides TAU protein targeting compounds and related methods of use. The present disclosure relates to bifunctional compounds useful as tan protein modulators. In particular, the present disclosure relates to bifunctional compounds containing on one terminal a VHL or cerebellar protein ligand that binds to the E3 ubiquitin ligase and on the other terminal a moiety that binds to a tan protein such that the tan protein is positioned in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the tan. The present disclosure shows a broad range of pharmacological activities associated with degradation / inhibition of tan protein. Diseases or conditions caused by tan protein aggregation or accumulation are treated or prevented with the compounds and compositions of the present disclosure.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080063078.1, entitled “TAU protein targeting compounds and related methods of use”, filed on July 17, 2020.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 875,500, filed on July 17, 2019, entitled TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE, which is incorporated herein by reference in its entirety for all purposes.

[0004] Incorporated by reference

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

[0006] The present disclosure provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators for targeting ubiquitination of Tau protein, which then leads to degradation and / or inhibition of Tau protein.

[0007] 2. Background Information

[0008] Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination and, therefore, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of E3 ligase ligands has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutlin, additional compounds targeting E3 ligases have been reported.

[0009] The Von Hippel-Lindau (VHL) tumor suppressor is 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 the crystal structure was obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, the primary substrate of VHL.

[0010] Cerebellin is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Cerebellin forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through mechanisms not yet fully elucidated, cerebellin 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 cerebellin, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0011] Bifunctional compounds, such as those described in U.S. Patent Application Publications 2015 / 0291562 and 2014 / 0356322 (incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation in the proteasomal degradation pathway. In particular, the publications cited above describe bifunctional or proteolysis-targeting chimeric Protein degradation compounds, which can be used as targeted ubiquitination modulators of a variety of polypeptides and proteins, which are then degraded and / or inhibited by the bifunctional compounds.

[0012] Tau protein is an abundant protein in the central nervous system found primarily in neuronal cells, although Tau is expressed at lower levels in other cells of the central nervous system. In healthy neurons, Tau binds to microtubules and regulates microtubule stability, which is crucial for axonal growth and neuronal plasticity. When pathological changes occur, Tau molecules cannot stabilize microtubules and tend to form insoluble aggregates. Once Tau protein forms insoluble aggregates in cells, cell dysfunction occurs, axonal transport is impaired, and neuronal loss ensues. The accumulation of abnormal Tau aggregates in neurons is an important pathological feature of various neurodegenerative diseases (neurodegenerative diseases), including Alzheimer's disease. Under certain pathological conditions, Tau aggregation leads to double helical filaments (PHFs), straight filaments (SFs), and / or neurofibrillary tangles (NFTs). The accumulation of PHFs and NFTs in neurons is directly associated with microtubule dysfunction and neuronal degeneration. Neurons containing tau PHFs, SFs, and / or NFTs activate different cellular mechanisms to try to remove abnormal protein aggregates in cells.

[0013] Recent studies suggest that, instead of large, insoluble filaments, soluble tau oligomers may play a more critical role in the onset and progression of the disease, prior to the development of PHF- or NFT-induced neurotoxicity. Tau oligomeric species can serve as seeds for native tau aggregation, thereby promoting neurotoxic tau aggregation. Accumulating evidence has suggested that tau aggregates can spread from cell to cell in a prion-like manner.

[0014] Tau alterations and dysfunction, as well as widespread neuronal loss, have long been associated with several neurodegenerative diseases, now collectively referred to as tauopathies. The term "tauopathy" or "tauopathies" refers to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or glial fibrillary tangles in the human brain. Examples of tauopathies include, but are not limited to, AD, Down syndrome, frontotemporal dementia (FTLD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

[0015] Due to its pathological significance in various neurodegenerative diseases, tau is an important therapeutic target. Preventing tau aggregation is a potential strategy for treating tau-related neurodegenerative disorders. Significant efforts have been made to identify the molecular mechanisms of tau aggregation and to find therapeutic agents to halt the progression of neurodegeneration. However, tau aggregation inhibitors that have shown promising preclinical data have proven ineffective in recent clinical trials for the treatment of various tauopathies.

[0016] Therefore, there exists a need in the art for effective treatments of diseases and conditions associated with Tau aggregation in neurodegenerative disorders, such as tauopathies. Summary of the Invention

[0017] This disclosure describes heterobifunctional compounds and methods for their preparation and use, which function to recruit Tau protein to E3 ubiquitin ligases for targeted ubiquitination and subsequent proteasomal degradation. Specifically, this disclosure provides heterobifunctional compounds that can be used as modulators of targeted ubiquitination and degradation of Tau protein aggregates. Additionally, this specification provides methods for using an effective amount of the compounds of this disclosure for treating or ameliorating disease conditions such as tauopathies caused by Tau protein accumulation or aggregation. These diseases or conditions include, but are not limited to, neurological conditions or neurodegenerative conditions.

[0018] Where applicable or not specifically stated, it is contemplated that any one of the embodiments described herein can be combined with any other embodiment or embodiments, even if the embodiments are described under different aspects of the present disclosure. As such, the foregoing general areas of utility are given only as examples and are not intended to limit the scope of the present disclosure and the appended claims. Based on the claims, the specification, and the examples, one of ordinary skill in the art will understand additional objects and advantages associated with the compositions, methods, and methods of the present disclosure. For example, the various aspects and embodiments of the present disclosure can be utilized in numerous combinations, all of which are expressly contemplated by this specification. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to illustrate the background of the present disclosure and, in certain cases, to provide additional details on practice are incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] 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 are not to be construed as limiting the present disclosure. Additional 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 illustrative embodiments of the present disclosure.

[0020] Figure 1 Total tau levels in hippocampal homogenates are shown. Data are shown in the graphs, where each data point represents a single animal. Statistically significant differences between the test item (TI) treatment groups relative to the vehicle control group are indicated by asterisks **p<0.01, *p<0.05 according to one-way ANOVA followed by Dunneett's multiple comparison test.

[0021] Figure 2A 、 Figure 2B and Figure 2C Tau targeting bifunctional molecules are shown to be effective in vitro P301L tau degraders, which is dependent on binding to both the tau binding moiety and the E3 ligase binding moiety (ULM). (2A) Tau expression was induced for 24 hours by adding (+) doxycycline (1 μg / ml) to ChoK1-Tau P301L clone D1, followed by a 24-hour doxycycline washout period in the presence of the bifunctional molecule alone. Treatment with 250 nM, 125 nM, or 50 nM exemplary compound 82 resulted in concentration-dependent degradation of tau compared to negative (-) control treatment with 0.1% DMSO, and exhibited a DC50 of less than 50 nM. (2B) Degradation by exemplary compound 82 was achieved by binding to an E3 ligase ligand (pomalidomide); Figure 2C) were incubated with a 10-fold molar excess of tau. Figure 2C ) similar competition with tau1,2-dihydro-1,3-dihydro-1-oxo-1-oxo-2-oxo-2-oxo-3 ...

[0022] Figure 3A and Figure 3B The results show that after parenteral administration in vivo, the exemplary bifunctional compound degraded more than 95% of pathological tau in the Tg2508 brain. Tg2508 tauopathy mice (12 animals per group) were intravenously dosed with 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382 or vehicle. Twenty-four hours after dosing, the animals were sacrificed and brain cortex samples were analyzed for pathological tau by Wes capillary gel electrophoresis. Figure 3A The lanes from the vehicle control were compared with Figure 3B 82 or 382. A greater than 95% reduction in pathological tau was observed following treatment of Tg2508 animals with either Exemplary Compound 82 or Exemplary Compound 382.

[0023] Figure 4A 、 Figure 4B and Figure 4C The inhibition of Tg2508 in vitro seeding of P301L CHO MC1 by an exemplary bifunctional compound as shown by high content image analysis. Figure 4A Briefly, ChoK1-Tau P301L cells were treated with K18 tau preformed fibrils (PFFs) or extracts from Tg2508 brain samples. Docking conformational tau species were detected by MC1 antibody positivity and quantified as the average intensity of MC1 spots per cell on the Image Express high-content platform. Figure 4B Shown is the induction of plated conformational tau induced by K18 PFFs compared to background staining of tau without doxycycline induction or negative control antibody. Figure 4C Significant inoculation induction by Tg2508 cerebral cortex (CTX) extracts was shown, and this inoculated tau species was effectively degraded by a single parenteral treatment of Tg2508 mice with 15 mpk of exemplary compound 82 or with 30 mpk of exemplary compound 382 for 24 hours.

[0024] Figure 5The exemplary bifunctional compound is shown to reduce Tau in the brain of Tauopathy mice in a dose-dependent manner. As described in the Materials and Methods, Tg2508 animals were intravenously administered 15, 3, 1, or 0.3 mpk of bifunctional compound 382. As shown in the figure, at each given dose, the pathological tau level of hippocampal extracts was analyzed by Wes or bifunctional compound levels. A clear dose-response relationship was demonstrated. Specifically, Figure 5 It was demonstrated that the concentration of tau protein was dose-dependently reduced in the hippocampus of Tg2508 24 hours after administration with the exemplary bifunctional compound. DETAILED DESCRIPTION

[0025] Presently described are compounds, compositions, and methods related to the surprising discovery that an E3 ubiquitin ligase (e.g., VHL E3 ubiquitin ligase, cerebellum E3 ubiquitin ligase, or IAP E3 ubiquitin ligase) promotes ubiquitination of Tau protein when the E3 ubiquitin ligase and Tau protein are placed in close proximity via a heterobifunctional compound that binds both the E3 ubiquitin ligase and Tau protein. Accordingly, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase targeting moiety ("ULM") coupled to a protein targeting moiety ("PTM") that targets Tau protein via a chemical linker (L), which compounds and compositions cause ubiquitination of Tau protein and lead to its degradation by the proteasome.

[0026] In certain aspects, the present disclosure provides a Tau protein targeting moiety ("PTM") that binds to a Tau protein. In certain embodiments, the PTM inhibits interactions between Tau proteins. In certain embodiments, the PTM is a PTM moiety as described herein.

[0027] In another aspect, the present disclosure provides heterobifunctional compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or ("ULM" group)) and a Tau-binding moiety (i.e., a protein targeting moiety or a "PTM" group that is a Tau ligand / moiety), such that the Tau protein is placed in proximity to the ubiquitin ligase to achieve ubiquitination and subsequent degradation (and / or inhibition) of the Tau protein. In a preferred embodiment, the ULM (ubiquitin ligase binding moiety) is a cerebellum E3 ubiquitin ligase binding moiety (CLM), an apoptosis inhibitor E3 ubiquitin ligase binding moiety (ILM), or a VHL E3 ubiquitin ligase binding moiety (VLM). For example, the structure of a heterobifunctional compound can be depicted as follows, wherein the PTM and the ULM are directly covalently linked together:

[0028] PTM-ULM

[0029] The corresponding positions of PTM and ULM moieties (eg, CLM, ILM, or VLM) and their numbers as shown herein are provided by way of example only and are not intended to limit the compounds in any way.

[0030] 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 be varied as desired.

[0031] In any embodiment, the heterobifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as:

[0032] PTM-L-ULM,

[0033] wherein: PTM is a Tau targeting moiety, L is a linker, such as a bond or a chemical linking group coupling PTM and ULM, and ULM is an E3 ubiquitin ligase binding moiety.

[0034] In certain embodiments, the compound has the following general structure (A)

[0035] PTM-L-VLM(A)

[0036] wherein: PTM is a Tau targeting moiety; "L" is a linker (e.g., a bond or chemical linking group) coupling PTM and VLM; and VLM is a VHL E3 ubiquitin ligase binding moiety

[0037] In certain embodiments, the compound has the following general structure (B)

[0038] PTM-L-ILM(B)

[0039] wherein: PTM is a Tau targeting moiety; "L" is a linker (e.g., a bond or chemical linking group) coupling PTM and ILM; and ILM is an IAP E3 ubiquitin ligase binding moiety (ILM).

[0040] In certain embodiments, the compound has the following general structure (C)

[0041] PTM-L-CLM(C)

[0042] Wherein: PTM is a Tau targeting moiety; "L" is a linker (e.g., a bond or chemical linking group) coupling PTM and CLM; and CLM is a cerebellum protein E3 ubiquitin ligase binding moiety. As will be appreciated by those skilled in the art, heterobifunctional compounds as described herein can be synthesized such that the number and position of the corresponding functional moieties can be varied as desired.

[0043] In certain embodiments, the PTM in Structure (A) is a ligand that binds to Tau and the VHL E3 ubiquitin ligase.

[0044] In certain embodiments, the PTM in Structure (B) is a ligand that binds to Tau and an IAP E3 ubiquitin ligase.

[0045] In certain embodiments, the PTM in Structure (C) is a ligand that binds to Tau and cerebellum E3 ubiquitin ligase.

[0046] In any aspect or embodiment described herein, the compound as described herein comprises a plurality of independently selected ULMs, a plurality of independently selected PTMs, a plurality of chemical linkers, or a combination thereof.

[0047] In any aspect or embodiment described herein, the PTM is a small molecule that binds to Tau protein. In any aspect or embodiment described herein, the PTM is a small molecule that binds to Tau protein. In any aspect or embodiment described herein, the small molecule binds to Tau protein as described herein.

[0048] In one embodiment, the VLM is a derivative of trans-3-hydroxyproline, wherein both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides. Other contemplated CLMs are described in U.S. Patent Application Publication No. 2016 / 0272639 and U.S. Patent Application Publication No. 2014 / 0356322, each of which is incorporated herein by reference in its entirety.

[0049] In any aspect or embodiment described herein, 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 a certain embodiment, the CLM is selected from thalidomide, lenalidomide, pomalidomide, its analogs, its isosteres, and derivatives thereof. Other contemplated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein by reference in its entirety.

[0050] In any aspect or embodiment described herein, "L" is a bond. In further embodiments, the linker "L" is a chemical linking moiety / group having a linear non-hydrogen atom number ranging from 1 to 40 (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, or 40). The linker "L" may contain, but is not limited to, one or more functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. In the linker, substitution by halogen (such as Cl, F, Br and I) or alkyl (such as methyl, ethyl, isopropyl and tert-butyl) may be included. In the case of fluorine substitution, single or multiple fluorine may be included.

[0051] On the other hand, the present disclosure provides a therapeutic composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The therapeutic composition can be used to trigger targeted degradation of Tau in a patient or subject, for example, an animal (such as a human), and can be used to treat or improve one or more disease states, conditions or symptoms causally related to Tau, the treatment being achieved by degradation or inhibition of Tau protein, or can be used to control or reduce Tau protein levels in a patient or subject. In any aspect or embodiment described herein, the therapeutic composition as described herein can be used to achieve degradation of Tau to treat or improve, for example, a disease or condition causally related to the accumulation or aggregation of Tau protein (e.g., neuronal disease).

[0052] In another aspect, the present disclosure provides a method for ubiquitinating TAU in a cell (e.g., in vitro or in vivo). In any aspect or embodiment described herein, the method comprises administering a heterobifunctional compound as described herein to achieve degradation of Tau protein, the heterobifunctional compound comprising a PTM that binds to Tau protein and a ULM (such as CLM or VLM) preferably connected by a chemical linker portion as described herein. Although not wanting to be limited by theory, the inventors believe that according to the present disclosure, when Tau protein is placed near an E3 ubiquitin ligase using a heterobifunctional compound, polyubiquitination will occur, thereby triggering subsequent degradation of Tau via the proteasome pathway, and control or reduction of Tau protein levels in cells (such as cells of a subject in need of such treatment). The control or reduction of Tau protein levels provided by the present disclosure provides, for example, treatment of Tau causally related disease states, conditions, or related symptoms that are regulated by reducing the amount of Tau protein and its mutant forms in subject cells.

[0053] In another aspect, the present disclosure provides a method for treating or ameliorating a disease, condition, 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 heterobifunctional compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or ameliorating the disease, condition, or symptom thereof in the subject.

[0054] In any aspect or embodiment described herein, the PTM is a molecule that binds to Tau protein (TBM), and the ULM is a molecule that binds to cerebellum E3 ubiquitin ligase (CLM), inhibitor of apoptosis E3 ubiquitin ligase (ILM), or VHL E3 ubiquitin ligase (VLM), each exemplified by the following general structures:

[0055] TBM-L-CLM;

[0056] TBM-L-ILM; and

[0057] TBM-L-VLM.

[0058] It will be appreciated that the general structure is exemplary and that the various parts may be spatially arranged in any desired order, number or configuration.

[0059] In any aspect or embodiment described herein, the description provides a bifunctional compound having a structure selected from compounds 332, 335, 337-586, and 589-686 (eg, compounds selected from Table 1), salts, polymorphs, and prodrugs thereof.

[0060] In a further embodiment, this specification provides a composition comprising a bifunctional compound having a structure selected from Table 1 (e.g., a chemical structure selected from compounds 332, 335, 337-586, and 589-686), its salts, polymorphs, and prodrugs. For example, this specification provides a composition comprising a compound as described herein and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the composition is a therapeutic composition or a pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the therapeutic composition or pharmaceutical composition comprises another bioactive agent, for example, an agent effective for treating a neuronal disease.

[0061] In any aspect or embodiment described herein, the therapeutic composition comprising a compound described herein can be in any suitable dosage form, e.g., solid or liquid, and configured for delivery by any suitable route, e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

[0062] In another aspect, the present disclosure provides a method for modulating Tau protein, its ubiquitination and subsequent degradation in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to the subject an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising the same effectively modulates Tau ubiquitination and degradation in the subject.

[0063] In another aspect, the present disclosure provides a method for treating or ameliorating the symptoms of a disease associated with TAU activity in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to a subject in need thereof an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising the compound effectively treats or ameliorates the symptoms of a disease associated with TAU activity in the subject. In certain embodiments, the disease to be treated is a neurological disease or a neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, dementia, etc.

[0064] In any aspect or embodiment described herein, the subject is a human.

[0065] In another aspect, the present description provides methods of using the compounds according to the present disclosure for identifying the effects of target protein (eg, Tau protein) degradation in a biological system.

[0066] In another aspect, the present disclosure provides methods and intermediates for preparing the disclosed heterobifunctional compounds capable of targeting ubiquitination and degradation of Tau protein in cells (eg, in vivo or in vitro).

[0067] In one aspect, the present disclosure provides compounds wherein a PTM binds to a Tau protein. The present disclosure also provides a library of compositions and their use for causing targeted degradation of a Tau protein in a cell.

[0068] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations 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.

[0069] In any aspect or embodiment described herein, the present disclosure provides a compound 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 an E3 ubiquitin ligase, such as cerebellin, IAP, or VHL E3 ubiquitin ligase. The compound further comprises a small molecule portion capable of binding to a Tau protein in such a manner that the Tau protein is placed in proximity to an E3 ubiquitin ligase protein (e.g., VHL, IAP, and cerebellin) to achieve ubiquitination and degradation (and / or inhibition) of the Tau protein. In addition to the above, "small molecule" means that the molecule is non-peptidyl, i.e., it is not considered a peptide, e.g., comprises less than 4, 3, or 2 amino acid residues. According to the present specification, PTMs, ULMs, and heterobifunctional molecules are each small molecules.

[0070] 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 limit the disclosure.

[0071] Where a range of values ​​is provided, it is understood that each intervening value in that range, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (such as in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other stated or intervening value in the stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the stated limits, ranges excluding either or both of those included limits are also encompassed within the disclosure.

[0072] 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.

[0073] 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 unless otherwise specified.

[0074] 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 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" of the 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, in one embodiment, only A (optionally including elements in addition to B); in another embodiment, only B (optionally including elements in addition to A); in yet another embodiment, both A and B (optionally including other elements); and so on.

[0075] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including more than one of a number of elements or a list of elements, and optionally, additional unlisted items. Only terms that explicitly indicate the contrary, such as "only one" or "exactly one," or, when used in the claims, "consisting of," refer to exactly one element of a number of elements or a list of elements. In general, the term "or," as used herein, should only be interpreted to indicate exclusive alternatives (i.e., "one or the other but not both") when preceded by an exclusive term, such as "either," "one of," "only one," or "exactly one."

[0076] 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 understood as open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0077] 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") can 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.

[0078] It will also be understood that in certain methods or processes described herein that include more than one step or action, the order in which the method steps or actions are performed is not necessarily limited to the order in which the method steps or actions are described unless the context dictates otherwise.

[0079] The term "co-administration" or "combination therapy" refers to both concurrent administration (administering two or more therapeutic agents at the same time) and temporal administration (administering one or more therapeutic agents at different times than one or more additional therapeutic agents), as long as the two or more therapeutic agents are present in the patient simultaneously to some extent, preferably in effective amounts. In certain preferred aspects, one or more heterobifunctional compounds described herein are co-administered with at least one additional biologically active agent (e.g., an anti-neurodegenerative agent). In particularly preferred aspects, co-administration of such compounds results in synergistic activity and / or therapy, such as anti-neurodegenerative activity.

[0080] Unless otherwise indicated, the term "compound" as used herein refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and deuterated forms of any of the foregoing molecules (if applicable). Deuterated compounds are contemplated as those in which one or more hydrogen atoms contained in the drug molecule have been replaced with deuterium. Such deuterated compounds preferably have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent "undeuterated" compound.

[0081] 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 diseases, conditions, or symptoms that are specific to a particular animal, such as 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 terms are used, the terms "patient" and "subject" refer to human patients.

[0082] The terms "effective" and "therapeutically effective" are used to describe an amount of a compound or composition that, when used in the context of its intended use, and in the context of a treatment regimen, in a single dose or, more preferably, after multiple doses, achieves a desired result, such as amelioration of a disease or condition, or improvement or reduction in one or more symptoms associated with a disease or condition. The terms "effective" and "therapeutically effective" encompass all other "effective amount" or "effective concentration" terms otherwise described or used in this application.

[0083] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitins to specific substrate proteins. The addition of several ubiquitin chains (polyubiquitination) targets substrate proteins for degradation. For example, cerebellum, VHL, and IAP are E3 ubiquitin ligase proteins that, alone or in combination with E2 ubiquitin conjugating enzymes, ultimately cause the attachment of ubiquitin to lysine on the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases involve polyubiquitination, such that a first ubiquitin is attached to a lysine on the target protein, a second ubiquitin is attached to the first ubiquitin; a third ubiquitin is attached to the second ubiquitin, and so on, to the third ubiquitin. This type of polyubiquitination marks proteins for degradation by the proteasome.

[0084] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0085] 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.

[0086] The term "alkyl" in this context shall mean a straight-chain, branched or cyclic fully saturated hydrocarbon group, preferably a C1-C 10, more preferably C1-C6 or more preferably C1-C3 alkyl groups, said alkyl groups may optionally be substituted with one or more any suitable functional groups. Examples of alkyl groups are 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, the alkyl group is end-capped with a halogen group (At, Br, Cl, F or I).

[0087] The term "lower alkyl" refers to an alkyl group having not more than six carbon atoms, such as methyl, ethyl or propyl.

[0088] The term "lower alkoxy" refers to an alkoxy group having not more than six carbon atoms, such as methoxy, ethoxy or propoxy.

[0089] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0090] The term "alkynyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0091] 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 suitable functional group), which is further substituted with a polyethylene glycol chain (a polyethylene glycol chain of 1 to 10, preferably 1 to 6, or more preferably 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with a single halo group (preferably a chloro group) (preferably, but not exclusively, at the distal end of the polyethylene glycol chain). 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, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0092] 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.

[0093] 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 includes hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halo (preferably 1, 2 or 3 halo, especially alkyl, especially methyl such as trifluoromethyl), alkyl groups (preferably C1-C1-C2), ...1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1 10、 C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy group (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (preferably 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 group rather than at the ester function, the ester function preferably being substituted with a C1-C6 alkyl or aryl group), halogen (preferably F or Cl), amine (including five or six-membered cyclic alkyleneamines, also including C1-C6 alkylene esters), thioether (preferably C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl) (including alkylene esters ... The present invention also provides an alkylamine or C1-C6 dialkylamine, wherein the alkyl group may be substituted with one or two hydroxyl groups) or an optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (which may be further substituted with a polyethylene glycol chain, an alkyl group containing a single halogen, preferably a chlorine substituent, further bonded to the polyethylene glycol chain), a hydrazine, an acylamino group (preferably substituted with one or two C1-C6 alkyl groups) (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), an alkanol (preferably C1-C6 alkyl or aryl), or an alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, a -SiR1R2R3 group, wherein each of R1 and R2 is as described elsewhere herein, and R3 is H or a C1-C6 alkyl group, preferably R1, R2, and R3 together are a C1-C3 alkyl group (including an isopropyl or tert-butyl group). 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). m -or-(CH2) n -groups or other chains such as ethylene glycol chains can be substituted anywhere along the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which can be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F), or the side chains of amino acids as described elsewhere herein, and optionally substituted amides (preferably carboxamides substituted as described above) or carbamate groups (often with one or two C0-C6 alkyl substituents, which can be further substituted). In certain embodiments, the alkylene group (typically a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most typically methyl or O-methyl, or the side chains of amino acids as described elsewhere herein. In the present disclosure, a moiety in the molecule can be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure, a substituted moiety is substituted with one or two substituents.

[0094] 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 amine, which may be optionally substituted with one or two hydroxy groups). Within the context, unless otherwise specified, 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 1, 2, 3, 4, 5 or 6 in this context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) nOC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S 、-S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. 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 groups (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, where R1 and R2 are as described elsewhere herein, but many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, preferably 1 or 2 substituents. It should be noted that in cases where compounds where substitution at a particular position of the molecule is desired (primarily due to valency) but no substitution is indicated, that substituent is interpreted or understood to be H unless the context of the substitution suggests otherwise.

[0095] In this context, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group (e.g., a 5-16 membered ring) having a single ring (e.g., benzene, phenyl, benzyl, or a 5-, 6-, 7-, or 8-membered ring) or a fused ring (e.g., naphthyl, anthracenyl, phenanthrenyl, a 10-16 membered ring, 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" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or a fused ring system, 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, phenanthren, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, the radicals furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, and the like, all of which may be optionally substituted.

[0096] 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 groups 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 at the ortho, meta and / or para position, preferably the para position, of the phenyl ring), optionally substituted phenyl groups (the phenyl groups themselves are preferably linked to the PTM group, including the ULM group, via a linker group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (at 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

[0014] The present invention also includes but is not limited to 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 diazole groups (including methyldiazole groups), optionally substituted triazole groups (including methyl substituted triazole groups), optionally substituted pyridine groups (including halo- (preferably F) or methyl substituted pyridine groups or oxapyridine groups (wherein the pyridine group is linked to a 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.

[0097] "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.

[0098] The term "heteroaryl" or "hetaryl" may refer to, but is in no way limited to, 5-16 membered heteroaryl (e.g., a 5-, 6-, 7-, or 8-membered monocyclic ring or a 10-16 membered heteroaryl with multiple fused rings), 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-azaindolizine, 3-azaindolizine, or 4-azaindolizine), optionally substituted quinoline (including dihydroindole ... indoleazine), optionally substituted benzimidazole, benzodiazole, benzofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably substituted with a methyl group), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted with a methyl group and / or a thiol), optionally substituted isothiazole, optionally substituted triazole (preferably 1, 2, 3-triazole substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH2) m -O-C1-C6 alkyl group or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (2-pyridine, 3-pyridine or 4-pyridine), or a group that conforms to the following chemical structure:

[0099]

[0100] in:

[0101] S c It is CHR SS NR URE or O;

[0102] 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);

[0103] 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);

[0104] R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluoro groups), or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0105] 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).

[0106] 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.

[0107] 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 through 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.

[0108] The term "heterocycle" refers to a cyclic group containing at least one heteroatom (e.g., O, N, or S) and can be aromatic (heteroaryl) or non-aromatic. Therefore, depending on the context in which it is used, heteroaryl moieties are included under the definition of heterocycle. Exemplary heteroaryls are as described above. Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxane, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxane, dioxolane, ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, 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.

[0109] 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, hydroxyl, 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, imidazolidinyl, imidazoline, piperidine, piperazine, indoline, N-morpholinyl, piperidinyl, tetrahydrofuranyl, and the like, and 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.).

[0110] 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.

[0111] “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.

[0112] One aspect of the present disclosure provides compounds that can be used to modulate protein activity. The compound comprises an E3 ubiquitin ligase binding portion and a protein targeting portion, both preferably connected or coupled together by a chemical linker, wherein the E3 ubiquitin ligase binding portion recognizes an E3 ubiquitin ligase, such as cerebellin, VHL, or IAP, and the protein targeting portion recognizes a target protein (e.g., Tau). Such compounds may be referred to herein as heterobifunctional compounds / molecules or compounds having the following general chemical structure:

[0113] PTM-L-ULM,

[0114] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

[0115] in:

[0116] ULM is a small molecule E3 ubiquitin ligase-binding moiety that binds to E3 ubiquitin ligase;

[0117] PTM is a small molecule comprising a tau-targeting moiety that degrades tau; and

[0118] L is a bond or chemical linking moiety connecting the ULM and the PTM.

[0119] In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety targets a member of the group consisting of Vyper-Lindau (VLM), Cerebellin (CLM), and IAP (ILM).

[0120] In one aspect, the present disclosure provides a Tau protein binding moiety (PTM). In any aspect or embodiment described herein, the PTM is represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, or Formula XV:

[0121]

[0122]

[0123] in:

[0124] A, B, C, D, E, and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, wherein contact between circles indicates ring fusion and overlapping circles indicate spirocycles; and

[0125] L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups selected from the groups -O-, -S-, -NR 1 PTM -(where R 1 PTM selected from H or alkyl), -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O- or -OC(O)NH-, wherein the functional group is optionally located at either end of the linker.

[0126] In any aspect or embodiment described herein, the PTM is represented by Formula I, II, III, IV, XII, XIII, XIV, and XV:

[0127]

[0128]

[0129] in:

[0130] A, B, C, D, E, and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, wherein contact between circles indicates ring fusion and overlapping circles indicate spirocycles;

[0131] L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups selected from the groups -O-, -S-, -NR 1PTM -, -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, wherein the functional groups are optionally located at either end of the linker; and

[0132] R 1PTMis selected from H, alkyl, or fluoroalkyl, wherein the PTM is coupled to the ULM via a chemical linker (L) via at least one of A, B, C, D, E, or F (e.g., A, C, D, or E; or A, C, D, E, or F).

[0133] In any aspect or embodiment described herein, the PTM is represented by Formula I, II, III, IV, XII, XIII, XIV, and XV:

[0134]

[0135]

[0136] in:

[0137] A, B, C, D, E, and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, wherein contact between circles indicates ring fusion and overlapping circles indicate spirocycles;

[0138] L PTM A bond optionally interrupted by one or more functional groups, an alkyl, an alkenyl or an alkynyl group, the functional groups being selected from the group -O-, -NR 1PTM -, -C(O)-, wherein the functional group is optionally located at either end of the linker; and

[0139] R 1PTM is selected from H, alkyl or fluoroalkyl.

[0140] In any aspect or embodiment described herein, the aryl and heteroaryl rings of A, B, C, D, and F of the PTM are optionally substituted with 1-8 (e.g., 1-3) substituents, each of which is independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups are further optionally substituted.

[0141] In any aspect or embodiment described herein, the ring of at least one of A, B, C, F, or a combination thereof, is selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring;

[0142] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula I, wherein:

[0143] Rings A, B, and C are independently 5- or 6-membered fused aryl or heteroaryl rings;

[0144] L PTM is selected from a bond or an alkyl group, and

[0145] D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,

[0146] wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino or cyano.

[0147] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula I, wherein:

[0148] A and C are phenyl or a 6-membered heteroaryl ring;

[0149] B is a 5-membered heteroaryl ring;

[0150] L PTM is a key; and

[0151] D is a 6-membered heteroaryl or 6-membered heterocycloalkyl ring;

[0152] wherein each A, B, C and D is independently optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino or cyano, and wherein the nitrogen atom of any one of the A, B, C and D rings is not directly attached to a heteroatom or carbon atom, another heteroatom is directly attached to the heteroatom or carbon atom.

[0153] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula III or IV, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L PTM is selected from a bond or alkyl, and D and E are 5 or 6 membered fused aryl or heteroaryl rings, wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino or cyano.

[0154] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I or III, wherein:

[0155] Two of rings A, B, and C are independently selected from 5- or 6-membered aryl or heteroaryl rings, each of which is optionally substituted with 1-3 substituents independently selected from optionally substituted straight or branched alkyl, optionally substituted straight or branched alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano; and

[0156] L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups, the functional groups may include -O-, -S-, -NR 1 -(where R 1selected from H or alkyl), -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, wherein the functional group may optionally be located at either end of the linker (i.e., directly adjacent to the C or D ring).

[0157] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0158]

[0159] in:

[0160] X PTM1 and X PTM2 One of them is N and the other is C;

[0161] X PTM3 、X PTM4 、X PTM5 are independently C or N;

[0162] X PTM6 is CH or N;

[0163] R 1 H, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2);

[0164] Each R 7 Independently: (i) when the atom to which it is attached is carbon, it is H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 a fluoroalkyl group (e.g., -CF3); or (ii) when the atom to which it is attached is nitrogen, it is absent;

[0165] R 7a H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CF3);

[0166] Each R 8 are independently H or halogen (e.g., F, Cl, Br);

[0167] Each R 9 Independently: (i) when the atom to which it is attached is carbon, it is H, halogen (e.g., F, Cl, Br), C 1-C4 Alkyl (e.g., methyl), C 1-3fluoroalkyl (e.g., CF3) or -CN; or (ii) its absence when the atom to which it is attached is nitrogen; and

[0168] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM,

[0169] in:

[0170] Only one R 7 or R 7a Halogen, C 1-4 Alkyl or C 1-3 Fluoroalkyl;

[0171] No more than two (e.g., 0, 1, or 2) R 9 is halogen or -CN; and

[0172] X PTM3 、X PTM4 、X PTM5 and X PTM6 0, 1 or 2 of them are N.

[0173] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0174]

[0175]

[0176] in:

[0177] X PTM7 and X PTM8 independently nitrogen or carbon;

[0178] Each R 7 are independently H or halogen (e.g., F, Cl, Br);

[0179] Each R 9 Independently: (i) when the atom to which it is attached is carbon, it is a halogen, H or C 1-3 fluoroalkyl (e.g., -CF3); or (ii) when the atom to which it is attached is nitrogen, it is absent; and

[0180] It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

[0181] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0182]

[0183] in:

[0184] X PTM9 or X PTM10 One of them is N and the other is CH2;

[0185] X PTM11 is nitrogen or CH;

[0186] R 1 H, C 1-4 Alkyl (e.g., methyl), C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2);

[0187] R 7 (i) when the atom to which it is attached is carbon, it is H; or (ii) when the atom to which it is attached is nitrogen, it is H or C1-3 alkyl;

[0188] R 9 is H, halogen, halogen (e.g., F, Cl, Br) or C 1-2 Fluoroalkyl (-CF3); and

[0189] It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

[0190] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0191]

[0192] in:

[0193] Each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen atoms to complete the valence, wherein X PTM12 and X PTM13 At least one of is nitrogen;

[0194] X PTM14 is nitrogen or CH;

[0195] L PTM For key, C 1-3 Alkyl, C 2-3 Alkynyl (e.g., C3 alkynyl), wherein a carbon of the alkyl group is optionally replaced by O or C(=O);

[0196] L PTM1 C 1-C4 alkyl;

[0197] R 1 H, C 1-4Alkyl (e.g., methyl), C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2);

[0198] R 7 H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CF3);

[0199] Each R 9 are independently H or halogen (e.g., F, Cl, Br); and

[0200] It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

[0201] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0202]

[0203]

[0204] in:

[0205] X PTM7 and X PTM8 independently nitrogen or carbon;

[0206] Each R 7 are independently H or halogen (e.g., F, Cl, Br);

[0207] Each R 9 independently: (i) when the atom to which it is attached is carbon, it is a halogen or H; or (ii) when the atom to which it is attached is nitrogen, it is absent; and

[0208] It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

[0209] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0210]

[0211] in:

[0212] Each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen atoms to complete the valence, wherein X PTM12 and X PTM13 At least one of is nitrogen;

[0213] Each R 7 are independently H or halogen (e.g., F, Cl, Br);

[0214] Each R 9 are independently H or halogen (e.g., F, Cl, Br); and

[0215] It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

[0216] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0217]

[0218]

[0219]

[0220] in:

[0221] X PTM14 N or CH;

[0222] R 10 and R 11 independently selected from H, methyl and ethyl;

[0223] R 12 and R 13 are independently selected from H, methyl, ethyl, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (eg, methyl) and C 1-2 alkyl halide;

[0224] R 14 is selected from H, methyl, ethyl and halogen (e.g., F, Cl, Br);

[0225] R 15 are 1 to 2 substituents independently selected from H, methyl, ethyl and halogen;

[0226] R 16 H, OH or C 1-3 alkoxy (e.g., methoxy);

[0227] R 17 is H, halogen (e.g., F, Cl, Br) or C 1-3 alkyl (e.g., methyl);

[0228] R 18 is H, halogen (e.g., F, Cl, Br) or C 1-2Haloalkyl (e.g., -CF3)

[0229] R 19 is H, halogen (e.g., F, Cl, Br), C 1-2 Haloalkyl (e.g., -CF3) or -NH2, N(R 20 )2;

[0230] Each R 20 are independently H or C 1-3 alkyl (e.g., methyl);

[0231] N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM; and

[0232] is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM.

[0233] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0234]

[0235] in:

[0236] X PTM17 、X PTM18 and X PTM19 Each of is independently N or CH;

[0237] X PTM15 and X PTM16 Each of is independently N or C;

[0238] R 21 :(i) when the atom to which it is attached is carbon, it is H or C 1-3 alkyl (e.g., methyl); or (ii) when the atom to which it is attached is nitrogen, it is absent;

[0239] R 22 (i) when the atom to which it is attached is carbon, it is H or a halogen (e.g., F, Cl, Br); or (ii) when the atom to which it is attached is nitrogen, it is absent;

[0240] R 23 is H or halogen (e.g., F, Cl, Br);

[0241] R 24 is H or halogen (e.g., F, Cl, Br);

[0242] R 25 H or C 1-3an alkyl group (e.g., methyl); and

[0243] is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM.

[0244] In any aspect or embodiment described herein, there are zero or one nitrogen per ring of the PTM.

[0245] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0246]

[0247] in:

[0248] R 1 is selected from H, optionally substituted alkyl (e.g., haloalkyl, fluoroalkyl, difluoromethyl, or trifluoromethyl), methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and

[0249] R 7 and R 8 Each of which is independently 1 or 2 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl, or cyano.

[0250] L PTM is selected from a bond optionally interrupted by one or more functional groups, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, the functional group is selected from the group -O-, -NR 1PTM -, -C(O)-, wherein the functional group is optionally located at either end of the linker; and

[0251] is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM.

[0252] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0253]

[0254] in:

[0255] Each R 1 and R 7 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F3) ,CN;

[0256] Each R 8 and each R 9 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0257] Each X PTM are independently C or N;

[0258] is a single bond or a double bond; and

[0259] is the attachment site for the chemical linking group (L).

[0260] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0261]

[0262] in:

[0263] Each R 1 and R 7 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0264] Each R 8 and each R 9 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0265] Each X PTM are independently C or N;

[0266] is a single bond or a double bond; and

[0267] is the attachment site for the chemical linking group (L).

[0268] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0269]

[0270] in:

[0271] Each R 1 and R 7 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0272] Each R 8 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0273] Each X PTM are independently C or N;

[0274] is a single bond or a double bond; and

[0275] is the attachment site for the chemical linking group (L).

[0276] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0277]

[0278] in:

[0279] Each R 21 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0280] Each X PTM are independently C or N;

[0281] is a single bond or a double bond; and

[0282] is the attachment site for the chemical linking group (L).

[0283] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:

[0284]

[0285] in:

[0286] Each R 26 is H, an optionally substituted cyclic group, a heterocyclic group, a heterobicyclic group or a member selected from

[0287]

[0288] is the coupling site to the pyrrolyl nitrogen, and

[0289] is the attachment site for the chemical linking group (L).

[0290] In one aspect, the present disclosure provides a compound of the following structure:

[0291] PTM-L-ULM,

[0292] Wherein: PTM is a Tau protein targeting moiety, L is a chemical linking moiety, and ULM is an E3 ubiquitin ligase binding moiety, and wherein

[0293] (i) The PTM is a structure selected from the group consisting of:

[0294]

[0295] in:

[0296] Each R 1 and R 7 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0297] Each R 8 and each R 9 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0298] Each R 21 are independently selected from H, halo, F, C 1-3 Alkyl, -CH(F 2) 、-CH2C(F 3) ,CN;

[0299] Each X PTM are independently C or N;

[0300] is a single bond or a double bond; and

[0301] is the attachment site for the chemical linker (L);

[0302] (ii) L is a structure selected from the group consisting of:

[0303]

[0304]

[0305] in is an attachment site to a ULM or PTM; and

[0306] (iii)ULM is based on the following structure:

[0307]

[0308] in:

[0309] R is independently H, halide, methoxy, or the site of attachment of a chemical linking group (L), and

[0310] n is an integer selected from 1, 2, 3 or 4,

[0311] wherein at least one R is an attachment site to a chemical linking group (L) or a pharmaceutically acceptable salt thereof.

[0312] In one aspect, the present disclosure provides a compound of the following structure:

[0313] PTM-L-ULM,

[0314] Wherein: PTM is a Tau protein targeting moiety, L is a chemical linking moiety, and ULM is an E3 ubiquitin ligase binding moiety, and wherein

[0315] (i) The PTM is a structure selected from the group consisting of:

[0316]

[0317] in:

[0318] Each R 26 is H, an optionally substituted cyclic group, a heterocyclic group, a heterobicyclic group or a member selected from

[0319] is the coupling site to the pyrrolyl nitrogen, and

[0320] is the attachment site for the chemical linking group (L).

[0321] (ii) L is a structure selected from the group consisting of:

[0322]

[0323] in is an attachment site to a ULM or PTM; and

[0324] (iii)ULM is based on the following structure:

[0325]

[0326] in:

[0327] R is independently H, halide, methoxy, or the site of attachment of a chemical linking group (L), and

[0328] n is an integer selected from 1, 2, 3 or 4,

[0329] wherein at least one R is an attachment site to a chemical linking group (L) or a pharmaceutically acceptable salt thereof.

[0330] In any aspect or embodiment described herein, the PTM is a chemical structure selected from the group consisting of:

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] where * and is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM.

[0342] In any aspect or embodiment described herein, the PTM is a chemical structure selected from the group consisting of:

[0343]

[0344]

[0345]

[0346] in is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM.

[0347] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

[0348]

[0349]

[0350]

[0351] in:

[0352] R 1 、R 2 and R 3 independently selected from H, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl;

[0353] R 4 and R 5 are independently selected from H, methyl, ethyl, halogen, haloalkyl, and cyano; and

[0354] R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen,

[0355] The PTM is coupled to the ULM via L.

[0356] In any aspect or embodiment described herein, the PTM is covalently coupled to one or more ULM (VLM or CLM) groups, or to a linker to which one or more ULM (VLM or CLM) groups are attached as described herein.

[0357] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

[0358]

[0359]

[0360]

[0361] in:

[0362] R 1 、R 2 and R 3is independently selected from H, optionally substituted alkyl (e.g., haloalkyl, fluoroalkyl, difluoromethyl, or trifluoromethyl), methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and

[0363] R 7 、R 8 、R 9 and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl, or cyano, and wherein PTM is coupled to ULM (VLM or CLM) via L.

[0364] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure:

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] In any aspect or embodiment described herein, the PTM has a chemical structure selected from the group consisting of:

[0372]

[0373]

[0374]

[0375] in represents the point of attachment to a linker group or ULM as described herein.

[0376] In any aspect or embodiment described herein, the point of linker attachment to the PTM is indicated by a dashed line:

[0377] .

[0379] In any aspect or embodiment described herein, the PTM has a chemical structure selected from the group consisting of:

[0380]

[0381]

[0382]

[0383]

[0384] in:

[0385] Each Z is N or CH;

[0386] Each of rings Z1, Z2, and Z3 is independently aryl or heteroaryl (e.g., each carbon of rings Z1, Z2, and Z3 is optionally substituted with a heteroatom such as N, O, or S);

[0387] Ring Z4 is cycloalkyl or heterocycloalkyl (eg, each carbon of Ring Z4 is optionally substituted with a heteroatom such as N, O, or S); and

[0388] represents the point of attachment to a linker group or ULM (eg, CLM, VLM, ILM, or MLM) as described herein.

[0389] In any aspect or embodiment described herein, Ring Z 1 is heteroaryl (eg, Ring Z 1 has one, two, or three carbons substituted with N, O, or S).

[0390] In any aspect or embodiment described herein, Ring Z2 is heteroaryl (eg, Ring Z2 has one, two, or three carbons substituted with N, O, or S).

[0391] In any aspect or embodiment described herein, Ring Z3 is heteroaryl (eg, Ring Z2 has one, two, or three carbons substituted with N, O, or S).

[0392] In any aspect or embodiment described herein, Ring Z4 is heteroaryl (eg, Ring Z4 has one, two, or three carbons substituted with N, NH, O, or S).

[0393] Example VLM:

[0394] In one aspect, the ULM is a VHL E3 ubiquitin ligase binding moiety (VLM).

[0395] In any aspect or embodiment described herein, the ULM is a VLM and is represented by the following chemical structure:

[0396]

[0397] in:

[0398] R 14 R in any aspect or embodiment as described herein 14 、 R14a or R 14b as defined in;

[0399] R 15 as defined in any aspect or embodiment described herein;

[0400] R 16 as defined in any aspect or embodiment described herein;

[0401] o as defined in any aspect or embodiment described herein; and

[0402] The dotted line indicates the attachment site to the PTM via a chemical linker (L), or alternatively, the attachment site is at R 16 Place.

[0403] For example, in any aspect or embodiment described herein, the ULM is a VLM and is represented by the following chemical structure:

[0404]

[0405] in:

[0406] R 14 is H, straight or branched C1-C3 alkyl (e.g., methyl), C 1-3 a haloalkyl group (e.g., fluoromethyl) or a hydroxymethyl group;

[0407] R 15 is a 5-membered heteroaryl group having one or two heteroatoms selected from N, S and O, optionally substituted with methyl;

[0408] R 16 is halo, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, hydroxy, optionally substituted C1-C3 alkoxy or optionally substituted C1-C3 haloalkoxy;

[0409] o is an integer from 0 to 2 (e.g., 0, 1, or 2); and

[0410] The dotted line indicates the attachment site to the PTM via a chemical linker (L), or alternatively, the attachment site is at R 16 Place.

[0411] In any aspect or embodiment described herein, the VLM is represented by a structure selected from the group consisting of:

[0412]

[0413]

[0414] The dashed line indicates the attachment site to the PTM via a chemical linker (L).

[0415] In any aspect or embodiment described herein, the ULM is a VLM and comprises a chemical structure selected from the group ULM-a:

[0416]

[0417] in:

[0418] wherein the dashed line indicates the attachment of at least one PTM, another ULM or VLM or CLM or ILM (i.e., ULM' or VLM' or CLM' or ILM'), or a chemical linker moiety coupling at least one PTM, ULM' or VLM' or CLM' or ILM' to a ULM;

[0419] Formula ULM-a X 1 and X 2 Each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2;

[0420] R of formula ULM-a Y3 and R Y4 Each independently selected from H, a linear or branched C optionally substituted by one or more halogen groups 1-6 Alkyl, optionally substituted C 1-6 Alkoxy (eg, optionally with 0-3 R P group substitution);

[0421] 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;

[0422] W of ULM-a 3 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;

[0423] Formula ULM-a X 3 C=O、R 1 、R 1a 、R 1b ;

[0424] R of formula ULM-a 1 、R 1a and 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;

[0425] T of formula ULM-a is selected from optionally substituted alkyl, -(CH2) n -group, linear or branched -(CH2) n -OC 1-6 alkyl or optionally substituted -(CH2) n -O-heterocyclyl, wherein each methylene group 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 linked to form an optionally substituted heterocyclic group, or an -OH group or an optionally substituted amino acid side chain;

[0426] W of ULM-a 4 is optionally substituted -NR1-T-aryl, wherein the aryl group may be optionally substituted with an optionally substituted 5-6 membered heteroaryl, an optionally substituted -NR1-T-heteroaryl or an optionally substituted -NR1-T-heterocycle, wherein -NR1 is covalently bonded to X 2 , and R1 is H or CH3, preferably H; and

[0427] n of formula ULM-a is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0428] In any aspect or embodiment 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 halogen, methyl, optionally substituted alkoxy, linear or branched C1-C6 alkyl groups optionally substituted by 1 or more halogens, C(O)NR 1 R 1a or NR 1 R 1a Substituents, or R 1 and R 1a are linked to form an optionally substituted heterocycle, or an -OH group, or an optionally substituted amino acid side chain; and

[0429] n is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0430] In any aspect or embodiment described herein, W of Formula ULM-a 4 for

[0431] in:

[0432] W 5 is optionally substituted (e.g., W 5 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 5-10 membered heteroaryl) (e.g., W 5 optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy);

[0433] R 14a and R 14b are each independently selected from H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14b together with the carbon atom to which they are attached, form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine;

[0434] o is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4); and

[0435] R 16 are independently selected from halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

[0436] In any aspect or embodiment described herein,

[0437] W 5 is selected from optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 5-10 membered heteroaryl (e.g., W 5 optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy); and

[0438] 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 haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

[0439] In the aspects or embodiments described herein, W of the substituent of formula ULM-a for use in the present disclosure 4 Also specifically included (and not limited to the specific compounds disclosed) are 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.

[0440] In any aspect or embodiment described herein, ULM-a is optionally replaced by 1-3 R P Group substitution, each R P are independently H, halo, -OH, C1-3 alkyl or C=O.

[0441] In any aspect or embodiment described herein, W 3 and W 4Can be independently covalently coupled to a chemical linking group to which one or more PTM groups are attached.

[0442] In any aspect or embodiment described herein, the ULM is a VLM and is represented by the following structure:

[0443]

[0444] in:

[0445] W of ULM-b 3 is selected from optionally substituted aryl, optionally substituted heteroaryl or

[0446] 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;

[0447] R of formula ULM-b 11 is selected from optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0448] R of formula ULM-b 12 is selected from H or optionally substituted alkyl;

[0449] 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;

[0450] R of formula ULM-b 14a and R 14b are each independently selected from H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CONR 27a R 27b 、CH2NHCOR 26 or (CH2)N(CH3)COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14btogether with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine;

[0451] W of ULM-b 5 is selected from optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl (e.g., W 5 optionally substituted with one or more [such as 1, 2, 3, 4 or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy or optionally substituted haloalkoxy);

[0452] 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;

[0453] Each R of the formula ULM-b 16 are independently selected from H, CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

[0454] o of formula ULM-b is 0, 1, 2, 3 or 4;

[0455] R of formula ULM-b 18 is independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; and

[0456] p of formula ULM-b is 0, 1, 2, 3 or 4; and

[0457] 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.

[0458] In any aspect or embodiment described herein, R 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b, OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, wherein each R 26 are independently selected from H, optionally substituted alkyl or NR 27a R 27b ; and each R 27a and R 27b are independently H, optionally substituted alkyl, or R 27a and R 27b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group.

[0459] In any aspect or embodiment described herein, R 15 for in:

[0460] 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

[0461] Xa is S or O.

[0462] In any aspect or embodiment described herein, R 17 Selected from methyl, ethyl, isopropyl and cyclopropyl.

[0463] In any aspect or embodiment described herein, R 15 Selected from the group consisting of:

[0464]

[0465] In any aspect or embodiment described herein, R 11 Selected from the group consisting of:

[0466]

[0467]

[0468] In any aspect or embodiment described herein, R 14a and R14b are each independently selected from H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 or CH2NCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14b Together with the carbon atoms to which they are attached, they form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; wherein the spirocycloalkyl or spiroheterocycloalkyl is itself optionally substituted with an alkyl, haloalkyl, or -COR 33 Substituted, where R 33 is an alkyl group or a halogenated alkyl group,

[0469] where R 30 R is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl, which is further optionally substituted; 26 and R 27 As mentioned above.

[0470] In any aspect or embodiment described herein, R 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl (e.g., optionally substituted fluoroalkyl), optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl include CH2OR 30 、CH2NHR 30、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 、CH2NCH3COR 26 or where R 26 、R 27 、R 30 and R 14 aAs described above.

[0471] In any aspect or embodiment described herein, R 14a and R 14b are each independently selected from H, optionally substituted haloalkyl, optionally substituted alkyl, CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 or CH2NCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14b Together with the carbon atoms to which they are attached, they form an optionally substituted 3- to 6-membered spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; wherein the spirocycloalkyl or spiroheterocycloalkyl itself is optionally substituted with an alkyl, haloalkyl or -COR 33 Substituted, where R 33 is an alkyl group or a halogenated alkyl group, wherein R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl, which is further optionally substituted;

[0472] R of formula ULM-b 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 27a SO2R 27b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, wherein the optional substitution of aryl, heteroaryl, cycloalkyl and heterocycloalkyl includes CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 、CH2NCH3COR 26 or where R 26 、R 27 、R 30 and R 14 aAs described above.

[0473] In any aspect or embodiment described herein, the ULM has a chemical structure selected from the group consisting of:

[0474]

[0475]

[0476] in:

[0477] 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 cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl;

[0478] R of formula ULM-c, ULM-d and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0479] 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, optionally substituted cycloalkyl or optionally substituted cycloheteroalkyl;

[0480] X of formula ULM-c, ULM-d and ULM-e is C, CH2 or C=O;

[0481] R3 of formula ULM-c, ULM-d and ULM-e is absent or is an optionally substituted 5- or 6-membered heteroaryl; and

[0482] The dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker group that couples at least one PTM or ULM', or both, to a ULM (ULM-a).

[0483] In any aspect or embodiment described herein, the ULM comprises a group according to the following chemical structure:

[0484]

[0485] in:

[0486] R of ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0487] R9 of formula ULM-f is H;

[0488] R of ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0489] R11 of formula ULM-f is or optionally substituted heteroaryl;

[0490] p of the formula ULM-f is 0, 1, 2, 3 or 4;

[0491] Each R of the formula ULM-f 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;

[0492] R of ULM-f 12 It is H, C=O;

[0493] 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,

[0494] R of ULM-f 15 is selected from H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl,

[0495]

[0496]

[0497] as well as

[0498] 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 (ULM-f).

[0499] In any aspect or embodiment described herein, the VLM is ligated via an R group such as R P 、R 1 、R 1a 、R 1b 、R Y3 、R Y4 , R9, R 10 、R 11 、R 12 、R 13 、R 14a 、R 14b 、R 15 、R 16 、R 17 、R 18 、R 26 、R27a、R 27b 、R 30 、R 33 ), W 3 、W 4 、W 5 ,X,X 1 、X 2 、X 3 Or T is covalently linked to a PTM or a chemical linker group (L).

[0500] In any aspect or embodiment described herein, the VLM is via R P 、R 1 、R 1a 、R 1b 、R Y3 、R Y4 , R9, R 10 、R 11 、R 12 、R 13 、R 14a 、R 14b 、R 15 、R 16 、R 17 、R 18 、R 26 、R27a、R 27b 、R 30 、R 33 、W 3 、W 4 、W 5,X,X 1 、X 2 、X 3 Or T is covalently linked to a PTM or a chemical linker group (L).

[0501] In any aspect or embodiment described herein, R P 、R 1 、R 1a 、R 1b 、R Y3 、R Y4 , R9, R 10 、R 11 、R 12 、R 13 、R 14a 、R 14b 、R 15 、R 16 、R 17 、R 18 、R 26 、R27a、R 27b 、R 30 、R 33 、W 3 、W 4 ,X,X 1 、X 2 、X 3 or T can be independently covalently coupled to a linker and / or a linker to which one or more PTM, ULM, and VLM groups are attached. In any aspect or embodiment described herein, ULM is selected from the following structures:

[0502]

[0503]

[0504] 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.

[0505] In any aspect or embodiment described herein, the ULM is selected from the following structures:

[0506]

[0507]

[0508] wherein n is 0 or 1 and 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.

[0509] In any aspect or embodiment described herein, the ULM is selected from the following structures:

[0510]

[0511]

[0512]

[0513]

[0514]

[0515] 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, 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 ULM-a.

[0516] In any aspect or embodiment described herein, the phenyl rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 can be functionalized as esters to make them part of a prodrug.

[0517] In any aspect or embodiment described herein, 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.

[0518] In any aspect or embodiment described herein, the ULM or VLM is represented by:

[0519]

[0520] or a pharmaceutically acceptable salt thereof,

[0521] in:

[0522] R1 is H, optionally substituted alkyl or optionally substituted cycloalkyl;

[0523] R3 is an optionally substituted 5-6 membered heteroaryl;

[0524] W 5 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted pyridyl;

[0525] R14a and R 14b wherein one of them is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14b together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine;

[0526] R 15 is CN, optionally substituted fluoroalkyl, Optionally substituted (For example, where R 28a is halo, optionally substituted alkyl or fluoroalkyl) or

[0527] Each R 16 independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy;

[0528] Each R 26 are independently H, optionally substituted alkyl or NR 27a R 27b ;

[0529] Each R 27a and R 27b are independently H, optionally substituted alkyl, or R 27a and R 27b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0530] R 28 is H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl;

[0531] o is 0, 1, or 2; and

[0532] 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.

[0533] In any aspect or embodiment described herein, the ULM has the formula:

[0534]

[0535] in:

[0536] X 4 、X 5 and X 6 each selected from CH and N, not more than 2 of which are N;

[0537] R 1 is a C1-6 alkyl group;

[0538] R3 is an optionally substituted 5-6 membered heteroaryl;

[0539] R 14a and R 14b wherein one of them is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a and R 14b together with the carbon atom to which they are attached, form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine;

[0540] R 27a and R 27b are each independently H or C 1-6 alkyl;

[0541] q is 1, 2, 3, or 4;

[0542] R 15 yes or CN;

[0543] R 28 It is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C1-4 Alkyl, NH2,

[0544] R 28C is H, methyl, fluorine or chlorine;

[0545] R 16 It is H, C 1-4 Alkyl, fluorine, chlorine, CN or C 1-4 alkoxy; and

[0546] 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.

[0547] In any aspect or embodiment described herein, R 14a and R 14b Selected from: H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyloxyalkyl, C 1-4 Alkyl-NR 27a R 27b and CONR 27a R 27b .

[0548] In any aspect or embodiment described herein, R 14a and R 14b At least one of them is H (e.g., R 14a and R 14b Both are H).

[0549] In any aspect or embodiment described herein, R 14a and R 14b At least one of them is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 Alternatively, in any aspect or embodiment described herein, R 14a and R 14bwherein one of them is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 ; and R 14a and R 14b The other one is H.

[0550] In any aspect or embodiment described herein, R 14a and R 14b Together with the carbon atoms to which they are attached, they form where R 23 Selected from H, C 1-4 Alkyl, -C(O)C 1-4 alkyl.

[0551] In any aspect or embodiment described herein, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0552]

[0553] or a pharmaceutically acceptable salt thereof,

[0554] in:

[0555] X is CH or N;

[0556] R1 is H, optionally substituted alkyl or optionally substituted cycloalkyl;

[0557] R3 is an optionally substituted 5-6 membered heteroaryl;

[0558] R 14a and R 14b wherein one of them is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 、CONR 27a R 27b 、NHCOR 26 or NHCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14btogether with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine;

[0559] R 15 is CN, optionally substituted fluoroalkyl, Optionally substituted (For example, where R 28a is halo, optionally substituted alkyl or fluoroalkyl) or

[0560] Each R 26 are independently H, optionally substituted alkyl or NR 27a R 27b ;

[0561] Each R 27a and R 27b are independently H, optionally substituted alkyl, or R 27a and R 27b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0562] R 28 is H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl; and

[0563] 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.

[0564] In any aspect or embodiment described herein, R1 is C 1-6 alkyl.

[0565] In any aspect or embodiment described herein, R 14a and R 14b One of them is H, C 1-6 Alkyl, C 1-6 Haloalkyl, optionally substituted C 1-4 Alkylamine, C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy-C3-C7 heterocycloalkyl, (CH2) q OH, (CH2) q NR 27a R27b 、(CH2) q NHCOC 1-6 Alkyl, C 3-6 Cycloalkyl or NR 27a R 27b ; R 26 Each independently is H, C 1-6 Alkyl or NR 27a R 27b ; R 27a and R 27b are each independently H or C 1-6 alkyl; and q is 1, 2, 3 or 4.

[0566] In any aspect or embodiment described herein, R 14a and R 14b One of them is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, optionally substituted C 1-4 Alkylamine, (CH2) q C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy-C3-C7 heterocycloalkyl, (CH2) q OH, (CH2) q NR 27a R 27b 、(CH2) q NHCOC 1-6 Alkyl, C 3-6 Cycloalkyl or NR 27a R 27b ; R 26 Each independently is H, C 1-4 Alkyl or NR 27a R 27b ; R 27a and R 27b are each independently H or C 1-4 alkyl; and q is 1 or 2.

[0567] In any aspect or embodiment described herein, R 28 It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, (CH2) q OC 1-6 Alkyl, (CH2) q OH, (CH2) q NR 27a R 27b 、(CH2) q NHCOC1-6 Alkyl or

[0568] R 29 It is H, C 1-6 Alkyl, NR 27a R 27b or q NHCOC 1-6 alkyl; and

[0569] where q is 1 or 2.

[0570] In any aspect or embodiment described herein, R 3 In any aspect or embodiment described herein, X is CH.

[0571] In any aspect or embodiment described herein, the ULM is according to the formula:

[0572]

[0573] or a pharmaceutically acceptable salt thereof,

[0574] in:

[0575] R1, R 14a and R 14b As mentioned in this article;

[0576] X is CH or N;

[0577] R 30 is H, F or Cl;

[0578] R 16 It is H, C 1-4 Alkyl, fluorine, chlorine, CN or C 1-4 alkoxy;

[0579] R 28 It is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, as well as

[0580] 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.

[0581] In any aspect or embodiment described herein, the ULM is according to the formula:

[0582]

[0583] or a pharmaceutically acceptable salt thereof,

[0584] in:

[0585] R1, R 14a 、R 14b Each of which is as described herein;

[0586] R 30 is H, F, or Cl; and

[0587] 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.

[0588] In any aspect or embodiment described herein, the VLM is ligated via an R group such as R 1 、R 3 、R 14a 、R 14b 、R 15 、R 16 、R 23 、R 26 、R 27a 、R 27b 、R 28 、R 28a 、R 28C 、R 29 、R 30 ), X, X 4 、X 5 or X 6 Covalently linked to a PTM or chemical linker group (L).

[0589] In any aspect or embodiment described herein, the VLM is via R 1 、R 3 、R 14a 、R 14b 、R 15 、R 16 、R 23 、R 26 、R 27a 、R 27b 、R 28 、R 28a 、R 28C 、R 29 、R 30 ,X,X 4 、X 5 or X 6 Covalently linked to a PTM or chemical linker group (L).

[0590] In any aspect or embodiment described herein, R 1、R 3 、R 14a 、R 14b 、R 15 、R 16 、R 23 、R 26 、R 27a 、R 27b 、R 28 、R 28a 、R 28C 、R 29 、R 30 ,X,X 4 、X 5 or X 6 The linker may be independently covalently coupled to a linker and / or to which one or more PTM, ULM and VLM groups are attached.

[0591] 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.

[0592] In any aspect or embodiment described herein, the ULM moiety is selected from the group consisting of:

[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 aryl, heteroaryl, phenyl or phenyl groups such as indole groups, optionally via any suitable functional group such as amine, ester, ether, alkyl or alkoxy groups.

[0616] Example CLM:

[0617] In any aspect or embodiment described herein, the present disclosure provides CLMs that can be used to bind and recruit cerebellin.

[0618] In any aspect or embodiment described herein, the ULM is selected from the group consisting of the following chemical structures:

[0619]

[0620]

[0621] in:

[0622] W of formulae (a1) to (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)) is independently selected from CHO, CHR, C═O, SO2, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl;

[0623] W3 of formula (a2) is C or N;

[0624] Each X of formulae (a) to (f) is independently selected from absent, O, S, and CH2;

[0625] Each Y of formula (a1) to (f e) is independently selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0626] Each Z of formula (a1) to (e) is independently selected from absent, O, S or CH2, except that X and Z cannot both be CH2 or cannot both be absent;

[0627] Each G and G' of formula (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl (e.g., optionally substituted by R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0628] Each of Q1, Q2, Q3 and Q4 of formulae (a1) to (e) represents N or carbon C substituted by a group independently selected from H, R, N and N-oxide;

[0629] A of formula (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

[0630] each n of formulae (a1) to (e) represents an integer independently selected from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0631] Each R in formula (a1) to (e) is independently selected from: H, -C(=O)R' (e.g., a carboxyl group), -CONR'R" (e.g., an amide group), -OR' (e.g., OH), -NR'R" (e.g., an amine group), -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., alkylaryl 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 5-7 membered heteroaryl), unsubstituted or substituted straight or branched chain alkyl (e.g., optionally substituted with one or more halogens), cycloalkyl (e.g., 3-6 membered cycloalkyl) or aryl (e.g., 5-7 membered heteroaryl), C1-C6 straight or branched alkyl substituted with an optionally substituted 3-7 membered cycloalkyl), an optionally substituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy or hexyloxy; wherein the alkoxy group may be substituted with one or more halogen, alkyl, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl) or aryl (e.g., C5-C7 aryl)), an optionally substituted cycloalkyl (e.g., an optionally substituted 3-7 membered cycloalkyl), an optionally substituted heterocyclyl (e.g., an optionally substituted 3- -7-membered heterocyclyl), -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO 2NR'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(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 or -OCF3, wherein at least one W, X, Y, Z, G, G', R, R', R", Q1, Q2, Q3, Q4 or A is modified to be covalently attached to a PTM, a chemical linker (L), a ULM, a CLM or a combination thereof;

[0632] R' and R" of formulae (a1) to (e) are each independently selected from a bond, H, an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, and an optionally substituted heterocyclyl group;

[0633] n' of formulas (a1) to (e) is an integer of 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0634] represents a single bond or a double bond; and

[0635] Each of formulas (a1) to (e) represents a stereospecific ((R) or (S)) or non-stereospecific bond.

[0636] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0637]

[0638]

[0639] in:

[0640] Each W of formulae (a1) to (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)) is independently selected from CHO, CHR, C═O, SO2, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and an N-alkyl group;

[0641] W3 of formula (a2) is selected from C and N;

[0642] Each X of formula (a1) to (e) is independently selected from absent, O, S and CH2;

[0643] Each Y of formula (a1) to (e) is independently selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0644] Each Z of formula (a1) to (e) is independently selected from absent, O, S and CH2, except that X and Z cannot both be CH2 or cannot both be absent;

[0645] Each of G and G' in formulas (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl (e.g., optionally substituted by R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted by R', and benzyl optionally substituted by R';

[0646] Q1, Q2, Q3 and Q4 of formulae (a1) to (e) each independently represent nitrogen or carbon substituted by a group independently selected from H, R, N and N-oxide;

[0647] A of formula (a1) to (e) is independently selected from H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;

[0648] n of formulae (a1) to (e) represents an integer independently selected from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0649] R in formulas (a1) to (e) is selected from the group consisting of: H, -C(=O)R' (e.g., a carboxyl group), -CONR'R" (e.g., an amide group), -OR' (e.g., OH), -NR'R" (e.g., an amine group), -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., alkylaryl 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 5-7 membered heteroaryl), optionally substituted straight or branched chain alkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl) 1-C6 straight or branched alkyl), optionally substituted alkoxy groups (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 cycloalkyl (e.g., optionally substituted C3-C6 cycloalkyl), optionally substituted heterocyclyl (e.g., (optionally substituted 3-7 membered 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 W, X, Y, Z, G, G', R, R', R", Q1, Q2, Q3, Q4 or A is covalently linked (directly or indirectly, e.g., via a functional group or an atom such as O, S, N) to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof;

[0650] R' and R" of formulae (a1) to (e) are each independently selected from a bond, H, an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, an optionally substituted heterocyclyl group;

[0651] n' of formulas (a1) to (e) is an integer selected from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10); and

[0652] represents a single bond or a double bond;

[0653] Each of formulas (a1) to (e) represents a stereospecific ((R) or (S)) or non-stereospecific bond.

[0654] In any aspect or embodiment described herein, the CLM or ULM has the chemical structure of Formula (g):

[0655]

[0656] in:

[0657] W of formula (g) is selected from CH2, O, C=O, NH and N-alkyl;

[0658] A of formula (g) is selected from H, methyl or an optionally substituted linear or branched alkyl group;

[0659] n is an integer selected from 1 to 4;

[0660] R of formula (g) is independently selected from H, O, OH, N, NH, NH2, -Cl, -F, -Br, -I, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted linear or branched alkoxy (e.g., optionally substituted linear or branched 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), wherein at least one R or W is modified to be covalently linked to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof; and

[0661] Each of formula (g) Independently represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0662] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0663]

[0664] in:

[0665] Q1, Q2, Q3, Q4, Q5 each independently represent nitrogen or carbon substituted by a group independently selected from R, N or N-oxide;

[0666] W is selected from CH2 and C=O;

[0667] A is H or linear or branched C 1-3 an alkyl group (e.g., methyl or ethyl);

[0668] n is an integer selected from 1-4 (e.g., 1, 2, or 3; or 1 or 2);

[0669] G is H or linear or branched C 1-3 alkyl (e.g., methyl);

[0670] Each R is independently selected from H, O, OH, N, NH, NH2, -Cl, -F, -Br, linear or branched C 1-3 Alkyl (eg, methyl or ethyl), linear or branched C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2) or linear or branched C 1-3 an alkoxy group (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linking group (L); and

[0671] Each Independently represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0672] In any aspect or embodiment described herein, the CLM or ULM is represented by the following chemical structure:

[0673]

[0674] in:

[0675] Q1, Q2, Q3, Q4, Q5 each independently represent nitrogen or carbon substituted by a group independently selected from R', N or N-oxide;

[0676] R 4 is H or methyl;

[0677] R' is H, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (e.g., methyl or ethyl) or C 1-3 an alkoxy group (e.g., methoxy or ethoxy); and

[0678] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0679] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0680]

[0681]

[0682]

[0683] in:

[0684] A is H or linear or branched C 1-3 an alkyl group (e.g., methyl or ethyl);

[0685] G is H or linear or branched C 1-3 alkyl (e.g., methyl);

[0686] One R is hydrogen and the other R is H, O, OH, N, NH, NH2, -Cl, -F, -Br, straight or branched C 1-3 Alkyl (eg, methyl or ethyl), linear or branched C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2) or linear or branched C 1-3 an alkoxy group (e.g., methoxy or ethoxy); and

[0687] R' is H, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (e.g., methyl or ethyl) or C 1-3 Alkoxy (e.g., methoxy or ethoxy);

[0688] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific;

[0689] N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM (e.g., N* is a nitrogen atom that is (i) covalently linked to the PTM via the chemical linker (L) with full valence of H or methyl, or (ii) is shared with the chemical linker (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker (L));

[0690] is a single bond or a double bond; and

[0691] The site of attachment of the PTM via a chemical linker is indicated.

[0692] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0693]

[0694]

[0695]

[0696]

[0697]

[0698] in:

[0699] N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM (e.g., N* is a nitrogen atom that is (i) covalently linked to the PTM via the chemical linker (L) with full valence of H or methyl, or (ii) is shared with the chemical linker (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker (L)); and

[0700] The site of attachment of the PTM via a chemical linker (L) is indicated.

[0701] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0702]

[0703] in:

[0704] A is H or linear or branched C 1-3 an alkyl group (e.g., methyl or ethyl);

[0705] G is H or linear or branched C 1-3 alkyl (e.g., methyl);

[0706] Each R is independently H, OH, NH2, -Cl, -F, -Br, linear or branched C 1-3 Alkyl (eg, methyl or ethyl) or linear or branched C 1-3 an alkoxy group (e.g., methoxy or ethoxy); and

[0707] N* is covalently linked to the PTM via a chemical linker group (L) with full valence of H or methyl or to a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L).

[0708] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0709]

[0710] in:

[0711] A is H or linear or branched C1-3 an alkyl group (e.g., methyl or ethyl);

[0712] G is H or linear or branched C 1-3 alkyl (e.g., methyl);

[0713] One R is hydrogen and the other R is H, OH, NH2, -Cl, -F, -Br, straight or branched C 1-3 Alkyl (eg, methyl or ethyl) or linear or branched C 1-3 an alkoxy group (e.g., methoxy or ethoxy); and

[0714] N* is covalently linked to the PTM via a chemical linker group (L) with full valence of H or methyl or to a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L).

[0715] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0716]

[0717] in:

[0718] A is H or linear or branched C 1-3 an alkyl group (e.g., methyl or ethyl);

[0719] G is H or linear or branched C 1-3 Alkyl (e.g., methyl), preferably H;

[0720] One R is hydrogen and the other R is H, -Cl, -F, -Br, straight or branched C 1-3 Alkyl (eg, methyl or ethyl) or linear or branched C 1-3 Alkoxy (eg, methoxy or ethoxy); and

[0721] N* is covalently linked to the PTM via a chemical linker group (L) with full valence of H or methyl or to a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L).

[0722] In any aspect or embodiment described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4 or A of a CLM can be independently covalently coupled to a linker and / or a linker to which one or more PTM, ULM or CLM groups are attached.

[0723] In any aspect or embodiment described herein, R is selected from H, 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, and carboxyl.

[0724] In any aspect or embodiment described herein, at least one R (e.g., an R group) is selected from the following: H, 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, or W is modified to be covalently linked to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof.

[0725] In any aspect or embodiment described herein, n is an integer from 1 to 4, and on the aryl or heteroaryl group of the CLM, each R is an independently selected functional group or atom, such as O, OH, N, -Cl, -F, 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, and optionally, one of them is modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

[0726] More specifically, non-limiting examples of CLMs include those shown below and those "hybrid" molecules resulting from a combination of one or more of the different features shown in the following molecules, wherein at least one R or W is modified to be covalently linked to a PTM, a chemical linker (L), a ULM, a CLM, or a combination thereof.

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0738]

[0739]

[0740]

[0741]

[0742] in:

[0743] W is independently selected from O, CH2, CHR, C=O, SO2, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl (e.g., CH2, CHR, C=O, SO2, NH, and N-alkyl);

[0744] Q1, Q2, Q3, Q4, Q5 each independently represent nitrogen or carbon substituted by a group independently selected from R', N and N-oxide;

[0745] R 1 is selected from the group consisting of absent, H, OH, CN, C1-C3 alkyl, and C=O;

[0746] R 2 Selected from absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2;

[0747] R 3 is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxy), and substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

[0748] R 4 is selected from H, alkyl and substituted alkyl;

[0749] R 5 and R 6 Each independently selected from H, halogen, C(=O)R', CN, OH and CF3;

[0750] X is C, CH, C═O or N;

[0751] X1 is C=O, N, CH or CH2;

[0752] R' is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), NR 2 R 3 、C(=O)OR 2 and optionally substituted phenyl;

[0753] n is 0-4;

[0754] is a single bond or a double bond; and

[0755] The CLM is covalently linked to the PTM via a covalent bond or via a chemical linker group (L).

[0756] In any aspect or embodiment described herein, CLM is mediated via an R group (such as, R, R 1 、R 2 、R 3 、R 4 or R'), W, X or Q groups (such as, Q1, Q2, Q3, Q4 or Q5) are covalently linked directly to the PTM, or are linked through a chemical linking group (L).

[0757] In any aspect or embodiment described herein, CLM is via W, X, R, R 1 、R 2 、R 3 、R 4 、R 5 , R', Q1, Q2, Q3, Q4 and Q5 are covalently linked directly to the PTM or through a chemical linking group (L).

[0758] In any aspect or embodiment described herein, W, X, R 1 、R 2 、R 3 、R 4 , R', Q1, Q2, Q3, Q4 or Q5 can be independently covalently coupled to a linker to which one or more PTM, ULM or CLM groups are attached.

[0759] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds resulting from combining one or more features of the following compounds:

[0760]

[0761]

[0762]

[0763] in:

[0764] W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0765] R 1 is selected from the group consisting of absent, H, CH, CN, and C1-C3 alkyl;

[0766] R 2 is H or C1-C3 alkyl;

[0767] R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;

[0768] R 4 is methyl or ethyl;

[0769] R 5 is H or halogen;

[0770] R 6 is H or halogen;

[0771] n is an integer from 0 to 4;

[0772] R and R' are H, independently H, a functional group or atom (eg, H, a halogen (such as -Cl or -F), an amine, C 1-3 Alkyl, C 1-3 Alkoxy, NR 2 R 3 or C(=O)OR 2 ); or the point of attachment of a PTM or chemical linker (L);

[0773] Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl; and

[0774] Is a single bond or a double bond.

[0775] In any of the embodiments described herein, W, R 1 、R 2 , Q1, Q2, Q3, Q4, R or R' can be independently covalently coupled to a linker to which one or more PTM groups are attached.

[0776] In any of the embodiments described herein, R 1 、R 2 , Q1, Q2, Q3, Q4, R and R' can be independently covalently coupled to a linker to which one or more PTM groups are attached.

[0777] In any of the embodiments described herein, Q1, Q2, Q3, Q4, R, and R' can be independently covalently coupled to a linker to which one or more PTM groups are attached.

[0778] In any aspect or embodiment described herein, R is modified to be covalently linked to a linker group (L) or directly to a PTM, or a combination thereof.

[0779] In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

[0780]

[0781]

[0782] Where R' is a halogen, and R 1 As described in any aspect or embodiment described herein.

[0783] In any aspect or embodiment described herein, a "CLM" can be an imide that binds to cerebellum protein E3 ligase. These imide and linker attachment points can be, but are not limited to, one of the following structures:

[0784]

[0785]

[0786] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0787]

[0788]

[0789]

[0790]

[0791]

[0792] in:

[0793] N* is (i) covalently linked to the PTM via a chemical linker group (L) with full valence of H or methyl or (ii) a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl group of the chemical linker group (L); and

[0794] CLM The point of attachment to the linker group or PTM is indicated.

[0795] In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

[0796]

[0797] in:

[0798] N* is a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with the optionally substituted heterocycloalkyl group of the chemical linker group (L)); and

[0799] CLM The point of attachment to the linker group or PTM is indicated.

[0800] In any aspect or embodiment described herein, the CLM is selected from the group consisting of:

[0801]

[0802]

[0803] in:

[0804] CLM Indicates the point of attachment to the linker group or PTM;

[0805] N* is a nitrogen atom shared with a chemical linker group or PTM; and

[0806] W, Q4, and Q5 are each as defined in any aspect or embodiment described herein;

[0807] Example ILM:

[0808] AVPI tetrapeptide fragment

[0809] In any aspect or embodiment described herein, the ILM may comprise an alanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment or a non-natural mimetic thereof. In any aspect or embodiment described herein, the ILM is selected from the group consisting of the chemical structures represented by ILM-I, ILM-II, ILM-III, and ILM-IV:

[0810]

[0811]

[0812] in:

[0813] R for ILM-I, ILM-II, ILM-III, and ILM-IV 1 Selected from H or C 1-3 an alkyl group (e.g., methyl or ethyl);

[0814] R for ILM-I, ILM-II, ILM-III, and ILM-IV 2 Selected from H or C 1-3 an alkyl group (e.g., methyl or ethyl);

[0815] R for ILM-I, ILM-II, ILM-III, and ILM-IV 3 selected from cycloalkyl and heterocycloalkyl;

[0816] R for ILM-I, ILM-II, ILM-III, and ILM-IV 5 is H;

[0817] R of ILM-I, ILM-II and ILM-III 4 is selected from cycloalkyl (e.g., 5-7 membered cycloalkyl), heterocycloalkyl (e.g., 5-7 membered heterocycloalkyl), aryl (e.g., 5-7 membered aryl), heteroaryl (e.g., 5-7 membered heteroaryl), a bicyclic group, the bicyclic group optionally having 1, 2 or 3 heteroatoms such as O or N (e.g., a 9-12 membered bicyclic group having 1, 2 or 3 heteroatoms such as O or N), further optionally substituted with 1-3 substituents as described above; and

[0818] R of ILM-IV 4a Selected from -(CH2) x -aryl (e.g., 5-7 membered aryl), -(CH2) x - heteroaryl (e.g., 5-7 membered heteroaryl), which is further optionally substituted with 1-3 substituents as described above;

[0819] ILM-IV x is 0, 1, 2, or 3; and

[0820] The ILM is via R 4 、R 4a or R 5 Attached to a chemical linker (L) or PTM;

[0821] In any aspect or embodiment described herein, at least one of the following:

[0822] R for ILM-I, ILM-II, ILM-III, and ILM-IV 1 is a methyl group;

[0823] R for ILM-I, ILM-II, ILM-III, and ILM-IV 2 is a methyl group;

[0824] R for ILM-I, ILM-II, ILM-III, and ILM-IV3 is a C6 cycloalkyl group or a C6 heterocycloalkyl group (for example, );

[0825] R of ILM-I, ILM-II and ILM-III 4 is an 11-membered bicyclic group, which optionally includes one heteroatom (wherein the bicyclic group is optionally the point of attachment of the ILM to a chemical linker group (L) or a PTM, as described herein), or R of ILM-IV 4a -CH2CH2-C 5-7 Aryl, such as phenyl (wherein the C 5-7 The aryl or phenyl group is the point of attachment of the ILM to a chemical linker group (L) or PTM, as described herein); or

[0826] Its combination.

[0827] In any aspect or embodiment described herein, R of ILM-I, ILM-II, and ILM-III 4 for:

[0828]

[0829] In any aspect or embodiment described herein, the ILM or ULM is selected from the group consisting of:

[0830]

[0831]

[0832] in The site of attachment of the PTM via a chemical linker (L) is indicated.

[0833] In any aspect or embodiment described herein, the ILM may have the structure of Formula (XVII), which is based on the IAP ligand described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazoleamide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or a non-natural mimetic thereof:

[0834]

[0835] in:

[0836] R of formula (XVII) 1 Selected from Te group halogen (such as fluorine), cyano,

[0837] X of formula (XVII) is selected from O or CH2.

[0838] In any aspect or embodiment described herein, the ILM of the composition is selected from the group consisting of:

[0839]

[0840] In any aspect or embodiment described herein, the ILM of the compound is:

[0841]

[0842] In any aspect or embodiment described herein, the ILM of the compound has a chemical structure selected from the group consisting of:

[0843]

[0844] Exemplary linkers:

[0845] In any aspect or embodiment described herein, the compound as described herein comprises a PTM chemically linked to a ULM (e.g., CLM, VLM, ILM, or a combination thereof) via a chemical linker (L). In certain embodiments, the linker group L comprises one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), where A L 1 is a group coupled to PTM, and (A L ) q is the group coupled to the ULM.

[0846] In any aspect or embodiment described herein, the connection between the linker (L) and the ULM (e.g., VLM, ILM, or CLM) 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 (e.g., N, O, S), any additional heteroatoms (if present) are separated by at least one 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.

[0847] In any aspect or embodiment described herein, the linker group L is a bond or is of the formula -(A L ) q35, 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, 100 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 or 80), and wherein L is covalently bound to both the PTM and the ULM and provides for the binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase to achieve ubiquitination of the target protein.

[0848] In any aspect or embodiment described herein, the linker group L is a bond or is of the formula -(A L ) q -represented by a chemical linker group, wherein A is a chemical moiety, as described in any aspect or embodiment described herein, and q is an integer from 6 to 30 (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, or 25), and wherein L covalently binds to both the PTM and the ULM and provides sufficiently close binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase to cause ubiquitination of the target protein.

[0849] In any aspect or embodiment described herein, the linker group (L) is: -(A L ) q -、

[0850] in:

[0851] (A L ) q is a group that connects a ULM (such as a CLM, ILM, or VLM) to a PTM;

[0852] The linker q is an integer greater than or equal to 1;

[0853] Each A L Independently selected from the group consisting of: key, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 、C=O、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 , optionally 1-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted with 1-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 1-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 1-8 R L1 and / or R L2 C 5-13 Spiroheterocyclic group, optionally substituted by 1-6 R L1 and / or R L2 substituted aryl, optionally substituted with 1 to 6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently optionally linked to other groups to form optionally 1-4 R L5 an optionally substituted cycloalkyl and / or heterocyclyl moiety; and

[0854] R L1 、R L2 、R L3 、R L4 and R L5 Each independently selected from 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 (e.g., 5-membered, 6-membered, 7-membered, or 8-membered aryl), heteroaryl (e.g., 5-membered, 6-membered, 7-membered, or 8-membered 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, C≡CC 1-8 Alkyl, C≡CH, 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 and NHSO2NH2.

[0855] In any aspect or embodiment described herein, q is an integer greater than or equal to 1.

[0856] In any aspect or embodiment described herein, for example, when q of the linker is greater than 2, (A L ) q As A L 1 and (A L ) q A group wherein the linker couples the PTM to the ULM.

[0857] In any aspect or embodiment described herein, for example, when q of the linker is 2, A L 2 is connected to A L 1 and ULM groups.

[0858] In any aspect or embodiment described herein, q of the chemical linking group (L) is an integer from 1 to 100 (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 or 80).

[0859] 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 that connects the ULM moiety to the PTM moiety.

[0860] In any aspect or embodiment described herein, unit A of linker (L) L Contains a group represented by a general structure selected from the following:

[0861] -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(lower alkoxy)-OCH2-, -NR(CH2) n -(lower alkoxy)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(Heterocycloalkyl)-, -NR(CH2CH2O) n-(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(Heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocyclyl)-CH2, -NR(CH2CH2) n -(heterocyclyl)-(heterocyclyl)-CH2 and -N(R1R2)-(heterocyclyl)-CH2; wherein

[0862] n of the linker can be 0 to 10;

[0863] R of the linker may be H or lower alkyl; and

[0864] R1 and R2 of the linker may form a ring via the attached N.

[0865] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 、C 40 、C 41 、C 42 、C 43 、C 44 、C 45 、C 46 、C 47 、C 48 、C 49 or C 50 alkyl, and including all subranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), wherein each carbon is optionally substituted or replaced independently by: (1) a heteroatom selected from N, O, S, P, or Si atoms, with an appropriate number of hydrogens, substitutions, 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 covalently attached or adjacently positioned).

[0866] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、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 or C 50 alkyl), wherein:

[0867] Each carbon is optionally substituted or replaced independently by a group independently selected from the group consisting of: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 、C=O、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 , optionally 1-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted with 1-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 1-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 1-8 R L1 and / or R L2 C 5-13Spiroheterocyclic group, optionally substituted by 1-6 R L1 and / or R L2 substituted aryl, optionally substituted with 1 to 6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently optionally linked to other groups to form optionally 1-4 R L5 an optionally substituted cycloalkyl and / or heterocyclyl moiety; and

[0868] 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, 5-8 membered aryl (e.g., 5-, 6-, 7-, or 8-membered aryl), 5-8 membered heteroaryl (e.g., 5-, 6-, 7-, or 8-membered 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, C≡CC 1-8 Alkyl, C≡CH, 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 1-8Alkyl, 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 or NHSO2NH2.

[0869] In any aspect or embodiment described herein, the linker group is an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 、C 40 、C 41 、C 42 、C 43 、C 44 、C45 、C 46 、C 47 、C 48 、C 49 or C 50 Alkyl, and including all subranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), wherein each carbon atom is optionally substituted or replaced by:

[0870] O, N, S, P or Si atoms, with appropriate number of hydrogen, substitution (e.g., OH, halogen, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 alkoxy or methoxy) or both to complete the valence;

[0871] Optionally substituted aryl (e.g., optionally substituted 5-membered or 6-membered aryl) or bicyclic aryl (e.g., optionally substituted 9-20-membered bicyclic heteroaryl), such as optionally substituted aryl or bicyclic aryl, which is optionally substituted with OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or methoxy substitution;

[0872] Optionally substituted heteroaryl (e.g., optionally substituted 5-membered or 6-membered heteroaryl) or bicyclic heteroaryl (e.g., optionally substituted 9-20 membered bicyclic heteroaryl), such as optionally substituted heteroaryl or bicyclic heteroaryl, having one or more heteroatoms selected from N, O, S, P and Si, having an appropriate number of hydrogens, substitutions (e.g., OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl C 1-8 Hydroxyalkyl, C 1-8 alkoxy or methoxy) or both to complete the valence);

[0873] Optionally substituted C1-C6 alkyl, such as optionally substituted by OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or methoxy substitution;

[0874] Optionally substituted C2-C6 alkenyl, such as optionally substituted by OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8Alkoxy or methoxy substitution;

[0875] Optionally substituted C2-C6 alkynyl, such as optionally substituted by OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or methoxy substitution;

[0876] Optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl) or bicyclic cycloalkyl (e.g., optionally substituted C5-C20 bicyclic cycloalkyl), such as optionally substituted cycloalkyl or bicyclic cycloalkyl, which is optionally substituted by OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or methoxy substituted; or

[0877] Optionally substituted heterocycloalkyl (e.g., an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic group) or bicyclic heterocycloalkyl (e.g., an optionally substituted 5-20 membered bicyclic heterocycloalkyl), such as an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, having one or more heteroatoms independently selected from N, O, S, P, or Si atoms, having an appropriate number of hydrogens, substitutions (e.g., OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Halogenated alkyl C 1-8 Hydroxyalkyl, C 1-8 alkoxy or methoxy) or both to complete the valence.

[0878] In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted with one or more OH, halo, linear or branched C1-C6 alkyl (such as methyl or ethyl), linear or branched C1-C6 haloalkyl, linear or branched C1-C6 hydroxyalkyl, or linear or branched C1-C6 alkoxy (e.g., methoxy).

[0879] In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonding (eg, no heteroatoms are covalently linked or adjacently positioned).

[0880] In any aspect or embodiment described herein, the linker (L) comprises 1 to 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 or replaced with a heteroatom selected from N, S, P, or Si atoms, with an appropriate number of hydrogens to complete the valences.

[0881] In any aspect or embodiment described herein, the linker (L) is represented by the following chemical structure:

[0882]

[0883] in:

[0884] Y L1 is a bond, O or NH, C=O or C1-C3 alkyl;

[0885] W L2 is an optionally substituted 3-7 membered ring (e.g., 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl);

[0886] Y L2 is a bond, O, unsubstituted or substituted straight or branched C1-C6 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2;

[0887] W L3is a 3-7 membered ring (e.g., a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl), an 8-11 membered spiro ring, or an 8-11 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group, or C=O;

[0888] Y L3 is a bond, O, unsubstituted or substituted straight or branched C1-C6 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2;

[0889] W L4 is a 3-7 membered ring (e.g., 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl) or an 8-11 membered spiro ring, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group, or C=O);

[0890] Y L4is a bond, O, unsubstituted or substituted straight or branched C1-C4 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C4 alkenyl (e.g., optionally substituted C2-C3 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C4 alkynyl (e.g., optionally substituted C2-C3 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2;

[0891] Y L5 is a bond, O, unsubstituted or substituted straight or branched C1-C9 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C9 alkenyl (e.g., optionally substituted C2-C6 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2;

[0892] Y L6is a bond, O, unsubstituted or substituted straight or branched C1-C8 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C8 alkenyl (e.g., optionally substituted C2-C6 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C8 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2;

[0893] Y L7 is a bond, O, unsubstituted or substituted straight or branched C1-C10 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C10 alkenyl (e.g., optionally substituted C2-C8 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), 3, methyl, ethyl, isopropyl group or C=O) or unsubstituted or substituted straight or branched C1-C10 alkynyl (e.g., optionally substituted C2-C8 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of said alkyl, said alkenyl and said alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3); and

[0894] Y L7is a bond, O or unsubstituted or substituted linear or branched C1-C25 alkyl (e.g., unsubstituted or substituted linear or branched C1-C25 alkyl and / or optionally substituted with one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl groups, or C=O), said alkyl optionally having one or more (e.g., 1, 2, or 3) C atoms replaced by O, NH, NCH3, or NCH(CH3); and

[0895] Indicates the attachment site of a PTM or ULM,

[0896] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from the group consisting of:

[0897]

[0898]

[0899] in:

[0900] U L and U L1 are independently selected from a bond or O;

[0901] X L1 、X L2 、 Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is a key, and if Y L2 is N, then U L1 is the key;

[0902] n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1;

[0903] m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1;

[0904] R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are optionally 1 or 2 substituents when X L1 When it is N, it is not with X L1On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When N is not with Y L1 On adjacent carbon atoms, or when Y L2 When N is not with Y L2 On adjacent carbon atoms;

[0905] M L Selected from the following:

[0906] Among them, M L are optionally independently selected from methyl, halogen (eg, F), fluoroalkyl (eg, C 1-3 fluoroalkyl), 1 or 2 substituents of OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms;

[0907] Z L and Z L1 Each independently selected from O or NR 3 ;

[0908] R L3 is H, methyl, ethyl or isopropyl;

[0909] p is 0, 1, or 2; and

[0910] U L and U L1 is the attachment site for a PTM or ULM.

[0911] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from the group consisting of:

[0912]

[0913]

[0914] in:

[0915] U L and U L1 are independently selected from a bond or O;

[0916] X L1 、X L2 、 Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is a key, and if Y L2 is N, then U L1 is the key;

[0917] n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1;

[0918] m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1;

[0919] R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are optionally 1 or 2 substituents when X L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When N is not with Y L1 On adjacent carbon atoms, or when Y L2 When N is not with Y L2 On adjacent carbon atoms;

[0920] M L Selected from the following:

[0921] Among them, M L are optionally independently selected from methyl, halogen (eg, F), fluoroalkyl (eg, C 1-3 fluoroalkyl), 1 or 2 substituents of OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms;

[0922] Z L and Z L1 Each independently selected from O or NR L3 ;

[0923] R L3 is H, methyl, ethyl or isopropyl;

[0924] p is 0, 1, or 2;

[0925] q is 0, 1, 2, 3, 4 or 5, where Y L2 When N, q is not 0 or 1; and

[0926] U L and Z L is the attachment site for a PTM or ULM.

[0927] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from the group consisting of:

[0928]

[0929]

[0930] in:

[0931] U L and U L1 are independently selected from a bond or O;

[0932] X L1 、X L2 、 Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is a key, and if Y L2 is N, then U L1 is the key;

[0933] n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1;

[0934] m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1;

[0935] R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are optionally 1 or 2 substituents when X L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When N is not with Y L1 On adjacent carbon atoms, or when Y L2 When N is not with Y L2 On adjacent carbon atoms;

[0936] W L1 and W L2 Each independently selected from N or CH, wherein when W L2 When N, then U L1 is the key;

[0937] r1 is 1 or 2, and r2 is 0, 1 or 2, where Y L1 and W L2 When both are N, r1 is 2 and r2 is 1 or 2;

[0938] R L3 represents a radical independently selected from methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are optionally 1 or 2 substituents when X L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When N is not with Y L1 On adjacent carbon atoms, or when Y L2 When N is not with Y L2 On adjacent carbon atoms;

[0939] M L1 Selected from the following:

[0940] Among them, M L1 are optionally independently selected from methyl, halogen (eg, F), fluoroalkyl (eg, C 1-3 fluoroalkyl), 1 or 2 substituents of OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms;

[0941] Z L and Z L1 Each independently selected from O or NR 3 ;

[0942] p is 0, 1, or 2; and

[0943] U L and U L1 is the attachment site for a PTM or ULM.

[0944] In any aspect or embodiment described herein, the linker (L) is selected from:

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964] where each * and is the attachment site for a PTM or ULM.

[0965] In any aspect or embodiment described herein, the linker (L) is selected from:

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986] where each * and is the attachment site for a PTM or ULM.

[0987] In any aspect or embodiment described herein, the linker (L) is selected from:

[0988]

[0989]

[0990] where each * is an attachment site for a PTM or ULM.

[0991] In any aspect or embodiment described herein, the linker (L) comprises the following chemical structure:

[0992]

[0993] in:

[0994] W L1 and W L2 Each independently absent, 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 QThe groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[0995] 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 NR YL1 substituted, optionally substituted C1-C6 alkene and optionally one or more C atoms are replaced by O, optionally substituted C1-C6 alkyne and optionally one or more C atoms are replaced by O, or optionally substituted straight or branched C 1-6 C alkoxy;

[0996] R YL1 is H or an optionally substituted straight or branched chain C 1-6 alkyl;

[0997] n is 0-10; and

[0998] Indicates the point of attachment to the PTM or ULM section.

[0999] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the group consisting of:

[1000]

[1001] in:

[1002] W L1 and W L2 are each independently absent, piperazine, piperidine, morpholine, optionally replaced by R Q Replace, each R Q are independently H, -Cl-, -F-, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl (e.g., methyl, ethyl), optionally substituted linear or branched C1-C6 alkoxy (e.g., methoxy, ethoxy);

[1003] Y L1 are each 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 NR YL1 replacement; optionally substituted C1-C6 alkene and optionally one or more C atoms are replaced by O, optionally substituted C1-C6 alkyne and optionally one or more C atoms are replaced by O, or optionally substituted straight or branched C1-C6 alkoxy;

[1004] R YL1 is H or an optionally substituted straight or branched chain C 1-6 alkyl (e.g., methyl, ethyl);

[1005] n is 0-10; and

[1006] Indicates the point of attachment to the PTM or ULM section.

[1007] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the group consisting of:

[1008]

[1009] in:

[1010] W L1 and W L2 Each independently does not exist, is aryl, heteroaryl, ring, heterocycle, C 1-6 Alkyl and optionally one or more C atoms are replaced by O or NR YL1 Replacement, 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 substituted by RQ, each RQ independently being H, halo, 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 YL1 R YL2 , 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;

[1011] 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;

[1012] Q L is a 3-6 membered alicyclic, bicyclic 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 C 1-6 Alkyl (eg, optionally substituted with one or more halo or C1-6 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;

[1013] 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 YL1 、R YL2 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms;

[1014] n is 0-10; and

[1015] Indicates the point of attachment to the PTM or ULM section.

[1016] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the group consisting of:

[1017]

[1018] in:

[1019] W L1 and W L2 Each independently does not exist, is cyclohexane, cyclopentane, piperazine, piperidine, morpholine, C 1-6 Alkyl and optionally one or more C atoms are replaced by O or NR YL1 Replacement, C 1-6 olefins 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, or C 1-6 Alkyne and optionally one or more C atoms are replaced by O, each optionally replaced by R Q Replace, each R Q are independently H, -Cl, -F, OH, CN, CF3, hydroxyl, optionally substituted linear or branched C1-C6 alkyl (e.g., methyl, ethyl), or optionally substituted linear or branched C1-C6 alkoxy;

[1020] Y L1 Each independently is a bond, NR YL1 ,O,CR YL1 R YL2 , C=O, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms are replaced by O or NR YL1 Replacement, C 1-6olefins and optionally one or more C atoms are replaced by O, C 1-6 an alkyne and optionally one or more C atoms are replaced by O, or an optionally substituted straight-chain or branched C1-C6 alkoxy group;

[1021] Q L is a 3-6 membered heterocyclic, heterobicyclic or heteroaromatic ring, optionally substituted by 0-6 R Q Replace, each R Q are independently H or an optionally substituted linear or branched C 1-6 Alkyl (e.g., optionally substituted with one or more halo, C 1-6 alkoxy substituted);

[1022] R YL1 、R YL2 are each independently H or an optionally substituted linear or branched C 1-6 Alkyl (e.g., methyl, ethyl, optionally substituted with one or more halogen or C 1-6 alkoxy substituted);

[1023] n is 0-10; and

[1024] Indicates the point of attachment to the PTM or ULM section.

[1025] In any aspect or embodiment described herein, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc. ethylene glycol units), about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units; or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl group. In certain embodiments, the linker can be asymmetric or symmetric.

[1026] In any aspect or embodiment described herein, the linker group can be any suitable moiety described herein. In any aspect or embodiment described herein, 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.

[1027] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 、C 40 、C 41 、C 42 、C 43 、C 44 、C 45 、C 46 、C 47 、C 48 、C 49 or C 50alkyl), wherein each carbon is optionally substituted with: (1) a heteroatom selected from N, S, P or Si atoms, with an appropriate number of hydrogens, substitutions, 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) does not have heteroatom-heteroatom bonding (e.g., no heteroatoms are covalent linkers or adjacently positioned).

[1028] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 、C 40 、C 41 、C 42 、C 43 、C 44 、C 45 、C 46 、C 47 、C 48 、C 49 or C 50 alkyl), wherein: each carbon is optionally substituted with: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NRL3 ,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 , optionally 0-6 R 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 Heterocyclyl, optionally substituted by 0-8 R L1 and / or R L2 C 5-13 Spiroheterocyclyl, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently optionally linked 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 1-8 Cycloalkyl, SC1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl)C(C 1-8 alkyl)=C(C 1-8 alkyl)2、Si(OH)3、Si(C 1-8 Alkyl)3, Si(OH)(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 In any aspect or embodiment described herein, the linker (L) has no heteroatom-heteroatom bonding (eg, no heteroatoms are covalently linked or adjacently positioned).

[1029] 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 hydrogens to complete the valence. For example, in any aspect or embodiment described herein, the linker (L) has a chemical structure selected from:

[1030]

[1031]

[1032] , wherein 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.

[1033] In some embodiments, L is an optionally substituted polyethyleneoxy group comprising 1 to 10 units.

[1034] In some further embodiments, L is a polyethylene group comprising 1 to 10 ethylene glycol units, optionally substituted with an aryl or phenyl group.

[1035] In any embodiment, the compound comprises multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[1036] Although the ULM group and the PTM group can be covalently linked to the linker group via 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 via 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.

[1037] Exemplary Tau Bifunctional Degrading Compounds

[1038] As noted above, in certain aspects, the present description provides bifunctional compounds comprising at least one PTM group, a linker, and at least one ULM (VLM or CLM) group as described herein.

[1039] In certain embodiments, the compound is selected from the group consisting of compounds 332, 335, 337-586, and 589-686 (eg, selected from Table 1), and salts and polymorphs thereof.

[1040] In certain embodiments, the compound is selected from Table 1 (ie, the compound is selected from compounds 332, 335, 337-586, and 589-686), and salts and polymorphs thereof.

[1041] In any aspect or embodiment described herein, the compound is selected from Formulas CI to CV:

[1042]

[1043]

[1044] in:

[1045] R 101 are 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

[1046] R 102 is selected from H, alkyl, haloalkyl, cycloalkyl or heterocycloalkyl;

[1047] R 103 are 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

[1048] R 104 are 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

[1049] R 105 are 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl or cyano;

[1050] R 106 、R 107 、R 109 、R 110 、R 111 、R 112 、R 113 、R 114 、R 116 、R 117 、R 120 、R121 、R 126 、R 127 、R 122 and R 123 are each independently selected from H, alkyl, halogen or haloalkyl;

[1051] R 108 are 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, cyano or methoxy;

[1052] R 115 is selected from H, alkyl and haloalkyl;

[1053] R 118 and R 119 are independently selected from H, alkyl, halogen or haloalkyl, or R 118 and R 119 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, such as cyclopropane or oxetane;

[1054] R 124 and R 125 are independently selected from H, alkyl, halogen or haloalkyl, or R 124 and R 125 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, such as cyclopropane or oxetane;

[1055] G is phenyl or a 5- or 6-membered heteroaryl ring; and

[1056] Z is CH2 or C=O.

[1057] In any aspect or embodiment described herein, at least one of the following:

[1058] R 101 is H, F or Cl;

[1059] R 102 is H, CH3 or CF2H;

[1060] R 103 is H or F;

[1061] R 104 is H, CH3, F or CN;

[1062] R 105 is H, CN, CH3 or CF3;

[1063] R 106 and R 107 are each independently H, F or CH3;

[1064] R 108is H, F or CH3O;

[1065] R 109 and R 110 are each independently H or CH3;

[1066] R 111 and R 112 are each independently H, F or CH3;

[1067] R 113 and R 114 are each independently H or CH3;

[1068] R 115 is H or CH3;

[1069] R 116 and R 117 are each independently H or CH3;

[1070] R 118 and R 119 are each independently H, CH3, F, or R 118 and R 119 Together with the carbon atoms to which they are attached, represent a cyclopropane or oxetane ring;

[1071] R 120 and R 121 are each independently H or CH3;

[1072] R 122 and R 123 are each independently H or CH3;

[1073] R 124 and R 125 are each independently H, CH3, F, or R 124 and R 125 Together with the carbon atoms to which they are attached, represent a cyclopropane or oxetane ring;

[1074] R 126 and R 127 are each independently H or CH3;

[1075] A is pyridine or pyrimidine;

[1076] Z is CH2 or C=O; or

[1077] Its combination.

[1078] Therapeutic compositions

[1079] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one bifunctional compound as described herein in combination with a pharmaceutically acceptable carrier, additive, or excipient.

[1080] On the other hand, the present description provides a therapeutic composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient, and optionally another bioactive agent. The therapeutic composition achieves targeted 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 degrading the target protein. In certain embodiments, the therapeutic composition as described herein can be used to achieve protein degradation to treat or improve Tau-related diseases or conditions, such as Tau protein accumulation or aggregation or neurodegenerative diseases associated with Tau accumulation or aggregation. In any aspect or embodiment described herein, the disease or disorder comprises at least one of: acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Addison's pupil, Addison's syndrome, adrenoleukodystrophy, corpus callosum dysgenesis, agnosia, Acardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, hypoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Alzheimer's disease, - Kleinberg anomaly, arteriovenous malformation, Asperger syndrome, ataxia, ataxia, telangiectasia, ataxia and cerebellar / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, dysautonomia, back pain, Barthel syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhardt-Rodriguez syndrome, Binswanger disease, blepharospasm, Budd-Soeur syndrome, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome Symptoms, brain and spinal tumors, cerebral aneurysms, brain injuries, Brown-Sequard syndrome, bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, cavernous tumors, cavernous hemangiomas, cavernous malformations, central cervical cord syndrome, central cord syndrome, central pain syndrome, cranial diseases, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, brain atrophy, cerebral beriberi, cerebral gigantism, brain hypoxia, cerebral palsy, cerebro-oculofacial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, choreoacanthocytosis, chronic inflammation Congenital demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, chronic pain type II, Cockayne syndrome, Koch-Lössler syndrome, COFS, syringoencephalitis, coma and persistent vegetative state, complex regional pain syndrome, congenital facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformation, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus infection, chorea, Dan-Walker syndrome, Dawson disease, DeMosier syndrome,Deep brain stimulation for Parkinson's disease, Dejerine-Klumpke palsy, dementia, dementia - multi-infarct, dementia - semantic, dementia - subcortical, dementia with Lewy bodies, dentate-cerebellar ataxia, dentate-rubral atrophy, dermatomyositis, developmental movement disorder, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dysphagia, movement disorders, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, and myotonia disorders, early infantile epilepsy, encephalopathy, empty sella syndrome, encephalitis lethargica, encephalocele, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, Erb-Duchenne and Dejerine-Klumpke palsies, Oberle's palsy, Fabry disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic basal ganglia, calcifications, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome Syndrome), floppy infant syndrome, Friedreich's Ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, spherocytic leukoencephalopathy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, head injury, headache, hemicrania continua, hemifacial spasm, crossed hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary ataxia (polyneuritis), herpes zoster, herpes zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-related disorders, myelopathy, Huntington's disease Disease), hydrocephalus, hydrocephalus, normal-pressure hydrocephalus, hydromyelia, hyperactivity, hypercortisolism, lethargy, hypertonia, infantile hypotonia, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, occipital schizencephaly, enterogenic lipodystrophy, intracranial cysts, intracranial hypertension, Isaac's syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy's disease, Kinsbourne syndrome,Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Klüver-Bucy Syndrome, Korsakoff's Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral Femoral Cutaneous Nerve Entrapment, Dorsolateral Medullary Syndrome, Learning Disability, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine-Critchley Syndrome, Lewy Body Dementia, Lipid Storage Disease, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus Neurological Sequelae, Lyme Disease Neurological complications, Machado-Joseph Disease, Megalepharia, Mania, Megalepharia, Melkersson-Rosenthal syndrome, Meningitis, Meningitis and encephalitis, Menkes Disease, Meralgia paresthesia, Metachromatic leukodystrophy, Microcephaly, Migraine, Miller Fisher syndrome, Mini-stroke, Mitochondrial myopathy, Mobius syndrome, Monomelic muscular dystrophy, Motor neuron disease, Moyamoya disease, Mucolipidosis, Mucopolysaccharidosis, Multifocal motor neuropathy, Multi-infarct dementia, Multiple sclerosis, Multiple system atrophy, Multiple system atrophy with orthostatic hypotension, Muscular dystrophy, Congenital myasthenia, Myasthenia gravis Gravis), diffuse myeloblastic sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, hyperthyroid myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, brain iron deposition neurodegenerative diseases, neurofibromatosis, neuroleptic malignant syndrome, neurologic complications of AIDS, neurologic complications of Lyme disease, neurologic consequences of cytomegalovirus infection, neurologic manifestations of Pompe disease, neurologic sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid, lipofuscinosis, neuronal migration disorder, hereditary neuropathy, neurosarcoidosis, neurotoxicity, cavernous nevus,Niemann-Pick Disease, Normal Pressure Hydrocephalus, Occipital Neuralgia, Obesity, Occult Spinal Tube Incompleteness Sequence, Ohtahara Syndrome, Olivoptocerebellar Atrophy, Opsoclonus and Myoclonus, Orthostatic Hypotension, O'Sullivan-McLeod Syndrome, Overuse Syndrome, Chronic Pain, Paine Disease, Pantothenate Kinase-Related Neurodegeneration, Paraneoplastic Syndromes, Paresthesias, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry-Romberg, Peyer's-Merck disease, Pena Shokeir II syndrome, fascicular cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, nerve pinch, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, trephine cerebri, postherpetic neuralgia, postinfectious encephalomyelitis, postpoliomyelitis syndrome, postural hypotension, postural orthostatic hypotension, tachycardia syndrome, postural tachycardia syndrome, primary dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial Facial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing gray matter dystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (formerly known as), Ramsay Hunt syndrome II (formerly known as), Rasmussen's encephalitis, reflex sympathetic dystrophy, Refsum's disease, Refsum's disease of infancy, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Reye-Dieter syndrome, sacral nerve root cyst, Saint Vitus's chorea Vitus Dance), salivary gland disease, Sandhoff Disease, Schilder's Disease, schizencephaly, Seitelberger Disease, epilepsy, semantic dementia, septo-optic dysplasia, shaken baby syndrome, Shingles Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski Syndrome, stiff-person syndrome, striatonigral degeneration, stroke,Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy, SUNCT Headache Dysphagia, Sydenham Chorea, Syncope, Syphilitic Myelosclerosis, Syringomyelia, Syringomyelia, Systemic Lupus Erythematosus, Tardive Dyskinesia with Tabes Dorsalis, Tarlov Cyst, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord Syndrome, Thomsen's Myotonia, Thoracic Outlet Syndrome, Hyperthyroid Myopathy, Tic Douloureux, Todd's Paralysis, Tourette Syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, Von Economo disease, VHL, Von Recklinghausen's disease, Wallenberg's syndrome, Werdnig-Hoffman disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash, Whipple's disease, Williams syndrome, Wilson's disease Disease), X-linked spinal and bulbar muscular atrophy or Zellweger Syndrome. For example, in any aspect or embodiment described herein, the disease or condition is a neurological condition associated with at least one of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injury, epilepsy, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, brain aneurysm, dural arteriovenous fistula, headache, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors and stroke. For example, in any aspect or embodiment described herein, the disease or condition is at least one of primary tauopathy (FTDP-17, progressive supranuclear palsy (PSP), corticobasal disease (CBD) and most frontotemporal dementias,Secondary tauopathies (Alzheimer's disease), Huntington's disease, muscular dystrophy, Parkinson's disease, Batten disease, spinal cord and brain injuries, epilepsy, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, brain aneurysms, dural arteriovenous fistulas, headaches, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors, and stroke.

[1081] In an alternative aspect, the present disclosure relates to a method for treating a disease state in a subject in need thereof or improving one or more symptoms of a disease or condition by degrading Tau protein, 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 herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient and optionally co-administered with another bioactive agent, wherein the composition is effective in treating or improving the disease or condition or one or more symptoms thereof in the subject. The methods according to the present disclosure can be used to treat certain disease states, conditions, or symptoms, including neurological diseases or conditions, such as neurodegenerative diseases or conditions, by administering an effective amount of at least one therapeutically effective compound as described herein. For example, the methods according to the present disclosure can be used to treat conditions causally related to the accumulation and / or aggregation of Tau protein, such as neurological / neurodegenerative diseases or conditions.

[1082] Where applicable, the present disclosure also includes compositions comprising pharmaceutically acceptable salts, especially acid or base addition salts, of the compounds described herein.

[1083] The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned compounds that can be used according to this aspect are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)] salts, and the like.

[1084] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of compounds of the present invention are those chemical bases that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium ions) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium ions), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and other basic salts of lower alkanolammonium and pharmaceutically acceptable organic amines, etc.

[1085] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrug groups) that, when administered to a patient, directly or indirectly provides a compound of the invention or an active metabolite of a compound of the invention.

[1086] The effective compound for the treatment as described herein can be applied in single dose or divided dose according to the present disclosure by oral, parenteral or local route. The application range of active compound can be from continuous (intravenous drip) to several times a day application (for example, QID) and can include such as oral, local, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include penetration enhancers), through buccal, sublingual, intranasal, intraocular, intrathoracic, vaginal and suppository application and other administration routes. As used herein, term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion technology. Enteric coated oral tablets can be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form depends on the pharmacokinetics of the selected specific agent and the type, position and severity of the patient's disease, condition or symptom and the health status of the patient.

[1087] Compounds according to the present disclosure may also be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration. Therefore, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. Compounds according to the present disclosure may be administered in an intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but may also be administered as suppositories and transdermal or other topical forms. Intramuscular injection in the form of liposomes or depot formulations may also be used to control or maintain the release of the compound at the injection site.

[1088] The compositions as described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in a controlled release formulation. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin, and combinations thereof.

[1089] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, dimethyl sulfoxide (DMSO), β-cyclodextrin and its derivatives, and isotonic sodium chloride solution. Alternatively, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, may be used to prepare injectables, as may natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Phthalates or similar alcohols.

[1090] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch, as well as other carriers known in the art. For oral administration in capsule form, useful diluents include lactose and corn starch. When an aqueous suspension is desired for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or coloring agents may also be added, as desired. Lubricants, such as magnesium stearate, are also typically added.

[1091] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[1092] Pharmaceutical compositions as described herein can also be administered topically. For topical application, pharmaceutical compositions can be formulated into transdermal patches, which can be reservoir or matrix patches that contain the active compound in combination with one or more carriers, buffers, absorption enhancers, and provide continuous administration for 1 day to two weeks.

[1093] Alternatively, the pharmaceutical compositions of the present disclosure may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[1094] Alternatively, the pharmaceutical compositions of the present disclosure may be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[1095] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated for ophthalmic use. For example, the pharmaceutical compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical compositions can be formulated as an ointment such as petrolatum.

[1096] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[1097] The amount of active pharmaceutical ingredient that can be combined with the carrier material to prepare a single dosage form in the pharmaceutical compositions as described herein will vary depending on the condition of the subject and the disease, condition or symptom being treated, the particular mode of administration, and the condition of the subject. Preferably, the composition should be formulated to contain from about 0.05 mg to about 750 mg or more, more preferably from about 1 mg to about 600 mg, and even more preferably from about 10 mg to about 500 mg of the active ingredient, either alone or in combination with another compound according to the present disclosure.

[1098] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on the judgment of the attending physician based on a variety of factors, including the activity and bioavailability of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease or condition being treated.

[1099] A patient or subject in need of treatment with a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, alone or in combination with another known therapeutic agent.

[1100] In any aspect or embodiment described herein, the active compound is combined with a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount for the desired indication to the patient without causing an undue degree of severe toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein are in the range of about 10 nanograms / kilogram (ng / kg) to 300 milligrams / kilogram (mg / kg), preferably 0.1 to 100 mg / kg per day, such as 0.5 to about 25 mg / kg of recipient / patient body weight per day.

[1101] In any aspect or embodiment described herein, the compound is conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 milligram (mg), 1 mg to 3000 mg, or 5 mg to 500 mg of active ingredient per unit dosage form. An oral dose of about 25 mg to 250 mg is generally convenient.

[1102] In certain aspects, it is preferred to administer the active ingredient to achieve a peak plasma concentration of the active compound of about 0.00001-30 millimolar (mM), preferably about 0.1-30 micromolar (μM). This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or as a bolus injection of the active ingredient. Oral administration is also suitable for generating effective plasma concentrations of the active agent.

[1103] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, metabolism and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage value will also change with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the physician administering or supervising the administration of the composition, and the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or can be divided into many smaller doses, administered at different time intervals.

[1104] Oral compositions will typically contain an inert diluent or edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be mixed with excipients and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition.

[1105] Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the types mentioned above, a liquid carrier such as a fatty oil. Furthermore, the dosage unit form may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.

[1106] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[1107] The active compound or its pharmaceutically acceptable salt may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect, such as anti-neurodegenerative agents, particularly as described herein. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another biologically active agent (such as an anti-neurodegenerative agent), as further described herein.

[1108] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methyl paraben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate and an agent for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[1109] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[1110] In any aspect or embodiment, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[1111] Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods well known to those skilled in the art, for example, as described in U.S. Patent number 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations can be prepared by dissolving appropriate lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonic acid phosphatidylcholine and cholesterol) in an organic solvent, then evaporating the organic solvent, leaving a film of dry lipids on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release lipid material and disperse lipid aggregates from the side of the container, thereby forming a liposomal suspension.

[1112] Treatment

[1113] In another aspect, the present disclosure provides a method of treatment comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the composition further comprises an effective amount or a synergistic amount of another bioactive agent that is not a bifunctional degradation compound.

[1114] The term "biologically active agent" is used to describe agents, other than the bifunctional compounds described herein, that are used in combination with the compounds of the invention as agents having biological activity to help achieve the intended therapy, inhibition, and / or prevention / prophylaxis for which the compounds of the invention are used. Preferred biologically active agents for use herein include those that help achieve the intended therapy, such as P-gp inhibitors or agents with similar pharmacological activity to that for which the compounds of the invention are used or administered, and include, for example, anti-neurodegenerative agents.

[1115] The term "P-gp" is used to describe the "permeability glycoprotein" or P-glycoprotein (ABCB1) discovered in rodent cells in 1976. The presence of "endogenous or physiological" P-gp is a potential problem in achieving targeted exposure with therapeutic agents. P-gp is expressed in barrier tissues (such as the blood-brain barrier) and secretory / absorptive tissues (such as the gastrointestinal tract) for shelter sites (Cordon-Cardo et al., 1989, 1990). This protein acts as a cellular defense agent and affects the overall pharmacokinetic profile of numerous drugs by actively pumping them out of the intracellular environment (efflux), thereby reducing drug penetration of barrier tissues. In particular, P-gp efflux reduces drug permeability across the gastrointestinal membrane and can result in reduced systemic exposure of the drug. P-gp efflux can also reduce drug entry across the blood-brain barrier. P-gp inhibitors can indirectly contribute to efficacy by increasing bifunctional compound exposure, particularly CNS exposure.

[1116] The term "additional anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that can be combined with a bifunctional compound according to the present description to treat a neurodegenerative disease.

[1117] In any aspect or embodiment described herein, the bifunctional compound is used with a P-gp inhibitor.

[1118] In any aspect or embodiment described herein, the P-gp inhibitor is selected from, but not limited to, amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, elacridar, and verapamil.

[1119] The therapeutic methods can be used to achieve protein degradation in a patient or subject, eg, an animal, such as a human, in need thereof, for treating or ameliorating a disease state, condition, or associated symptoms that can be treated by targeted protein degradation.

[1120] In another aspect, the present disclosure provides a method for regulating protein ubiquitination and degradation in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to the subject an effective amount of a heterobifunctional compound as described herein or a composition comprising an effective amount of a heterobifunctional compound as described herein, wherein the compound or composition comprising the same effectively regulates protein ubiquitination and degradation in the subject. In certain embodiments, the protein is Tau protein.

[1121] In certain embodiments, the disclosure provides a method for modulating protein activity of Tau protein by degrading Tau aggregates in a patient in need thereof, comprising administering to the patient an amount of a compound as described herein.

[1122] In yet other embodiments, the present disclosure provides a method of treating a disease state or condition in a patient, wherein dysregulated protein activity (Tau aggregation and accumulation) is responsible for the disease state or condition, the method comprising administering to the patient an effective amount of a compound as described herein so as to modulate the protein activity in the patient. In certain embodiments, the protein is Tau.

[1123] As used herein, the terms "treat," "treating," and "treatment" and the like refer to any action that provides a benefit to a patient to whom the compounds of the present invention may be administered, including treatment of any disease state, condition, or symptom associated with a protein to which the compounds of the present invention bind. Disease states or conditions that can be treated using the compounds according to the present disclosure are described above, including neurological and neurodegenerative diseases or disorders.

[1124] This specification provides therapeutic methods for achieving degradation of target proteins to treat or ameliorate diseases, such as neurological and neurodegenerative diseases or conditions. Therefore, in another aspect, the present disclosure provides methods for ubiquitination / degradation of target proteins in cells. In any aspect or embodiment described herein, the method comprises administering a bifunctional compound of the present disclosure. Controlling or reducing the level of a specific protein in a subject's cells as provided herein provides treatment for a disease state, condition, or symptom. In any aspect or embodiment, the method comprises administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[1125] In another embodiment, 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 as described herein or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent or a combination thereof, wherein the composition is effective in treating or improving the disease, disorder or symptom of the subject.

[1126] In any aspect or embodiment described herein, the disease or disorder is associated with Tau accumulation or aggregation in a subject, eg, a cell, a tissue, a mammal, or a human patient.

[1127] In any aspect or embodiment described herein, the disease or disorder is a neurological disorder including, but not limited to, absence of septum pellucidum, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Addison's pupil, Addison's syndrome, adrenoleukodystrophy, corpus callosum dysgenesis, agnosia, Acardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, hypoxia, aphasia, apraxia, arachnoid cyst, meningitis, A-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, ataxia, and cerebellar / Spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barthel syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Rodriguez syndrome, Binswanger disease, blepharospasm, Budd-Sud syndrome, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal tumors, brain aneurysm, brain injury, Brown-Sequard syndrome, bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, cavernous tumor, cavernous hemangioma, cavernous malformation, central cervical cord syndrome, central cord syndrome, central pain syndrome, cranial disease, cerebellar degeneration, Cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-oculofacial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, choreoacanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, chronic pain type II, Cockayne syndrome, Colle-Lübeck syndrome, COFS, syringoencephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformation, cortical basal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, macrocytic Cytokine infection, chorea, Dan-Walker syndrome, Dawson disease, Demosier syndrome, deep brain stimulation for Parkinson's disease, Dejerine-Klumpke palsy, dementia, dementia - multi-infarct, dementia - semantic, dementia - subcortical, dementia with Lewy bodies, dentate-cerebellar ataxia, dentate-rubral atrophy, dermatomyositis, developmental movement disorder, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dysphagia, movement disorders, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early infantile epilepsy, encephalopathy, empty sella syndrome, encephalitis lethargica, encephalocele, encephalopathy, encephalopathy, cerebral trigeminal angiomatosis, epilepsy,Erb-Duchenne and Dejerine-Klumpke palsies, Oberle's palsy, Fabry disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangioma, familial idiopathic basal ganglia, calcifications, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher disease, Joseph's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, spherocytic leukoencephalopathy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervord en-Spatz disease, head injury, headache, hemicranial pain, hemifacial spasm, crossed hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary ataxia with polyneuritis, herpes zoster, herpes zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-related disorders, myelopathy, Huntington disease, hydrocephalus, hydrocephalus, normal-pressure hydrocephalus, hydromyelia, hyperactivity, hypercortisolism, lethargy, hypertonia, infantile hypotonia, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinence pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease , infantile Refsum disease, infantile spasms, inflammatory myopathy, occipital schizencephaly, enterogenic lipodystrophy, intracranial cysts, intracranial hypertension, Isaacs syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kingsborne syndrome, Kleifven syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Klüver-Bucy syndrome, Korsakoff amnestic syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral femoral cutaneous nerve entrapment, dorsolateral medullary syndrome, learning disability, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage disease, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lupus-neurological sequelae, Lyme disease-neurological complications, Machado-Joseph disease, megalencephaly, mania, megalencephaly, Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, meralgia paresthesia, metachromatic leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mini-stroke, mitochondrial myopathy, Moebius syndrome, monomelic muscular dystrophy, motor neuron disease, moyamoya disease, mucolipidosis, mucopolysaccharidosis,Multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, diffuse myeloblastic sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, hyperthyroid myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, neurodegenerative diseases with brain iron deposition, neurofibromatosis, neuroleptic malignant syndrome, neurologic complications of AIDS, neurologic complications of Lyme disease, neurologic consequences of cytomegalovirus infection, neurologic manifestations of Pompe disease, neurologic sequelae of lupus, neuromyelitis optica, neurologic Myotonia flexurea, neuronal ceroid disease, lipofuscinosis, neuronal migration disorder, hereditary neuropathy, neurosarcoidosis, neurotoxicity, cavernous nevus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, occult spinal canal dysraphismus sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, Paine disease, pantothenate kinase-related neurodegeneration, paraneoplastic syndrome, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal migraine, Parry-Romberg, Peyer's-Merck disease, Pena Shokeir II syndrome, fascicular cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, nerve pinch, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, trephine, postherpetic neuralgia, postinfectious encephalomyelitis, postpoliomyelitis syndrome, postural hypotension, postural orthostatic hypotension, tachycardia syndrome, postural tachycardia syndrome, primary dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerotic gray matter dyskinesia Malnutrition, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (formerly known as), Ramsay Hunt syndrome II (formerly known as), Rasmussen's encephalitis, reflex sympathetic dystrophy, Refsum's disease, Refsum's disease of infancy, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Reye-Dieter syndrome, sacral nerve root cyst, St. Vitus' chorea, salivary gland disease, Sandhoff disease, Scheldt's disease, schizencephaly, Satterberg disease, epilepsy, semantic dementia, septo-optic dysplasia, shaken baby syndrome, Shingles Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury,Spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Stevens-Willi syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Stevens-Willi syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache dysphagia, Sydenham's chorea, syncope, syphilitic myelosclerosis, syringomyelia, syringomyelia, systemic lupus erythematosus, tardive dyskinesia with tabes dorsalis, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tethered cord syndrome, Thomson myotonia, thoracic outlet syndrome, hyperthyroid myopathy, painful seizures Convulsions, Todd's palsy, Tourette syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, Von Economo disease, VHL, Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash, Whipple disease, Williams syndrome, Wilson disease, X-linked spinal and bulbar muscular atrophy, or Zellweger syndrome.

[1128] In any aspect or embodiment described herein, the disease or disorder is at least one of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injury, epilepsy, seizures, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, brain aneurysms, dural arteriovenous fistulas, headaches, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors, and stroke.

[1129] In any aspect or embodiment described herein, the disease or disorder is Alzheimer's disease.

[1130] In another aspect, the present disclosure provides methods for identifying the effects of target protein degradation in a biological system using the compounds according to the present disclosure.

[1131] In another aspect, the present disclosure provides a method for preparing a molecule that can cause degradation of Tau protein in a cell (e.g., in vivo or in vitro), the method comprising the following steps: (i) providing a small molecule that binds to Tau protein or a mutant form thereof; (ii) providing an E3 ubiquitin ligase binding moiety (ULM), preferably a CLM or VLM or ILM as described herein; and (iii) covalently coupling the small molecule of step (i) to the ULM of step (ii) via a chemical linker (L) to form a compound that binds to the E3 ubiquitin ligase and Tau protein in the cell, allowing the E3 ubiquitin ligase to approach the Tau protein and ubiquitinate the bound Tau protein, and then degrading the ubiquitinated Tau.

[1132] In another aspect, the present disclosure provides a method for detecting whether a molecule can trigger degradation of a Tau protein in a cell (e.g., in vivo or in vitro), the method comprising the following steps: (i) providing a molecule to be tested for its ability to trigger degradation of a Tau protein in a cell, the molecule comprising the structure: ULM-L-PTM, wherein ULM is an E3 ubiquitin ligase binding portion capable of binding to an E3 ubiquitin ligase in a cell, wherein the ULM is as described herein (e.g., CLM, VLM, or ILM); PTM is a protein targeting portion, which is a small molecule that binds to a Tau protein, the Tau having at least one lysine residue that can be ubiquitinated by an E3 ubiquitin ligase that binds to the ULM of the molecule; and L is a chemical linker that covalently links the ULM to the PTM to form a molecule; (ii) incubating a cell expressing a Tau protein in the presence of the molecule of step (i); and (iii) detecting whether the Tau protein in the cell has been degraded.

[1133] In any aspect or embodiment described herein, the small molecule capable of binding to Tau protein is a small molecule that binds to Tau protein. In any aspect or embodiment described herein, the small molecule that binds to Tau protein is as described herein.

[1134] In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition, or symptom causally related to Tau protein (e.g., expression, overexpression, mutation, aggregation, accumulation, misfolding, or dysregulation), wherein degradation of Tau protein will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another biologically active agent.

[1135] The disease state, condition or symptom may be caused by a microbial or other exogenous agent (such as a virus, bacteria, fungus, protozoa or other microorganism), or may be a disease state caused by the expression, overexpression, mutation, misfolding or dysregulation of Tau protein, which results in a disease state, condition or symptom.

[1136] In another aspect, the present disclosure provides a method for treating or ameliorating at least one symptom of a disease or condition in a subject, comprising the steps of: providing a subject identified as having symptoms of a disease or condition causally related to the expression, overexpression, mutation, misfolding or disorder of Tau protein in the subject, wherein the symptoms of the disease or condition are treated or alleviated by degrading Tau protein in cells of the subject; and administering to the subject a therapeutically effective amount of a compound comprising a small molecule of the present invention, such that Tau protein is degraded, thereby treating or ameliorating at least one symptom of the disease or condition in the subject.

[1137] The term "disease state" or "condition" is used to describe any disease state or condition in which protein expression, overexpression, mutation, misfolding, or dysregulation occurs (i.e., the amount of protein expressed in a patient is elevated), and in which Tau protein degradation in the patient provides beneficial therapy or relief of symptoms to the patient in need thereof. In some cases, the disease state or condition can be cured.

[1138] Disease states or conditions that can be treated using the compounds according to the present disclosure include neurological / neuronal disorders or diseases, such as neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injury, epilepsy, seizures, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, brain aneurysms, dural arteriovenous fistulas, headaches, memory impairment, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, stroke.

[1139] As used herein, the term "neurological disorder" or "neurological disorders" refers to any condition, disease and / or syndrome due to or resulting from neurological, psychiatric, psychological and / or cerebrovascular symptomatology or origin. As used herein, the term "neurological disorder" or "neurological disorders" also refers to a disease, condition or condition of the brain and nervous system or a psychiatric disorder or condition. Neurological disorders include, but are not limited to, absent septum pellucidum, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Addison's pupil, Addison's syndrome, adrenoleukodystrophy, corpus callosum dysgenesis, agnosia, Aicardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, hypoxia, aphasia, apraxia, arachnoid cyst, meningitis, Akkerman-Chiari malformation, arteriovenous malformation, Alzheimer's disease, Steffen's syndrome, ataxia, ataxia, telangiectasia, ataxia and cerebellar / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, dysautonomia, back pain, Barthel syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Roggen syndrome, Binswanger disease, blepharospasm, Budd-Soeur syndrome, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal tumors, cerebral aneurysm , brain injury, Brown-Sequard syndrome, bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, cavernous tumor, cavernous hemangioma, cavernous malformation, central cervical cord syndrome, central cord syndrome, central pain syndrome, cranial disease, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, cerebral beriberi, cerebral gigantism, brain hypoxia, cerebral palsy, cerebro-oculofacial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, choreoacanthocytosis, chronic inflammatory demyelinating polyneuropathy ( CIDP), chronic orthostatic intolerance, chronic pain type II, Cockayne syndrome, Koch-Lössler syndrome, COFS, syringoencephaly, coma and persistent vegetative state, complex regional pain syndrome, congenital facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformations, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus infection, chorea, Dan-Walker syndrome, Dawson disease, Demosier syndrome, deep brain stimulation for Parkinson's disease,Dejerine-Klumpke palsy, dementia, dementia - multi-infarct, dementia - semantic, dementia - subcortical, dementia with Lewy bodies, dentate-cerebellar ataxia, dentate-rubral atrophy, dermatomyositis, developmental movement disorder, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dysphagia, movement disorders, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early infantile epilepsy, encephalopathy, empty sella syndrome, encephalitis lethargica, encephalocele, encephalopathy, encephalotrigeminal angiomatosis, epilepsy, Erb-Duchenne and Dejerine-Klumpke palsy, Oberle's palsy, Fabry disease, Fahr syndrome Syncope, familial dysautonomia, familial hemangioma, familial idiopathic basal ganglia, calcifications, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher disease, Joseph's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, spherocytic leukoencephalopathy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, head injury, headache, hemicrania continua, hemifacial spasm, crossed hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary polyneuritis Ataxia, herpes zoster, herpes zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated disorders, myelopathy, Huntington disease, hydrocephalus, hydrocephalus, normal-pressure hydrocephalus, hydromyelia, hyperactivity, hypercortisolism, lethargy, hypertonia, infantile hypotonia, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinence pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, occipital schizencephaly, enterogenic lipodystrophy, intracranial cysts, intracranial hypertension, Isaacs syndrome, Joubert syndrome, Kearns-Sayr syndrome e syndrome, Kennedy disease, Kingsborne syndrome, Klein-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Klüver-Bucy syndrome, Korsakoff amnestic syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment, dorsolateral medullary syndrome, learning disability, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome,Lewy body dementia, lipid storage disease, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lupus-neurologic sequelae, Lyme disease-neurologic complications, Machado-Joseph disease, megalencephaly, mania, megalencephaly, Melkersson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, meralgia paresthetica, metachromatic leukodystrophy, microcephaly, migraine, MillerFisher syndrome, mini-stroke, mitochondrial myopathy , Moebius syndrome, monolimbic muscular atrophy, motor neuron disease, moyamoya disease, mucolipid storage disease, mucopolysaccharidosis, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia gravis, diffuse myeloblastic sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, hyperthyroid myopathy, myotonia, congenital myotonia, narcolepsy, neuroacanthocytosis, Neurodegenerative diseases involving brain iron deposition, neurofibromatosis, neuroleptic malignant syndrome, neurologic complications of AIDS, neurologic complications of Lyme disease, neurologic consequences of cytomegalovirus infection, neurologic manifestations of Pompe disease, neurologic sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid disease, lipofuscinosis, neuronal migration disorder, hereditary neuropathies, neurosarcoidosis, neurotoxicity, cavernous nevus, Niemann-Pick disease, normal pressure encephalopathy Water, occipital neuralgia, obesity, occult spinal canal dysraphismus sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus and myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, Paine disease, pantothenate kinase-related neurodegeneration, paraneoplastic syndrome, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal migraine, Parry-Romberg, Peyer's-Merck disease, Pena Shokeir II syndrome, fascicular cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, nerve pinch, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, trephine, postherpetic neuralgia, postinfectious encephalomyelitis, postpoliomyelitis syndrome, postural hypotension, postural orthostatic hypotension, tachycardia syndrome, postural tachycardia syndrome, primary D entatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing gray matter dystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (formerly known as), Ramsay Hunt syndrome II (formerly known as), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome,Refsum's disease, infantile Refsum's disease, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Reye-Dieter syndrome, sacral nerve root cyst, St. Vitus's chorea, salivary gland disease, Sandhoff disease, Scheldt's disease, schizencephaly, Satterberg disease, epilepsy, semantic dementia, septo-optic dysplasia, shaken baby syndrome, Shingles Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Stevens-Lee-August syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Stevens-Willi syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache, dysphagia, Sydenham's chorea, syncope, syphilitic myelosclerosis, syringomyelia hydrops, syringomyelia, systemic lupus erythematosus, tardive dyskinesia with tabes dorsalis, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tethered cord syndrome, Thomson myotonia, thoracic outlet syndrome, hyperthyroid myopathy, tics, Todd's palsy, Tourette syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, Von Economo disease, Hippel-Lindau disease (VHL), Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash, Whipple disease, Williams syndrome, Wilson disease, X-linked spinal and bulbar muscular atrophy, or Zellweger syndrome.

[1140] The term "biologically active agent" is used to describe an agent, other than a compound according to the present disclosure, which is used in combination with a compound of the present disclosure as an agent having biological activity to help achieve the intended therapy, inhibition and / or prevention / prevention for which the compound of the present disclosure is used.

[1141] Where applicable, the term "pharmaceutically acceptable salt" is used throughout this specification to describe salt forms of one or more compounds described herein, which are used to increase the solubility of the compound in the gastric fluid of the patient's gastrointestinal tract to promote dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, as well as numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralized salts of the phosphates according to the present disclosure.

[1142] Example

[1143] The bifunctional compounds of the present disclosure are effective in Tau degradation. Exemplary compounds are presented in Table 1, with data for some exemplary compounds. In vivo, ex vivo, and ex vivo studies demonstrating tau protein degradation are shown in the figures.

[1144] General methods of chemical synthesis

[1145] The synthesis of the claimed chimeric compounds can be carried out according to general synthetic procedures known in the literature. The synthetic routes shown in the schemes of this disclosure illustrate one method that can be used to obtain the desired compounds. Other methods may also be useful to those skilled in the art of synthesis. The ULM and PTM described in the schemes represent only one of many ULMs and PTMs described in this patent application.

[1146] LC-MS method for purity analysis (quality control)

[1147] LCMS method :

[1148] Instruments: Agilent Infinity 1260LC; Agilent 6230TOF mass spectrometer

[1149] The analysis was performed at 45°C on a Poroshell 120EC C18 column (50 mm x 3.0 mm id, 2.7 μm packing diameter).

[1150] The solvents used are:

[1151] A = 0.1% v / v formic acid in water.

[1152] B = 0.1% v / v formic acid in acetonitrile.

[1153] The gradients used are as follows:

[1154]

[1155]

[1156] UV detection was the average signal from wavelengths 210 nm to 350 nm, and mass spectra were recorded on a mass spectrometer using positive mode electrospray ionization.

[1157] abbreviation:

[1158] ACN: acetonitrile

[1159] Boc2O: di-tert-butyl dicarbonate

[1160] DCM: dichloromethane.

[1161] DIPEA: N,N-diisopropylethylamine

[1162] DMA: N,N-dimethylacetamide

[1163] DMF: N,N-dimethylformamide

[1164] EA: ethyl acetate

[1165] HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[1166] HPLC: High Performance Liquid Chromatography

[1167] LC-MS: Liquid chromatography-mass spectrometry

[1168] Min: minutes

[1169] MTBE: Methyl tert-butyl ether

[1170] PE: Petroleum ether

[1171] RT: room temperature

[1172] SPB: Sodium Perborate

[1173] tBu: tert-butyl

[1174] TBACl: Tetrabutylammonium chloride

[1175] TFA: trifluoroacetic acid

[1176] THF: Tetrahydrofuran

[1177] TLC: Thin layer chromatography

[1178] TMS: trimethylsilyl

[1179] t R : Retention time

[1180] TsCl: p-Toluenesulfonyl chloride

[1181] Intermediates between ubiquitin E3 ligase targeting moieties (ULMs) and protein targeting moieties (PTMs)

[1182] Intermediate 1: (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

[1183]

[1184] Step 1: Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile

[1185] At room temperature, under a nitrogen atmosphere, to a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL), 4-methyl-1,3-thiazole (21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (21.66 g, 220.71 mmol) were added. The resulting mixture was heated to 150 ° C and stirred at this temperature for 5 hours, at which time LC-MS indicated that the reaction was complete. The mixture was cooled to room temperature, diluted with 1 L of water, and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: ethyl acetate / petroleum ether, v: v = 1: 5) to obtain the title compound as a white solid (yield: 91%).

[1186] Step 2: Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine

[1187] Under a nitrogen atmosphere, LiAlH4 (20 g, 526.32 mmol) was added portionwise to a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL) at 0°C over 10 minutes. The resulting mixture was then stirred at 60°C for 3 hours, at which point LC-MS indicated the reaction was complete. The mixture was cooled to 0°C and quenched by the addition of water (20 mL, slowly added), aqueous NaOH solution (15%, 20 mL), and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane / methanol (v:v=10:1)) to obtain the title compound as a yellow oil (yield: 56%).

[1188] Step 3: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate

[1189] To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) at room temperature were added DIPEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol), and [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine (2 g, 9.79 mmol). The resulting mixture was stirred at room temperature overnight, at which point LC-MS indicated the reaction was complete. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane / methanol (v:v=20:1)) to obtain the title compound as a yellow solid (yield: 56%).

[1190] Step 4: Preparation of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride

[1191] To a 1 L round-bottom flask containing a dioxane solution of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate (45 g, 107.78 mmol) was added a 4N dioxane solution of hydrogen chloride (300 mL). The resulting solution was stirred at room temperature for 2 hours. The solid was collected by filtration to obtain the title product as a yellow solid (yield: 98%).

[1192] Step 5: Preparation of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)]phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

[1193] To a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (15.7 g, 68.0 mmol) in N,N-dimethylformamide (500 mL) at room temperature were added DIPEA (29.2 g, 225.9 mmol), HATU (25.9 g, 68.1 mmol), and (2S,4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)-phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol).

[1194] The resulting solution was stirred at room temperature for 16 hours. LC-MS indicated the formation of the desired product. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (50 mL x 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether (v: v = 2: 1)) to obtain the title compound as a yellow solid (yield: 51%).

[1195] Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

[1196] To a stirred solution of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (12 g, 22.61 mmol) in dioxane (20 mL) was added a solution of hydrogen chloride in dioxane (4N, 80 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours, at which point LC-MS indicated the reaction was complete. The precipitated solid was collected by filtration to obtain the title product as a yellow solid (yield: 48%).

[1197] Yellow solid, yield: 48%).

[1198] 1 HNMR (400MHz, CD3OD): δ9.84-9.82 (s, 1H), 7.58-7.54 (m, 4H), 4.71-4.41 (m, 4H), 4.13-4.08 (m, 1H) , 3.86-3.71(m, 2H), 3.36(s, 1H), 2.60-2.58(s, 3H), 2.35-2.07(m, 2H), 1.19-1.12(m, 9H).LC-MS(ES + ):m / z 431.11[MH + ]、t R =0.73 minutes.

[1199] Intermediate 2: (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (ULM-2)

[1200]

[1201] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)ethylcarbamate

[1202] To a mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) and NaHCO (1.24 g, 14.8 mmol) in H O (10 mL) and ethyl acetate (10 mL) at 5 ° C., (Boc) O (5.20 g, 23.8 mmol) was added. The reaction was continued for 2 hours. TLC showed that the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 mL) and H O (10 mL) for 0.5 hour. The mixture was filtered, and the solid was collected and dried in an oven at 50 ° C. to obtain the title compound (5.9 g, 98.7%) as a white solid.

[1203] 1 HNMR (400MHz, DMSO-d6): δ1.28 (d, J=7.2Hz, 3H), 1.36 (s, 9H), 4.55-4.60 (m, 1H), 7.25 (d, J=8.4Hz, 2H), 7.39 (br, 1H), 7.49 (d, J=8.4Hz, 2H).

[1204] Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride

[1205] A mixture of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate (29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred at 90 ° C under N2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. H2O (50 mL) was added to the filtrate, and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50 ° C to obtain (S)-tert-butyl-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as a gray solid.

[1206] 1HNMR (400MHz, DMSO-d6): δ1.33 (d, J=7.2Hz, 3H), 1.38 (s, 9H), 2.46 (s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS[M+1] + :319.5

[1207] The solid material (1.9 g, 6.0 mmol) was dissolved in a 4N solution of hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 hours, then concentrated and triturated with diethyl ether. The mixture was filtered and the solid was collected and dried in an oven at 60° C. to give (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g, 85%) as a light green solid.

[1208] 1 HNMR (400MHz, DMSO-d6): δ1.56 (d, J=6.8Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H) , 7.57 (d, J=8.4Hz, 2H), 7.67 (d, J=8.4Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS[M+1] + :219.2

[1209] Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylic acid

[1210] Under nitrogen at 0°C, HATU (2.15 g, 5.7 mmol) was added to a solution of (S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (1.25 g, 5.4 mol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (0.98 g, 5.4 mmol), and DIPEA (2.43 g, 18.9 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature for 18 hours. TLC showed that the reaction was complete. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layers were washed with 5% citric acid (10 mL x 2), saturated NaHCO solution (10 mL x 2), brine (10 mL x 2), and dried over NaSO. The organic solution was filtered and concentrated to obtain (2S, 4R)-methyl 1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylate (1.93 g, 100% yield) as a light yellow oil. The crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were added to THF (20 mL) and H2O (10 mL). The resulting mixture was stirred at ambient temperature for 18 hours. THF was removed by concentration. The residue was diluted with ice water (10 mL) and slowly adjusted to pH 2-3 with 3N HCl. The resulting suspension was filtered and washed with H2O (6 mL × 2). The solid was collected by filtration and dried in an oven at 50 ° C to obtain the title compound as a white solid (1.4 g, 75% for two steps).

[1211] 1 HNMR (400MHz, DMSO-d6): δ6.50 (d, J=9.6Hz, 1H), 5.19 (br s, 1H), 4.32 (br s, 1H), 4.25 (t, J = 8.4Hz, 1H), 4.16 (d, J = 9.2Hz, 1H), 3.57-3.66 (m, 2H), 2.08-2.13 (m, 1H), 1.85-1.91 (m, 1H), 1.38 (s, 9H), 0.94 (s, 9H).

[1212] Step 4: Preparation of (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (ULM-2)

[1213] At 0°C, HATU (1.6 g, 4.2 mmol) was added to a stirred solution of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylic acid (1.21 g, 3.5 mmol), (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (0.9 g, 3.5 mmol) and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 mL). The resulting mixture was allowed to warm to ambient temperature and continued stirring for 2 hours. TLC showed that the reaction was complete. THF was removed by concentration. Water (15 mL) was added to the residue, and the resulting mixture was stirred for 4 hours. The resulting mixture was filtered. The solid was collected and dried in an oven at 50°C to give a white solid. This solid was added to methanol (10 mL) and activated carbon (150 mg) was added. The resulting mixture was heated at 80 ° C and stirred for 1 hour. The mixture was filtered when hot. At 80 ° C, water (5 mL) was added to the filtrate. The resulting mixture was cooled to ambient temperature and continued to stir for 18 hours. The suspension was filtered. The solid was collected and dried in an oven at 50 ° C to obtain tert-butyl-{(S)-1-[(2S, 4R)-4-hydroxy]-2-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamoyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutane-2-yl-carbamate (1.41 g, 74.2%) as a white solid.

[1214] 1 H NMR (400MHz, CDCl3): δ1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J=7.2Hz, 3H), 2.04-2.10 (m, 1H), 2.53 (s, 3H), 2.58-2.64 (m, 1H), 3.23 (s, 1H), 3.58 (dd, J=11.2Hz, 3.2Hz, 1 H), 4.11 (d, J=11.6Hz, 1H), 4.22 (d, J=9.2Hz, 1H), 4.51 (br, 1H), 4.79 (t, J=8.0Hz, 1H), 5.04-5.11(m, 1H), 5.22(d, J=8.8Hz, 1H), 7.36-7.42(m, 4H), 7.61(d, J=7.6Hz 1H)、8.68(s、1H).

[1215] The solid (1.04 g, 1.9 mmol) was dissolved in 4N hydrogen chloride in methanol (3.0 mL) and the mixture was stirred at ambient temperature for 3 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated to remove all volatiles under reduced pressure to give a light yellow solid. The solid was added to TBME (5 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered, and the solid was collected and dried in an oven at 50°C to give the title compound (0.92 g, 100%).

[1216] 1 H NMR (400MHz, DMSO-d6): δ1.03 (s, 9H), 1.38 (d, J=7.2Hz, 3H), 1.72-1.79 (m, 1H), 2.09-2.14(m, 1H), 2.49(s, 3H), 3.48-3.52(m, 1H), 3.75-3.79(m, 1H), 3.88-3.9 0 (m, 1H), 4.31 (br, 1H), 4.56 (t, J = 8.4Hz, 1H), 4.89-4.95 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 8.20 (br, 3H), 8.67 (d, J=7.6Hz, 1H), 9.22 (s, 1H); 13 C NMR (400MHz, DMSO-d6): δ170.7, 167.1, 153.0, 146.5, 145.7, 132.5, 129.4, 129. 3. 126.9, 69.4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8, 26.6, 23.0, 15.7; LC-MS[M+1] + :445.6 Intermediate 3: (2S,4R)-4-Hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (ULM-3)

[1217]

[1218] Step 1: Preparation of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile

[1219] Under a nitrogen atmosphere, a mixture of 4-bromo-2-hydroxybenzonitrile (15 g, 76 mmol), 4-methylthiazole (14 mL, 152 mmol), KOAc (14.9 g, 152 mmol) and Pd(OAc) (0.34 g, 1.52 mmol) in anhydrous NMP (125 mL) was stirred at 110 ° C for 6 hours. TLC showed that the reaction was complete. The mixture was first cooled to room temperature and then distributed between EtOAc and water. The combined organic fractions were filtered and the filtrate was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in toluene (100 mL) and evaporated again to obtain a crude product. The crude product was treated with cold MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL), and dried under vacuum to obtain the title compound (10.5 g, 64%) as a light yellow solid.

[1220] LC / MS:217.2[M+1] + .

[1221] 1 HNMR (400MHz, DMSO-d6): δ2.49 (s, 3H), 7.07 (dd, J=8.0, 1.6Hz, 1H), 7.13 (d, J=1.6Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 9.07 (s, 1H), 11.34 (s, 1H).

[1222] Step 2: Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

[1223] To a solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (2.9 g, 13.41 mmol) in anhydrous THF (150 mL) was added LiAlH4 (1.5 g, 40.23 mmol) portionwise at 0°C. The resulting mixture was stirred at 50°C under a nitrogen atmosphere for 3 hours. TLC indicated the reaction was complete. The mixture was cooled in an ice-water bath and then Na2SO4 was carefully added. . To the 4- hydroxy -1- 1- thiazole-5-yl) phenol (2.0g, 68%) of crude 2- (aminomethyl) -5- (4- methylthiazol-5-yl) phenol (2.0g, 68%) of light yellow solid was added 10H2O (5g) and stirred at this temperature for 1 hour. The mixture was filtered and the filter cake was washed four times with a 10% MeOH solution in DCM. The combined filtrate was concentrated to obtain a crude 2- (aminomethyl) -5- (4- methylthiazol-5-yl) phenol (2.0g, 68%) of light yellow solid. It was used in the next step without further purification.

[1224] LCMS: 221.2 [M+H] + .

[1225] 1HNMR (400MHz, DMSO-d6): δ2.43 (s, 3H), 3.54 (br, 2H), 6.11 (d, J = 7.2Hz, 1H), 6.40 (d, J = 11.6Hz, 1H), 6.83 (d, J = 7.6Hz, 1H), 8.81 (s, 1H).

[1226] Step 3: Preparation of (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid

[1227] L-valine (4.37 g, 37.3 mmol) was added to a solution of o-phthalaldehyde (5.0 g, 37.3 mmol) in acetonitrile (350 mL). The resulting mixture was refluxed for 5 hours. The reaction mixture was filtered while hot, and the filtrate was slowly cooled to room temperature. The resulting precipitate was filtered and dried to obtain (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid (6.45 g, 74%) as a white solid.

[1228] 1 HNMR (400MHz, DMSO-d6): δ0.85 (d, J=6.8Hz, 3H), 1.0 (d, J=6.8Hz, 3H), 2.25-2.34 (m, 1H), 4.51 (d, J=4.4Hz, 1H), 4.54 (d , J=3.6Hz, 1H), 4.64 (d, J=18.0Hz, 1H), 7.48-7.54 (m, 1H), 7.63 (d, J=3.6Hz, 2H), 7.72 (d, J=7.6Hz, 1H), 13.01 (br, 1H).

[1229] Step 4: Preparation of methyl (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butyryl)pyrrolidine-2-carboxylate

[1230] To a solution of 4-hydroxy-L-proline methyl ester hydrochloride (1.0 g, 5.52 mmol), (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid (1.16 g, 4.97 mmol), and DIPEA (2.58 g, 20 mmol) in anhydrous DMF (15 mL) at 0°C was added HATU (3.8 g, 10 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, and dried over anhydrous NaSO. The residue was purified by silica gel chromatography using 30-50% EtOAc in hexanes as eluent to obtain the title compound (1.21 g, 67.6%) as a light yellow solid.

[1231] LCMS: 361.3[M+1] + .

[1232] Step 5: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid

[1233] A mixture containing methyl (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate (1.2 g, 3.33 mmol), LiOH . A mixture of HO (559 mg, 13.32 mmol) was stirred at room temperature for 2 hours. TLC indicated the reaction was complete. The reaction mixture was acidified with 1N HCl to pH 1-2 and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated to afford the title compound (1.05 g, 91% yield) as a light yellow solid.

[1234] 1 HNMR (400MHz, CDCl3): δ0.91 (d, J=6.4Hz, 3H), 1.05 (d, J=6.8Hz, 3H), 2.30 (dd, J =8.4, 2.8Hz, 2H), 2.44-2.50 (m, 1H), 3.75 (dd, J=11.2, 3.2Hz, 1H), 4.42 (d, J=17 .6Hz, 1H), 4.50-4.55 (m, 2H), 4.66 (t, J=8.4Hz, 1H), 4.75 (d, J=17.6Hz, 1H), 4.8 3 (d, J=11.2Hz, 1H), 7.42-7.45 (m, 2H), 7.51-7.56 (m, 1H), 7.78 (d, J=7.6Hz, 1H).

[1235] Step 6: Preparation of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butyryl)pyrrolidine-2-carboxamide

[1236] To a solution of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid (1.0 g, 2.89 mmol), 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (954 mg, 4.33 mmol) and DIPEA (1.5 g, 11.55 mmol) in DMF (20 mL) at 0°C was added HATU (2.2 g, 5.77 mmol). The resulting mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, and dried over anhydrous NaSO. The residue was purified by silica gel column chromatography using 2-5% MeOH in DCM to obtain the title compound (650 mg, 43% yield) as a light yellow solid.

[1237] LCMS: 549.2[M+H] +

[1238] 1 HNMR (400MHz, CDCl3): δ0.80 (d, J=6.8Hz, 3H), 0.88 (d, J=6.8Hz, 3H), 1.96-2.01 (m, 1H), 2.34-2.40 (m, 1H), 2.47-2.53(m, 4H), 3.61(dd, J=11.6, 3.6Hz, 1H), 4.29-4.37(m, 2H), 4.38-4.41(m, 1H), 4.47-4.50(m, 2H), 4 .64-4.69 (m, 2H), 4.72 (s, 1H), 6.90 (dd, J=8.0, 2.0Hz, 1H), 7.01 (d, J=2, 0Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 7. 39-7.44 (m, 2H), 7.51-7.54 (m, 1H), 7.76 (d, J=7.6Hz, 1H), 8.03 (t, J=6.4Hz, 1H), 8.66 (s, 1H), 9.27 (br, 1H).

[1239] Intermediate 4: (2R,4S)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl]pyrrolidine-2-carboxamide hydrochloride (ULM-4)

[1240]

[1241] This compound was synthesized using the same method as described in the preparation of ULM-2 using (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride. 1 HNMR (400MHz, CD3OD): δ1.14 (s, 9H), 1.55 (d, J=6.8Hz, 3H), 2.00-2.05 (m, 1H), 2.51-2.58 (m, 1H), 2.65 (s, 3H), 3.77-3.81 (m, 1H), 3.88-3.92 (m, 1 H), 4.06 (br, 1H), 4.41-4.46 (m, 1H), 4.56-4.60 (m, 1H), 5.07-5.12 (m, 1H ), 7.58(d, J=8.0Hz, 2H), 7.67(d, J=8.0Hz, 2H), 10.02(s, 1H).LC-MS[M+H] + :445.3

[1242] Intermediate 5 and Intermediate 6: tert-Butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-A) and tert-Butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-B)

[1243]

[1244] Step 1: Synthesis of 2-(4-bromophenyl)oxirane

[1245] A mixture of 4-bromobenzaldehyde (2.52 g, 13.6 mmol), trimethylsulfonium iodide (2.87 g, 14.1 mmol), water (0.65 mL, 36.1 mmol) and potassium hydroxide (1.56 g, 27.7 mmol) in acetonitrile (20 mL) was heated to 55° C. and maintained for 4 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, dilute hydrochloric acid and brine, and dried over sodium sulfate. The crude product of 2-(4-bromophenyl)oxirane (2.20 g, 81.8% yield) was obtained by removing the organic solvent under reduced pressure and used in the next reaction without purification.

[1246] 1H NMR (400MHz, CDCl3) δ2.74 (1H, q, J=2.8Hz), 3.14 (1H, dd, J=4.0Hz, 5.2Hz), 3.82 (1H, dd, J=2.4Hz, 4.0Hz), 7.15 (2H, d, J=8.4Hz), 7.47 (2H, d, J=8.8Hz).

[1247] Step 2: Synthesis of 2-azido-2-(4-bromophenyl)ethanol

[1248] To a stirred suspension of 2-(4-bromophenyl)oxirane (5.0 g, 25.3 mmol) in distilled water (70 mL) was added sodium azide (3.28 g, 50.5 mmol), and the resulting mixture was stirred at 60 ° C for 4 hours and monitored by TLC. After completion of the reaction, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-azido-2-(4-bromophenyl)ethanol (5.5 g, 90.2%) as a light yellow oil. The crude product was used directly in the next step.

[1249] 1 H NMR (400MHz, CDCl3) δ1.94 (1H, s), 3.63-3.66 (2H, m), 4.57 (1H, dd, J=5.2Hz, 7.6Hz), 7.15 (2H, d, J=8.4Hz), 7.46 (2H, d, J=8.4Hz).

[1250] Step 3: Synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride

[1251] To a separate solution of 2-azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) in tetrahydrofuran (20.0 mL) and water (5.00 mL), triphenylphosphine (4.35 g, 16.6 mmol) was added. The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in HCl / dioxane (4 M, 10.0 mL) and stirred at room temperature for 1 hour. After concentration, the solid was washed with dichloromethane to obtain 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.5 g, 72.1% yield) as a white solid.

[1252] 1 H NMR (400MHz, CDCl3) δ3.70 (2H, s), 4.28 (1H, s), 5.55 (1H, s), 7.47 (2H, d, J = 8.4Hz), 7.63 (2H, d, J = 8.4Hz), 8.61 (3H, s); LC / MS216.2[M+H]+ .

[1253] Step 4: Synthesis of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylamine

[1254] At room temperature, to a solution of 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.80 g, 7.17 mmol) in dichloromethane (50 mL), imidazole (1.95 g, 2.87 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.63 g, 10.8 mmol) were added. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with dichloromethane (30 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain 1-(4-bromophenyl)-2-(tert-butyldimethylsilyl chloride)ethylamine (1.50 g, 63.6%) as a white solid.

[1255] LC / MS:330.1[M+H] + ;

[1256] Step 5: Synthesis of tert-butyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate

[1257] To a solution of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylamine (1.50 g, 4.56 mmol) in tetrahydrofuran (20 mL), triethylamine (0.69 g, 6.84 mmol) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol) were added. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with ethyl acetate (50 mL x 3) and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100: 1) to obtain tert-butyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (1.80 g, 92.0%) as a light yellow oil.

[1258] 1 H NMR (400MHz, CDCl3) δ0.01 (6H, d, J=9.6Hz), 0.86 (9H, s), 1.42 (9H, s), 3.65-3.70 (2H, m) , 4.60-4.63 (1H, m), 7.34 (2H, d, J = 8.0Hz), 7.39 (1H, d, J = 8.8Hz), 7.56 (2H, d, J = 8.4Hz).

[1259] Step 6: Synthesis of tert-butyl 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamate

[1260] A mixture of tert-butyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (4.0 g, 9.32 mmol), 4-methylthiazole (1.85 g, 18.6 mmol), potassium acetate (1.82 g, 18.6 mmol), palladium (II) acetate (0.11 g, 0.47 mmol) was dissolved in dimethylacetamide and stirred under argon. The mixture was heated to 140 ° C and stirred for 15 hours, then diluted with water. The aqueous phase was extracted with ethyl acetate (50 mL x 3) and washed with brine. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain a crude compound, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100: 1) to obtain tert-butyl 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (1.30 g, 41.8%) as a light yellow solid.

[1261] 1 H NMR (400MHz, CDCl3) δ1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J=6.0Hz), 4.55-4.58 (1H, m), 4.84 (1H, t, J = 6.0Hz), 7.30 (1H, d, J = 8.0Hz), 7.38-7.45 (4H, m), 8.99 (1H, s); LC / MS 335.2[M+H] + ; Rt = 1.859 minutes

[1262] Step 7: Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride

[1263] Tert-butyl 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (300 mg, 0.536 mmol) was dissolved in hydrochloric acid / dioxane (5 mL, 4 M). The resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo to afford 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride as a white solid, which was used in the next step without further purification.

[1264] Step 8: Synthesis of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-A) and tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-B)

[1265] A solution of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride (1000 mg, 3.70 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (995 mg, 5.19 mmol), 1-hydroxybenzotriazole (HOBT) (695 mg, 5.19 mmol), (2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1273 mg, 3.70 mmol), and triethylamine (747 mg, 7.40 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature under argon overnight, and then water (80 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 mL x 5). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC (dichloromethyl / methanol = 15:1) to afford tert-butyl (S)-1-((2S, 4R)-4-hydroxy-2-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (700 mg) and tert-butyl (S)-1-((2S, 4R)-4-hydroxy-2-((S)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (500 mg) as a pale yellow oil.

[1266] ULM-5-A: 1H NMR (400MHz, CDCl3) δ0.93 (9H, s), 1.39 (9H, s), 1.77-1.83 (1H, m), 2.01-2.06 (1 H, m), 2.46 (3H, s), 3.54-3.60 (4H, m), 4.13-4.19 (1H, m), 4.29-4.36 (1H, m), 4.50 (1H, t, J=8.0Hz), 4.78 (1H, t, J=5.6Hz), 4.81-4.88 (1H, m), 5.12-5.16 (1H, m), 6. 46 (1H, d, J = 9.2Hz), 7.36-7.46 (4H, m), 8.41 (1H, d, J = 8.0Hz), 8.99 (1H, s); LC / MS 561.2[M+H] + ; Rt = 1.897 minutes

[1267] ULM-5-B: 1 H NMR (400MHz, CDCl3) δ0.87 (9H, s), 1.38 (9H, s), 1.92-2.06 (2H, m), 2.45 (3H, s), 3.56 -3.69 (4H, m), 4.06-4.14 (1H, m), 4.36 (1H, s), 4.56 (1H, t, J = 7.6Hz), 4.76-4.81 (1H, m ), 4.87 (1H, t, J = 5.6Hz), 5.146 (1H, d, J = 2.8Hz), 6.47 (1H, d, J = 8.8Hz), 7.37 (2H, d, J =8.0Hz), 7.51 (2H, d, J = 8.0Hz), 8.37 (1H, d, J = 7.6Hz), 8.98 (1H, s); LC / MS561.2[M+H] + ; Rt = 1.887 minutes

[1268] Intermediate 7: (2S,4R)-N-[(4-chloro-2-hydroxyphenyl)methyl]-4-hydroxy-1-[3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide (ULM-6)

[1269]

[1270] This key intermediate was prepared using the synthetic route described above. The desired 3-methylisoxazole-5-acetic acid was prepared according to the literature (J. Org. Chem. 66, 6595-6603, 2001). Alkylation with 2-iodopropane has been described in the literature. The desired ULM-6 was prepared using the same synthetic method described for the preparation of intermediate ULM-3.

[1271] 1 H NMR (400MHz, CDCl3): δ9.33 (s, 0.5H), 9.20 (s, 0.5H), 8.07 (t, J=6.4Hz, 0.5H), 7.83 (t, J=6.0Hz, 0.5H), 6.99 (dd, J =2.4, 8.0Hz, 1H), 6.89-6.90(m, 1H), 6.76-6.78(m, 1H), 6.02(s, 0.5H), 5.99(s, 0.5H), 5.80-5.83(m, 0.5H), 4.35( q, J=6.4Hz, 1.5), 4.16-4.25 (m, 2H), 3.72-3.76 (m, 0.5H), 3.61 (d, J=9.2Hz, 1.0H), 3.51-3.55 (m, 1.5H), 2.30-2.4 6 (m, 2.5H), 2.26 (s, 1.5H), 2.24 (s, 1.5H), 1.95-2.05 (m, 1H), 1.01 (d, J=6.8Hz, 1.5H), 0.82-0.87 (m, 4.5H); LC-MS 436.1[M+1] + ; Rt = 3.57 minutes.

[1272] PTM synthesis:

[1273] Preferred PTM embodiments of the present disclosure can be prepared according to the synthetic routes in the schemes below. These routes can be modified and adapted to the synthesis of specific PTM embodiments using general methods known to those skilled in the art.

[1274]

[1275] The above method is most relevant to the case where both C and D are aromatic rings (aryl or heteroaryl).

[1276]

[1277] Where the above methods are relevant to the case where C is an aromatic ring and D (and optional ring E) is a (hetero)aryl or (hetero)cycloalkyl ring, the ring may be inherent in R', R" and R'" or may be installed subsequently following functional manipulation of R', R" and R'".

[1278] The general approach outlined above will also apply to cases where Ring C is absent and the tricyclic fused ring system of ABC is instead represented by the bicyclic fused ring of AB, and also to cases where the monocyclic ring D is instead represented by the bicyclic fused ring system DE.

[1279] One skilled in the art will recognize that the above-mentioned methods may include cases where the heterobifunctional linker has been pre-attached to ring D or ring E (with or without the presence of a ULM), as shown in the following examples and applicable to other examples.

[1280]

[1281] Alternatively, other sequences of steps can be used to assemble the complete heterobifunctional molecule. For example, in a nucleophilic substitution or reductive amination process as shown in the scheme below, the PTM can be linked to the rest of the molecule using a functional group on ring D to react with a functional group on a heterobifunctional linker previously attached to the ULM.

[1282]

[1283] Alternatively, the functional groups on the PTM and ULM fragments can be reversed as shown in the following scheme.

[1284]

[1285] Alternatively, the order of steps can be reversed and one end of the PROTAC linker can be attached to the PTM first, and then the functional group on the other end of the linker can be reacted with the ULM via a non-limiting method as shown in the following scheme, depending on the exact nature of the ULM group. One skilled in the art will appreciate that certain protecting group manipulations may be required during these transformations.

[1286]

[1287] Preferred embodiments of the present invention can be prepared using methods previously described in US20180125821 and further detailed in the schemes below.

[1288] Specifically, the preferred PTM of the present invention can be prepared as follows.

[1289]

[1290]

[1291] The most preferred PTMs of the present invention are described in detail below:

[1292]

[1293]

[1294]

[1295] Other synthetic routes that can be used to prepare exemplary PTMs of the present disclosure are shown below.

[1296]

[1297]

[1298] Exemplary Bifunctional Compound Synthesis:

[1299] Intermediate 1

[1300]

[1301] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

[1302]

[1303] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol) in DMF (10 mL) was added KCO (756 mg, 5.47 mmol) and 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methyl-benzenesulfonate (832 mg, 2.73 mmol) at 25°C. The resulting solution was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction was quenched with HO (10 mL) and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column to give the desired product (95 mg, 13% yield).

[1304] Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde

[1305]

[1306] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (95 mg, 0.23 mmol) in CHCN (5 mL) was added IBX (130 mg, 0.46 mmol) at 25°C. The reaction was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated to give crude Intermediate 1, 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde (90 mg), which was used without further purification.

[1307] Intermediate 2

[1308]

[1309] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (10 g, 36.2 mmol) in NMP (70 mL) were added tert-butylpiperazine-1-carboxylate (13.47 g, 72.5 mmol) and DIPEA (18.6 g, 14.5 mmol). The resulting mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction was quenched with water (100 mL) and the mixture was extracted with ErOAc (300 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=100-2 / 1) to obtain the desired product 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (14 g, 31.67 mmol, 87.5% yield) as a pale yellow solid.

[1310] Synthesis scheme of exemplary compound 51

[1311] Step 1: 3-(4-bromophenyl)-4-nitropyridine

[1312]

[1313] At room temperature, under a nitrogen atmosphere, to a stirred solution of 3-bromo-4-nitropyridine (100 g, 492.6 mmol), (4-bromophenyl)boronic acid (98.6 g, 492.6 mmol) and potassium carbonate (203.9 g, 1.47 mol) in toluene (1000 ml)-water (100 ml) was added tetrakis(triphenylphosphine)palladium (14.8 g, 12.8 mmol); the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 50° C. overnight. TLC showed that the reaction was complete. The solid was removed by filtration and washed with ethyl acetate (100 ml×3). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with brine (400 ml), dried over anhydrous sodium sulfate, and concentrat...

Claims

1. A bifunctional compound having the following chemical structure: PTM-L-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, in: (a) the PTM is a Tau protein targeting moiety represented by at least one of Formula I, Formula II, Formula III, Formula IV, Formula XII, Formula XIII, Formula XIV and Formula XV: in: A, B, C, D, E and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, wherein contact between circles indicates ring fusion and overlapping circles indicate spirocycles; L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups selected from the groups -O-, -S-, -NR 1PTM -, -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, wherein the functional groups are optionally located at either end of the linker; and R 1PTM is selected from H, alkyl or fluoroalkyl, wherein the PTM is coupled to the ULM via a chemical linker (L) via at least one of A, B, C, D, E or F; (b) the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase and is represented by a chemical structure selected from the group consisting of: (i) a cerebellin E3 ubiquitin ligase binding moiety (CLM) selected from the group consisting of: in: Q1, Q2, Q3, Q4, Q5 each independently represent nitrogen or carbon substituted by a group independently selected from R', N or N-oxide; W is selected from the group CH2 or C=O; A is H or straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl); n is an integer from 1 to 4 (e.g., 1, 2, 3 or 4); G is H or straight or branched C 1-3 Alkyl (e.g., methyl); Each R and R' is independently selected from H, O, OH, N, NH, NH2, -Cl, -F, -Br, linear or branched C 1-3 Alkyl (e.g., methyl or ethyl), straight chain or branched C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2) or straight chain or branched chain C 1-3 Alkoxy (e.g., methoxy or ethoxy), wherein one R is modified to be covalently linked to the PTM via a chemical linker (L); R 4 is H or methyl; R' is H, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (e.g., methyl or ethyl) or C 1-3 alkoxy (e.g., methoxy or ethoxy); and represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and (ii) a Hippel-Lindau E3 ubiquitin ligase binding moiety (VLM) selected from the group consisting of: in: R 14 H, straight chain or branched chain C 1-3 Alkyl (e.g., methyl), C 1-3 haloalkyl (e.g., fluoromethyl) or hydroxymethyl; R 15 is a 5-membered heteroaryl group having one or two heteroatoms selected from N, S and O, optionally substituted by methyl; R 16 is halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, hydroxy, optionally substituted C1-C3 alkoxy or optionally substituted C1-C3 haloalkoxy; o is an integer from 0 to 2 (e.g., 0, 1, or 2); and Dashed lines indicate attachment sites to PTMs via chemical linkers (L); (iii) an inhibitor of the ubiquitin ligase binding moiety (ILM) of an apoptotic protein E3 selected from: in: R of ILM-I, ILM-II, ILM-III and ILM-IV 1 Select from H or C 1-3 Alkyl (e.g., methyl or ethyl); R of ILM-I, ILM-II, ILM-III and ILM-IV 2 Select from H or C 1-3 Alkyl (e.g., methyl or ethyl); R of ILM-I, ILM-II, ILM-III and ILM-IV 3 is selected from cycloalkyl and heterocycloalkyl; R of ILM-I, ILM-II, ILM-III and ILM-IV 5 is H; R of ILM-I, ILM-II and ILM-III 4 is selected from cycloalkyl (e.g., 5-7 cycloalkyl), heterocycloalkyl (e.g., 5-7 heterocycloalkyl), aryl (e.g., 5-7 membered aryl), heteroaryl (e.g., 5-7 membered heteroaryl), a bicyclic group, the bicyclic group optionally having 1, 2 or 3 heteroatoms such as O or N (e.g., a 9-12 membered bicyclic group having 1, 2 or 3 heteroatoms such as O or N), further optionally substituted with 1-3 substituents as described above; and ILM-IV R 4a Selected from –(CH2) x -aryl (e.g., 5-7 membered aryl), -(CH2) x - heteroaryl (e.g., 5-7 membered heteroaryl); ILM-IV x is 0, 1, 2, or 3; and The ILM is transmitted via R 4 , R 4a or R 5 attached to a chemical linker (L) or a PTM; and (c) L is a bond or chemical linking group (L) connecting the ULM and the PTM.

2. The compound according to claim 1 or 2, wherein the PTM is represented by at least one of the following: in: A, B, C, D, E and F are independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, wherein contact between circles indicates ring fusion and overlapping circles indicate spirocycles; L PTM is selected from a bond, optionally interrupted by one or more functional groups, an alkyl, an alkenyl or an alkynyl group, the functional groups being selected from the groups -O-, -NR 1PTM -, -C(O)-, wherein the functional group is optionally located at either end of the linker; and R 1PTM is selected from H, alkyl or fluoroalkyl.

3. The compound according to claim 1 or 2, wherein at least one of the following: At least one of A, B, C, F or a combination thereof is selected from an optionally substituted 5-membered or 6-membered aryl or heteroaryl ring; The aryl and heteroaryl rings of A, B, C, D and E of PTM are optionally substituted with 1 to 8 substituents each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl and cyano, wherein the alkyl and alkenyl groups are further optionally substituted; or Its combination.

4. The compound according to claim 3, wherein the PTM is of formula I or formula III, and: Two of Ring A, Ring B and Ring C are independently selected from 5-membered or 6-membered aryl or heteroaryl rings, each of which is optionally substituted with 1-3 substituents independently selected from optionally substituted straight or branched alkyl, optionally substituted straight or branched alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino and cyano; and L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) or one or more functional groups, which may include -O-, -S-, -NR 1 -(where R 1 selected from H or alkyl), -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, wherein the functional group may be optionally located at either end of the linker (i.e., directly adjacent to the C ring or the D ring).

5. The compound according to any one of claims 1-4, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: X PTM1 and X PTM2 One of them is N and the other is C; X PTM3 , X PTM4 , X PTM5 are independently C or N; X PTM6 is CH or N; R 1 H, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2); Each R 7 Independently: (i) when the atom to which it is attached is carbon, it is H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 fluoroalkyl (e.g., -CF3); or (ii) when the atom to which it is attached is nitrogen, it is absent; R 7a H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CF3); Each R 8 are independently H or halogen (e.g., F, Cl, Br); Each R 9 Independently: (i) when the atom to which it is attached is carbon, it is H, a halogen (e.g., F, Cl, Br), C 1-C4 Alkyl (e.g., methyl), C 1-3 fluoroalkyl (e.g., -CF3) or -CN; or (ii) when the atom to which it is attached is nitrogen, it is absent; and is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM, in: Only one R 7 or R 7a For halogen, C 1-4 Alkyl or C 1-3 Fluoroalkyl; No more than two (e.g., 0, 1, or 2) R 9 is halogen or -CN; and X PTM3 , X PTM4 , X PTM5 and X PTM6 0, 1 or 2 of them are N.

6. The compound according to any one of claims 1-4, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: X PTM7 and X PTM8 independently nitrogen or carbon; Each R 7 are independently H or halogen (e.g., F, Cl, Br); Each R 9 Independently: (i) when the atom to which it is attached is carbon, it is a halogen, H or C 1-3 fluoroalkyl (e.g., -CF3); or (ii) when the atom to which it is attached is nitrogen, it is absent; and It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

7. The compound according to any one of claims 1-4, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: X PTM9 or X PTM10 One of them is nitrogen and the other is CH2; X PTM11 is nitrogen or CH; R 1 H, C 1-4 Alkyl (e.g., methyl), C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2); R 7 (i) when the atom to which it is attached is carbon, it is H; or (ii) when the atom to which it is attached is nitrogen, it is H or C1-3 alkyl; R 9 is H, halogen, halogen (e.g., F, Cl, Br) or C 1-2 Fluoroalkyl (-CF3); and It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

8. The compound of any one of claims 1-4, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: Each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen atoms completing the valence, wherein X PTM12 and X PTM13 At least one of is nitrogen; X PTM14 is nitrogen or CH; L PTM For key, C 1-3 Alkyl, C 2-3 Alkynyl (e.g., C3 alkynyl), wherein the carbon of the alkyl group is optionally replaced by O or C(═O); L PTM1 C 1-C4 alkyl; R 1 H, C 1-4 Alkyl (e.g., methyl), C 1-3 Fluoroalkyl (e.g., -CH2CF3, -CHF2); R 7 H, halogen, C 1-4 Alkyl (eg, methyl) or C 1-3 Fluoroalkyl (e.g., -CF3); Each R 9 are independently H or halogen (e.g., F, Cl, Br); and It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

9. The compound according to any one of claims 1-4, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: Each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen atoms completing the valence, where X PTM12 and X PTM13 At least one of is nitrogen; Each R 7 are independently H or halogen (e.g., F, Cl, Br); Each R 9 are independently H or halogen (e.g., F, Cl, Br); and It is the point of attachment of the PTM to a chemical linker (L) or directly to a ULM.

10. The compound of any one of claims 1-3, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: X PTM14 N or CH; R 10 and R 11 R is independently selected from H, methyl and ethyl; 12 and R 13 are independently selected from H, methyl, ethyl, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (e.g., methyl) and C 1-2 Haloalkyl; R 14 is selected from H, methyl, ethyl and halogen (e.g., F, Cl, Br); R 15 are 1 to 2 substituents independently selected from H, methyl, ethyl and halogen; R 16 H, OH or C 1-3 Alkoxy (e.g., methoxy); R 17 is H, halogen (e.g., F, Cl, Br) or C 1-3 Alkyl (e.g., methyl); R 18 is H, halogen (e.g., F, Cl, Br) or C 1-2 Haloalkyl (e.g., -CF3) R 19 is H, halogen (e.g., F, Cl, Br), C 1-2 Haloalkyl (e.g., -CF3) or -NH2, N(R 20 )2; Each R 20 are independently H or C 1-3 Alkyl (e.g., methyl); N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM; and is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

11. The compound of any one of claims 1-3, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: X PTM17 , X PTM18 and X PTM19 Each of is independently N or CH; X PTM15 and X PTM16 Each of is N or C; R 21 :(i) when the atom to which it is attached is carbon, it is H or C 1-3 alkyl (e.g., methyl); or (ii) when the atom to which it is attached is nitrogen, it is absent; R 22 (i) when the atom to which it is attached is carbon, it is H or a halogen (e.g., F, Cl, Br); or (ii) when the atom to which it is attached is nitrogen, it is absent; R 23 is H or halogen (e.g., F, Cl, Br); R 24 is H or halogen (e.g., F, Cl, Br); R 25 H or C 1-3 an alkyl group (eg, a methyl group); and is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

12. The compound of claim 11, wherein there is zero or one nitrogen per ring of the PTM.

13. The compound of any one of claims 1-3, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: R 1 is selected from H, optionally substituted alkyl (e.g., haloalkyl, fluoroalkyl, difluoromethyl, or trifluoromethyl), methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and R 7 and R 8 Each of which is independently 1 or 2 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl or cyano; L PTM is selected from a bond optionally interrupted by one or more functional groups, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl, the functional group is selected from the group -O-, -NR 1PTM -, -C(O)-, wherein the functional group is optionally located at either end of the linker; and is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

14. The compound of any one of claims 1-3, wherein the PTM is represented by a chemical structure selected from the group consisting of: in: R 1 , R 2 and R 3 is independently selected from H, optionally substituted alkyl (e.g., haloalkyl, fluoroalkyl, difluoromethyl, or trifluoromethyl), methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and R 7 , R 8 , R 9 and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl, or cyano.

15. The compound of any one of claims 1-14, wherein the PTM is represented by a chemical structure selected from the group consisting of: where * and is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

16. The compound of any one of claims 1-14, wherein the PTM is represented by a chemical structure selected from the group consisting of: in is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

17. The compound of any one of claims 1-16, wherein the ULM is a VLM.

18. The compound of any one of claims 1-16, wherein the VLM is represented by a structure selected from the group consisting of: The dashed line indicates the attachment site to the PTM via a chemical linker (L).

19. The compound of any one of claims 1-16, wherein the ULM is a CLM.

20. The compound of any one of claims 1-16 and 19, wherein the CLM has a chemical structure represented by: in: A is H or straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl); G is H or straight or branched C 1-3 Alkyl (e.g., methyl); One R is hydrogen and the other R is H, O, OH, N, NH, NH2, -Cl, -F, -Br, straight or branched C 1-3 Alkyl (e.g., methyl or ethyl), straight chain or branched C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2) or straight chain or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy); and R' is H, halogen (e.g., F, Cl, Br), C 1-3 Alkyl (e.g., methyl or ethyl) or C 1-3 Alkoxy (e.g., methoxy or ethoxy); represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM; is a single bond or a double bond; and The attachment site of the PTM via a chemical linker is indicated.

21. The compound of any one of claims 1-16, 19 or 20, wherein the CLM has a chemical structure selected from: N* is the point of attachment of the PTM to the chemical linker (L) or directly to the ULM; and The attachment site of the PTM via a chemical linker (L) is indicated.

22. The compound of any one of claims 1-16, wherein the ULM is an ILM.

23. A compound according to any one of claims 1-16 or 22, wherein at least one of the following: R of ILM-I, ILM-II, ILM-III and ILM-IV 1 is a methyl group; R of ILM-I, ILM-II, ILM-III and ILM-IV 2 is a methyl group; R of ILM-I, ILM-II, ILM-III and ILM-IV 3 is a C6 cycloalkyl group or a C6 heterocycloalkyl group (for example, ); R of ILM-I, ILM-II and ILM-III 4 is an 11-membered bicyclic group, which optionally includes one heteroatom (wherein the bicyclic group is optionally the point of attachment of the ILM to a chemical linking group (L) or a PTM, as described herein), or R of ILM-IV 4a -CH2CH2-C 5-7 Aryl, such as phenyl (wherein the C 5-7 The aryl or phenyl group is the point of attachment of the ILM to a chemical linker (L) or PTM, as described herein); or Its combination.

24. A compound according to any one of claims 1-16, 22 or 23, wherein R of ILM-I, ILM-II and ILM-III is 4 for:

25. The compound of any one of claims 1-16 or 22-24, wherein the ULM is selected from the group consisting of: in The attachment site of the PTM via a chemical linker (L) is indicated.

26. The compound according to any one of claims 1 to 25, wherein the linker (L) is represented by the following chemical structure: in: Y L1 is a bond, O or NH, C=O or C1-C3 alkyl; W L2 is an optionally substituted 3-7 membered ring (eg, 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl); Y L2 is a bond, O, unsubstituted or substituted straight or branched C1-C6 alkyl (e.g., optionally substituted by one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl and / or optionally substituted by one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF 3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; W L3 is a 3-7 membered ring (e.g., a 3-6 membered cycloalkyl, a 3-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl), an 8-11 membered spiro ring, or an 8-11 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group, or C=O; Y L3 is a bond, O, unsubstituted or substituted straight or branched C1-C6 alkyl (e.g., optionally substituted by one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl and / or optionally substituted by one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF 3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; W L4 is a 3-7 membered ring (e.g., a 4-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl) or an 8-11 membered spiro ring, each having 0-4 heteroatoms and optionally substituted with one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group, or C=O); Y L4 is a bond, O, unsubstituted or substituted straight or branched C1-C4 alkyl (e.g., optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C4 alkenyl (e.g., optionally substituted C2-C3 alkenyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF 3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C4 alkynyl (e.g., optionally substituted C2-C3 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; Y L5 is a bond, O, unsubstituted or substituted straight or branched C1-C9 alkyl (e.g., optionally substituted by one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C9 alkenyl (e.g., optionally substituted C2-C6 alkenyl and / or optionally substituted by one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF 3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C6 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; Y L6 is a bond, O, unsubstituted or substituted straight or branched C1-C8 alkyl (e.g., optionally substituted by one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C8 alkenyl (e.g., optionally substituted C2-C6 alkenyl and / or optionally substituted by one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF 3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C8 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; Y L7 is a bond, O, unsubstituted or substituted straight or branched C1-C10 alkyl (e.g., optionally substituted by one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), unsubstituted or substituted straight or branched C2-C10 alkenyl (e.g., optionally substituted C2-C8 alkenyl and / or optionally substituted by one or more (e.g., 1, 2 or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -C F3, methyl, ethyl, isopropyl group or C=O substituted) or unsubstituted or substituted straight or branched C1-C10 alkynyl (e.g., optionally substituted C2-C8 alkynyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl group or C=O), each of the alkyl, the alkenyl and the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2; Y L7 is a bond, O or unsubstituted or substituted linear or branched C1-C25 alkyl (e.g., unsubstituted or substituted linear or branched C1-C25 alkyl and / or optionally substituted with one or more (e.g., 1, 2 or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl groups or C=O), the alkyl optionally having one or more (e.g., 1, 2 or 3) C atoms replaced by O, NH, NCH3 or NCH(CH3)2 and The attachment site of the PTM or ULM is indicated.

27. The compound according to any one of claims 1-26, wherein the linker (L) is represented by a chemical structure selected from the group consisting of: in: U L and U L1 are independently selected from a bond or O; X L1 , X L2 , Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is the key; and if Y L2 is N, then U L1 is the key; n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1; m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1; R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When it is N, it is not with Y L1 On adjacent carbon atoms, or when Y L2 When it is N, it is not with Y L2 On adjacent carbon atoms; M L Select from the following: Among them, M L are optionally independently selected from methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 substituted with 1 or 2 substituents of fluoroalkyl), OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms; Z L and Z L1 Each independently selected from O or NR 3 ; R L3 is H, methyl, ethyl or isopropyl; p is 0, 1, or 2; and U L and U L1 is the attachment site for a PTM or ULM.

28. The compound according to any one of claims 1-26, wherein the linker (L) is represented by a chemical structure selected from the group consisting of: in: U L and U L1 are independently selected from a bond or O; X L1 , X L2 , Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is the key; and if Y L2 is N, then U L1 is the key; n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1; m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1; R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When it is N, it is not with Y L1 On adjacent carbon atoms, or when Y L2 When it is N, it is not with Y L2 On adjacent carbon atoms; M L Select from the following: Among them, M L are optionally independently selected from methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 substituted with 1 or 2 substituents of fluoroalkyl), OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms; Z L and Z L1 Each independently selected from O or NR L3 ; R L3 is H, methyl, ethyl or isopropyl; p is 0, 1, or 2; q is 0, 1, 2, 3, 4 or 5, where Y L2 When is N, q is not 0 or 1; and U L and Z L is the attachment site for a PTM or ULM.

29. The compound according to any one of claims 1-26, wherein the linker (L) is represented by a chemical structure selected from the group consisting of: in: U L and U L1 are independently selected from a bond or O; X L1 , X L2 , Y L1 and Y L2 are independently selected from N or CH, provided that if X L1 is N, then U L is the key; and if Y L2 is N, then U L1 is the key; n1 and n2 are each independently 0 or 1, wherein when X L1 and X L2 When both are N, n1 is 1 and n2 is 1; m1 and m2 are each independently 0 or 1, wherein when Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1; R L1 and R L2 Each represents a radical independently selected from methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When it is N, it is not with Y L1 On adjacent carbon atoms, or when Y L2 When it is N, it is not with Y L2 On adjacent carbon atoms; W L1 and W L2 Each independently selected from N or CH, wherein when W L2 When N is L1 is the key; r1 is 1 or 2, and r2 is 0, 1 or 2, where W L1 and W L2 When both are N, r1 is 2 and r2 is 1 or 2; R L3 represents independently selected from methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 fluoroalkyl), OH and CN, wherein the halogen (e.g., F), OH and CN substituents are L1 When it is N, it is not with X L1 On adjacent carbon atoms, when X L2 When it is N, it is not with X L2 On adjacent carbon atoms, when Y L1 When it is N, it is not with Y L1 On adjacent carbon atoms, or when Y L2 When it is N, it is not with Y L2 On adjacent carbon atoms; M L1 Select from the following: Among them, M L1 are optionally independently selected from methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 substituted with 1 or 2 substituents of fluoroalkyl), OH and CN, provided that the above-mentioned F, OH and CN substituents are not on carbon atoms adjacent to heteroatoms; Z L and Z L1 Each independently selected from O or NR 3 ; p is 0, 1, or 2; and U L and U L1 is the attachment site for a PTM or ULM.

30. The compound according to any one of claims 1-29, wherein the linker (L) is selected from the group consisting of: Each of these * and is the attachment site for a PTM or ULM.

31. The compound according to any one of claims 1-29, wherein the linker (L) is selected from the group consisting of: Each of these * and is the attachment site for a PTM or ULM.

32. The compound according to any one of claims 1-29, wherein the linker (L) is selected from the group consisting of: where each * is an attachment site for a PTM or ULM.

33. The bifunctional compound of claim 1, wherein the compound is selected from the group consisting of compounds 332, 335, 337-586 and 589-686 of Table 1 or pharmaceutically acceptable salts thereof.

34. The compound of claim 33, wherein the compound exhibits greater than 50% Tau protein degradation as measured in CHOK1 Tau P301L cells treated with 1 μM of the compound for 48 hours compared to untreated cells.

35. The compound of claim 33, wherein the compound exhibits less than or equal to 50% Tau protein degradation as measured in CHOK1 Tau P301L cells treated with 1 μM of the compound for 48 hours compared to untreated cells.

36. The compound of claim 33, wherein the compound exhibits Tau protein degradation in an in vivo tauopathy mouse model (e.g., Tg2508).

37. The compound of claim 33, wherein the compound exhibits Tau protein degradation of seedable pathological tau aggregates in vitro and in vivo.

38. A composition comprising the bifunctional compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. The composition of claim 35, wherein the composition further comprises at least one of an additional bioactive agent, another bifunctional compound according to any one of claims 1-37, or a combination thereof.

40. The composition of claim 39, wherein the additional bioactive agent is an anti-neurodegenerative agent.

41. The composition of claim 39, wherein the additional bioactive agent is a P-gp inhibitor.

42. The composition of claim 41, wherein the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporin, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, taliciquida, elacrida, or verapamil.

43. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to any one of claims 1-37, for use in a method of treating a Tau-related disease or condition in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound achieves Tau protein degradation, thereby treating or ameliorating at least one symptom of the disease or condition.

44. The composition of claim 43, wherein the disease or disorder is associated with Tau accumulation and aggregation.

45. The composition of claim 43 or 44, wherein the disease or disorder is a neurodegenerative disease associated with Tau accumulation and aggregation.

46. ​​A composition according to any one of claims 43-45, wherein the disease or disorder is at least one of the following: primary tauopathy (FTDP-17, progressive supranuclear palsy (PSP), corticobasal disease (CBD) and most frontotemporal dementias, secondary tauopathy (Alzheimer's disease), Huntington's disease, muscular dystrophy, Parkinson's disease, Batten disease, spinal cord and brain injury, epilepsy, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, brain aneurysms, dural arteriovenous fistulas, headaches, memory impairment, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors and stroke.

47. The composition of any one of claims 43-45, wherein the disease or disorder is Alzheimer's disease.

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