Tau protein-targeting compounds and associated methods of use

Abstract

To provide effective treatments of diseases and conditions that are related to the aggregation of tau in neurodegenerative disorders.SOLUTION: The present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, so that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 875,500, filed July 17, 2019, and entitled TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE, which is incorporated herein by reference in its entirety for all purposes.

[0002] Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed August 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719, U.S. Patent Application No. 15 / 206,497, filed July 11, 2016, published as U.S. Patent Application Publication No. 2017 / 0008904, U.S. Patent Application No. 15 / 209,648, filed July 13, 2016, published as U.S. Patent Application Publication No. 2017 / 0037004, U.S. Patent Application No. 15 / 730,728, filed October 11, 2017, published as U.S. Patent Application Publication No. 2018 / 0099940, U.S. Patent Application No. U.S. Patent Application No. 14 / 686,640, published as U.S. Patent Application Publication No. 2015 / 0291562, and U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872, and U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322, and U.S. Patent Application No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639, and U.S. Patent Application No. 2018 / 0215731, filed January 31, 2018 U.S. Patent Application No. 15 / 885,671, published as International Patent Publication No. A1, and International Patent Application No. PCT / US2016 / 023258, filed March 18, 2016, published as International Patent Publication No. WO2016 / 149668, are incorporated herein by reference in their entireties. Additionally, all references cited herein are incorporated herein by reference in their entireties. [Background technology]

[0003] 1. Field of discovery The present disclosure provides heterobifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination of Tau proteins, which are then degraded and / or inhibited.

[0004] 2. Background information Most small molecule drugs bind to enzymes or receptors in precise 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 (of which several hundred are known in humans) confer substrate specificity to ubiquitination and, in turn, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands for E3 ligases has proven difficult, due in part to the fact that they must interfere with protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds have been reported to target E3 ligases.

[0005] 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. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the vascular endothelial growth factor (VEGF) and the erythropoiesis-inducing cytokine (erythropoietin) in response to low oxygen levels. We generated the first small molecule ligand of VHL to the substrate-recognition subunit of the E3 ligase, obtained its crystal structure, and confirmed that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0006] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins increases levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 similarly regulates numerous developmental processes, such as limb and otic vesicle formation. The net result is that this ubiquitin ligase complex is critical for limb development in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage-binding protein.

[0007] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015 / 0291562 and 2014 / 0356322 (incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation in the proteasomal degradation pathway. Specifically, the above publications describe bifunctional or proteolysis-targeting chimeras (PROTACs) that find utility as regulators of targeted ubiquitination of various polypeptides and proteins, which are then degraded and / or inhibited by the bifunctional compounds. (登録商標) ) Protein degrader compounds are described.

[0008] Tau protein is an abundant protein in the central nervous system, found primarily in neurons, 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 important for axonal outgrowth and neuroplasticity. When pathologically altered, tau molecules are unable to stabilize microtubules and are prone to forming insoluble aggregates. When tau protein forms insoluble aggregates within cells, cellular dysfunction occurs, axonal transport is impaired, and neuronal loss follows. The accumulation of abnormal tau aggregates in neurons is a key pathological signature in multiple neurodegenerative diseases, including Alzheimer's disease. In certain pathological conditions, tau aggregation leads to paired helical filaments (PHFs), straight filaments (SFs), and / or neurofibrillary tangles (NFTs). The accumulation of PHFs and NFTs in neurons is directly correlated with microtubule dysfunction and neuronal degeneration. Neurons containing tau PHFs, SFs, and / or NFTs activate multiple cellular mechanisms to attempt to clear the cell of abnormal protein aggregates.

[0009] More recent studies have shown that soluble tau oligomers, instead of large insoluble filaments, are more important in the development and progression of disease before the occurrence of PHF- or NFT-induced neurotoxicity. Tau oligomeric species may act as seeds for the aggregation of native tau, thereby promoting neurotoxic tau aggregation. Accumulating evidence suggests that tau aggregates can be transmitted from one cell to another by prion-like propagation.

[0010] 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's syndrome, frontotemporal lobe dementia (FTLD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

[0011] Due to its pathological significance in multiple 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 that can halt the progression of neurodegeneration. However, tau aggregation inhibitors that have demonstrated promising preclinical data have proven ineffective in recent clinical trials for the treatment of various tauopathies.

[0012] Thus, there is a need in the art for effective treatments for diseases and conditions associated with tau aggregation in neurodegenerative disorders such as tauopathies. Summary of the Invention

[0013] The present disclosure describes a bifunctional compound that functions to recruit tau protein to E3 ubiquitin ligase for subsequent degradation in the proteasome degradation pathway and its preparation and use method.Specifically, the present disclosure provides a heterobifunctional compound that is useful as a regulator of targeted ubiquitination and degradation of tau protein aggregates.In addition, the present disclosure provides a method for using an effective amount of the compound of the present disclosure to treat or improve disease conditions caused by the accumulation or aggregation of tau protein, such as tauopathy.These diseases or disorders include, but are not limited to, neuropathies or neurodegenerative disorders.

[0014] Unless applicable or expressly denied, it is contemplated that any one of the embodiments described herein can be combined with any one or more other embodiments, even if the embodiments are described under different aspects of the present disclosure. Accordingly, the foregoing general areas of utility are provided by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be understood by those skilled in the art in light of the claims, description, and examples of the present disclosure. For example, the various aspects and embodiments of the present disclosure can be utilized in numerous combinations, all of which are expressly contemplated by this description. These additional 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 further details regarding implementation are incorporated by reference.

[0015] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are only for the purpose of illustrating one embodiment of the disclosure and are not to be construed as limiting the disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings illustrating exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 shows total tau levels in hippocampal homogenates. Data are displayed in charts where each data point represents an individual animal. Statistically significant differences between the test article (TI)-treated group and the vehicle control group by one-way ANOVA followed by Dunnett's multiple comparison test are indicated by asterisks: **p<0.01, *p<0.05. [Figure 2A]The tau-targeting bifunctional molecule is a potent P301L tau degrader, dependent on binding to both the tau-binding moiety and the E3 ligase-binding moiety (ULM) in vitro. (2A) Tau expression was induced by the addition of doxycycline (1 μg / ml) to ChoK1-tau P301L clone D1 for 24 hours (+), 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 of exemplary compound 82 caused concentration-dependent degradation of tau, demonstrating a DC50 of less than 50 nM, compared with a negative (-) control treatment with 0.1% DMSO. (2B) Degradation by exemplary compound 82 was completely inhibited by incubation with a 10-fold molar excess of a ligand for E3 ligase (pomalidomide; Figure 2C). Partial inhibition of tau degradation was observed by similar competition with the tau warhead ligand (flortaucipir, Figure 2C). These data indicate that tau degradation is dependent on both the E3 ligase and tau-binding components of the bifunctional compounds, thereby confirming that targeted degradation of tau is mediated by the bifunctional compounds via a proteolytic targeting chimera mechanism. [Figure 2B]The tau-targeting bifunctional molecule is a potent P301L tau degrader, dependent on binding to both the tau-binding moiety and the E3 ligase-binding moiety (ULM) in vitro. (2A) Tau expression was induced by the addition of doxycycline (1 μg / ml) to ChoK1-tau P301L clone D1 for 24 hours (+), 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 of exemplary compound 82 caused concentration-dependent degradation of tau, demonstrating a DC50 of less than 50 nM, compared with a negative (-) control treatment with 0.1% DMSO. (2B) Degradation by exemplary compound 82 was completely inhibited by incubation with a 10-fold molar excess of a ligand for E3 ligase (pomalidomide; Figure 2C). Partial inhibition of tau degradation was observed by similar competition with the tau warhead ligand (flortaucipir, Figure 2C). These data indicate that tau degradation is dependent on both the E3 ligase and tau-binding components of the bifunctional compounds, thereby confirming that targeted degradation of tau is mediated by the bifunctional compounds via a proteolytic targeting chimera mechanism. [Figure 2C]The tau-targeting bifunctional molecule is a potent P301L tau degrader, dependent on binding to both the tau-binding moiety and the E3 ligase-binding moiety (ULM) in vitro. (2A) Tau expression was induced by the addition of doxycycline (1 μg / ml) to ChoK1-tau P301L clone D1 for 24 hours (+), 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 of exemplary compound 82 caused concentration-dependent degradation of tau, demonstrating a DC50 of less than 50 nM, compared with a negative (-) control treatment with 0.1% DMSO. (2B) Degradation by exemplary compound 82 was completely inhibited by incubation with a 10-fold molar excess of a ligand for E3 ligase (pomalidomide; Figure 2C). Partial inhibition of tau degradation was observed by similar competition with the tau warhead ligand (flortaucipir, Figure 2C). These data indicate that tau degradation is dependent on both the E3 ligase and tau-binding components of the bifunctional compounds, thereby confirming that targeted degradation of tau is mediated by the bifunctional compounds via a proteolytic targeting chimera mechanism. [Figure 3A] The exemplary bifunctional compound degrades more than 95% of pathological tau in Tg2508 brains after parenteral administration in vivo. Tg2508 tauopathy mice were intravenously administered either 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382, ​​or vehicle (12 animals per group). Twenty-four hours after administration, the animals were euthanized, and cortical brain samples were analyzed for pathological tau by Wes capillary gel electrophoresis. Figure 3A is a graphical representation of the average pathological tau analysis shown for each animal tested, comparing the lane from the vehicle control with either exemplary compound 82 or exemplary compound 382, ​​as shown in Figure 3B. After treating Tg2508 animals with either exemplary compound 82 or exemplary compound 382, ​​a greater than 95% reduction in pathological tau was observed. [Figure 3B]The exemplary bifunctional compound degrades more than 95% of pathological tau in Tg2508 brains after parenteral administration in vivo. Tg2508 tauopathy mice were intravenously administered either 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382, ​​or vehicle (12 animals per group). Twenty-four hours after administration, the animals were euthanized, and cortical brain samples were analyzed for pathological tau by Wes capillary gel electrophoresis. Figure 3A is a graphical representation of the average pathological tau analysis shown for each animal tested, comparing the lane from the vehicle control with either exemplary compound 82 or exemplary compound 382, ​​as shown in Figure 3B. After treating Tg2508 animals with either exemplary compound 82 or exemplary compound 382, ​​a greater than 95% reduction in pathological tau was observed. [Figure 4A] Exemplary bifunctional compounds inhibit ex vivo seeding of P301L CHO MC1 Tg2508 cells by high-content image analysis. A schematic diagram of the assay is shown in Figure 4A. Briefly, ChoK1-tau P301L cells were treated with K18 tau preformed fibrils (PFFs) or extracts from Tg2508 brain samples. Seeded conformational tau seeds 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 shows the induction of seeded conformational tau induced by K18 PFFs compared to background staining of non-doxycycline-induced tau or a negative control antibody. Figure 4C shows significant seeding induction by Tg2508 cortical (CTX) brain extracts, and that the seeding-competent tau species were effectively degraded by a single 24-hour parenteral treatment of Tg2508 mice with 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382. [Figure 4B]Exemplary bifunctional compounds inhibit ex vivo seeding of P301L CHO MC1 Tg2508 cells by high-content image analysis. A schematic diagram of the assay is shown in Figure 4A. Briefly, ChoK1-tau P301L cells were treated with K18 tau preformed fibrils (PFFs) or extracts from Tg2508 brain samples. Seeded conformational tau seeds 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 shows the induction of seeded conformational tau induced by K18 PFFs compared to background staining of non-doxycycline-induced tau or a negative control antibody. Figure 4C shows significant seeding induction by Tg2508 cortical (CTX) brain extracts, and that the seeding-competent tau species were effectively degraded by a single 24-hour parenteral treatment of Tg2508 mice with 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382. [Figure 4C] Exemplary bifunctional compounds inhibit ex vivo seeding of P301L CHO MC1 Tg2508 cells by high-content image analysis. A schematic diagram of the assay is shown in Figure 4A. Briefly, ChoK1-tau P301L cells were treated with K18 tau preformed fibrils (PFFs) or extracts from Tg2508 brain samples. Seeded conformational tau seeds 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 shows the induction of seeded conformational tau induced by K18 PFFs compared to background staining of non-doxycycline-induced tau or a negative control antibody. Figure 4C shows significant seeding induction by Tg2508 cortical (CTX) brain extracts, and that the seeding-competent tau species were effectively degraded by a single 24-hour parenteral treatment of Tg2508 mice with 15 mpk of exemplary compound 82 or 30 mpk of exemplary compound 382. [Figure 5]The exemplary bifunctional compound reduced tau in the brains of tauopathy mice in a dose-dependent manner. Tg2508 animals were intravenously administered 15, 3, 1, or 0.3 mpk of bifunctional compound 382 as described in Materials and Methods. Hippocampal extracts were analyzed for pathological tau levels at each given dose, either Wes or bifunctional compound levels, as indicated. A clear dose-response relationship was demonstrated. Specifically, Figure 5 demonstrates that tau protein levels were dose-dependently reduced in the hippocampus of Tg2508 mice 24 hours after administration of the exemplary bifunctional compound. DETAILED DESCRIPTION OF THE INVENTION

[0017] Compounds, compositions, and methods are now described that relate to the surprising discovery that an E3 ubiquitin ligase (e.g., von Hippel-Lindau (VHL) E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, or IAP E3 ubiquitin ligase) promotes ubiquitination of tau protein when the E3 ubiquitin ligase and tau protein are brought into close proximity via a heterobifunctional compound that binds to both the E3 ubiquitin ligase and the tau protein. Accordingly, the present disclosure provides compounds and compositions that include an E3 ubiquitin ligase-binding moiety ("ULM") conjugated by a chemical linking group (L) to a protein targeting moiety ("PTM") that targets tau protein and results in ubiquitination of the tau protein, leading to degradation of the tau protein by the proteasome.

[0018] In certain aspects, the present disclosure provides a tau protein targeting moiety ("PTM") that binds to tau protein. In certain embodiments, the PTM inhibits tau protein-protein interaction. In certain embodiments, the PTM is a moiety described herein.

[0019] In an additional aspect, the present disclosure provides hetero-bifunctional compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase ("ULM" group)) and a moiety that binds to tau (i.e., a protein targeting moiety or "PTM" that is a tau ligand / moiety), thereby placing the tau protein in proximity to the ubiquitin ligase, resulting in ubiquitination and subsequent degradation (and inhibition) of the tau protein. In preferred embodiments, the ULM (ubiquitin ligase binding moiety) is a cereblon E3 ubiquitin ligase binding moiety (CLM), an inhibitor of apoptosis E3 ubiquitin ligase binding moiety (ILM), or a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (VLM). For example, the structure of a heterobifunctional compound can be represented as follows, where the PTM and ULM are directly covalently linked together: PTM-ULM The respective positions of the PTM and ULM moieties (e.g., CLM, ILM, or VLM), as well as their numbers, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way.

[0020] As will be appreciated by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0021] In any of the embodiments, the heterobifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be represented as follows: PTM-L-ULM wherein PTM is a tau targeting moiety, L is a linker, e.g., a bond or linking group, that joins the PTM to ULM, and ULM is an E3 ubiquitin ligase binding moiety.

[0022] In certain embodiments, the compound has the following general structure (A): PTM-L-VLM(A) where PTM is a tau targeting moiety, "L" is a linker (e.g., bond or linking group) that joins the PTM to the VLM, and VLM is a VHL E3 ubiquitin ligase binding moiety.

[0023] In certain embodiments, the compounds have the following general structure (B): PTM-L-ILM(B)

[0024] wherein PTM is a tau targeting moiety, "L" is a linker (e.g., bond or linking group) that connects the PTM to the ILM, and the ILM is an IAP E3 ubiquitin ligase binding moiety (ILM).

[0025] In certain embodiments, the compound has the following general structure (C): PTM-L-CLM(C) wherein PTM is a tau targeting moiety, "L" is a linker (e.g., a bond or linking group) that connects the PTM to the CLM, and the CLM is a cereblon E3 ubiquitin ligase binding moiety. As will be appreciated by those of skill in the art, the heterobifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0026] In certain embodiments, the PTM in structure (A) is a ligand that binds to tau as well as VHL E3 ubiquitin ligase.

[0027] In certain embodiments, the PTM in structure (B) is a ligand that binds to tau as well as an IAP E3 ubiquitin ligase.

[0028] In certain embodiments, the PTM in structure (C) is a ligand that binds to tau as well as cereblon E3 ubiquitin ligase.

[0029] In any aspect or embodiment described herein, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0030] In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to tau protein. In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to tau protein. In any of the aspects or embodiments described herein, the small molecule binds to tau protein as described herein.

[0031] In one embodiment, the VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and the carboxylic acid in the trans-3-hydroxyproline are functionalized as amides. Other contemplated VLMs are described in U.S. Patent Application Publication No. 2016 / 027224. No. 639, and U.S. Patent Application Publication No. 2014 / 0356322, each of which is incorporated herein by reference in its entirety.

[0032] 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 certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is selected from thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other contemplated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, the entire contents of which are incorporated herein by reference.

[0033] In any aspect or embodiment described herein, "L" is a bond. In additional embodiments, the linker "L" is a chemical linking moiety / group having a linear number of non-hydrogen atoms 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 connector "L" can contain one or more functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic, cyclic, bicyclic, or tricyclic moieties. The linker can contain substitutions with halogens such as Cl, F, Br, and I, or alkyls such as methyl, ethyl, isopropyl, and tert-butyl. In the case of fluorine substitution, it can contain single or multiple fluorines.

[0034] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition can be used to cause targeted degradation of tau in a patient or subject, e.g., an animal such as a human, and can be used to treat or ameliorate one or more disease states, conditions, or symptoms causally related to tau, which are achieved by degrading or inhibiting tau protein, or treated by controlling or reducing tau protein levels in a patient or subject. In any aspect or embodiment described herein, the therapeutic composition described herein can be used to cause degradation of tau, for example, to treat or ameliorate a disease or condition causally related to the accumulation or aggregation of tau protein (e.g., a neuronal disease).

[0035] In yet 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 preferably includes administering a heterobifunctional compound described herein comprising a PTM that binds to tau protein and a ULM (e.g., CLM or VLM), linked via a chemical linker moiety described herein, to achieve degradation of the tau protein. While not wishing to be limited by theory, the inventors believe that, according to the present disclosure, polyubiquitination of tau protein occurs when the heterobifunctional compound is placed in proximity to an E3 ubiquitin ligase, thereby causing subsequent degradation of tau via the proteasome pathway and resulting in the 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 the treatment of disease states, pathologies, or associated symptoms causally linked to tau, for example, regulated by reducing the amount of tau protein or a mutant form thereof in the subject's cells.

[0036] In yet another aspect, the present disclosure provides a method for the detection of a leukemia or leukemia virus in a subject or patient, e.g., an animal, such as a human. The present invention provides a method for treating or ameliorating a disease, condition, or symptom thereof causally associated with tau, 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 described herein or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0037] 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 cereblon E3 ubiquitin ligase (CLM), an inhibitor of apoptosis E3 ubiquitin ligase (ILM), or a VHL E3 ubiquitin ligase (VLM), respectively, as exemplified by the following general structures: TBM-L-CLM; TBM-L-ILM; and TBM-L-VLM.

[0038] It will be understood that the general structure is exemplary and that the moieties may be spatially arranged in any desired order, number, or configuration.

[0039] In any aspect or embodiment described herein, there is provided a bifunctional compound having a structure selected from the group consisting of compounds 332, 335, 337-586, and 589-686 (e.g., compounds selected from Table 1), salts, polymorphs, and prodrugs thereof.

[0040] In further embodiments, the present description provides compositions 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), salts, polymorphs, and prodrugs thereof. For example, the present description provides a composition comprising a compound described herein and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the therapeutic or pharmaceutical composition comprises an additional biologically active agent, for example, an agent effective in treating a neurological disorder.

[0041] In any of the aspects or embodiments described herein, the therapeutic compositions comprising the compounds described herein may be in any suitable dosage form, e.g., solid or liquid, and may be configured to be delivered by any suitable route, e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

[0042] In another aspect, the description provides a method of modulating tau proteins, their 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 described herein or a composition comprising an effective amount of the compound, wherein the compound or composition comprising the compound is effective to modulate tau ubiquitination and degradation in the subject.

[0043] In another aspect, the description provides a method of treating or ameliorating 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 of treatment or amelioration an effective amount of a compound described herein or a composition comprising an effective amount of the compound, wherein the compound or composition comprising the compound is effective to treat or ameliorate symptoms of a disease associated with tau activity in the subject. In embodiments, the disease to be treated is a neurological or neurodegenerative disease, such as Alzeimer's, Parkinson's, dementia, etc.

[0044] In any aspect or embodiment described herein, the subject is a human.

[0045] In an additional aspect, the description provides methods for determining the effect of degradation of a protein of interest (i.e., tau protein) in a biological system using compounds according to the present disclosure.

[0046] In another aspect, the description provides processes and intermediates for making the heterobifunctional compounds of the present disclosure that enable targeted ubiquitination and degradation of tau protein within a cell (e.g., in vivo or in vitro).

[0047] In embodiments, the present description provides compounds in which the PTM binds to tau protein. The present disclosure also provides libraries of compositions and uses thereof for causing targeted degradation of tau protein in cells.

[0048] The following is a detailed description of the invention, provided to aid those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0049] In any aspect or embodiment described herein, the disclosure provides heterobifunctional compounds that include a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), capable of binding to an E3 ubiquitin ligase, such as cereblon, IAP, or VHL E3 ubiquitin ligase. The compound also includes a small molecule moiety that can bind to a tau protein such that the tau protein is positioned in proximity to an E3 ubiquitin ligase protein (e.g., VHL, IAP, and cereblon), resulting in ubiquitination and degradation (and / or inhibition) of the tau protein. "Small molecule" additionally means that the molecule is nonpeptidyl, i.e., not considered a peptide, and contains, for example, fewer than 4, 3, or 2 amino acid residues. According to this description, each of the PTM, ULM, and heterobifunctional molecule is a small molecule.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0051] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value within that range, to the nearest tenth of the lower limit (e.g., in the case of a group containing a number of carbon atoms, each number of carbon atoms falling within the range is provided), and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are subject to any specifically excluded limit in the stated range, and are also encompassed within the disclosure. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0052] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term shall have the meaning it deserves in the context in which it is used in describing this disclosure. Terms are given their art-recognized meanings by those of ordinary skill in the art to which they apply.

[0053] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an" means one element or more than one element unless otherwise specified.

[0054] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are sometimes conjunctively present and other times disjunctively present. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0055] 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 two or more, of a number or list of elements, and optionally including additional, unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by exclusive terms such as "either," "one of," "only one of," or "exactly one of."

[0056] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like, are understood to be open-ended, i.e., to mean "including, but not limited to." Only the transitional phrases "consisting of" and "consisting essentially of" must be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0057] As used herein in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of every element specifically recited in the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for elements other than the specifically identified elements in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or the same and "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally two or more, A, and no B (and optionally including elements other than B); in another embodiment, to at least one, optionally two or more, B, and no A (and optionally including elements other than A); in yet another embodiment, to at least one, optionally two or more, A, and at least one, optionally two or more, B (and optionally including other elements).

[0058] It should also be understood that, in any particular method or process described herein that includes more than one step or act, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are recited, unless the context dictates otherwise.

[0059] The terms "co-administration" and "co-administering" or "combination therapy" refer to both combined administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time than the administration of the additional therapeutic agent(s)), so long as the two or more therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the heterobifunctional compounds described herein are co-administered with at least one additional bioactive agent, including, for example, an anti-neurodegenerative agent. In particularly preferred embodiments, co-administration of such compounds results in synergistic activity and / or therapy, such as, for example, anti-neurodegenerative activity.

[0060] As used herein, the term "compound," unless otherwise specified, refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and deuterated forms of any of the aforementioned molecules, if applicable. Contemplated deuterated compounds are 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 "non-deuterated" compound.

[0061] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of those diseases, conditions, or symptoms specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or farm animals such as horses, cows, sheep, etc. Generally, in this disclosure, the terms "patient" and "subject" refer to a human patient, unless otherwise stated or implied from the context of the use of the terms.

[0062] The terms "effective" and "therapeutically effective," when used within the context of its intended use and in a single dose, or more preferably, after multiple doses within the context of a treatment regimen, are used to describe an amount of a compound or composition that affects an intended result, such as amelioration of a disease or condition, or amelioration or reduction of one or more symptoms associated with a disease or condition. The terms "effective" and "therapeutically effective" encompass all other terms "effective amount" or "effective concentration" as otherwise described or used in this application.

[0063] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitin moieties to specific substrate proteins. The addition of several chains of ubiquitin (polyubiquitination) targets the substrate protein for degradation. For example, cereblon, VHL, and IAPs, alone or in combination with E2 ubiquitin-conjugating enzymes, ultimately result in the attachment of four ubiquitin moieties to lysines on the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases are involved in polyubiquitination, such that a first ubiquitin binds to a lysine on the target protein, a second ubiquitin binds to the first, a third ubiquitin binds to the second, and then a fourth ubiquitin binds to the third. Such polyubiquitination marks the protein for degradation by the proteasome.

[0064] The term "independently" is used herein to indicate that the variable, when applied independently, varies independently from application to application.

[0065] The term "hydrocarbyl" is intended to mean compounds that contain carbon and hydrogen and that may be fully saturated, partially unsaturated or aromatic, and that include aryl, alkyl, alkenyl and alkynyl groups.

[0066] The term "alkyl" refers, within its context, to a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical, preferably C1-C6, which may be optionally substituted with any suitable functional group or group. 10 , preferably C1-C6, or more preferably C1-C3 alkyl groups. Examples of alkyl groups are, inter alia, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl groups are terminally protected with a halogen group (At, Br, Cl, F, or I).

[0067] The term "lower alkyl" refers to an alkyl group having six or fewer carbon atoms, such as methyl, ethyl, or propyl.

[0068] The term "lower alkoxy" refers to an alkoxy group having six or fewer carbon atoms, such as methozy, ethoxy, or propoxy.

[0069] The term "alkenyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0070] The term "alkynyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0071] The term "alkylene," when used, refers to an optionally substituted -(CH) n n generally refers to an - group (n is an integer from 0 to 6). When substituted, the alkylene group is preferably substituted at one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups (preferably 1 to 3 halo groups), or one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain, as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other suitable functional group), which in turn is further substituted with a polyethylene glycol chain (of 1 to 10, preferably 1 to 6, or more preferably 1 to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively, at the distal end of the polyethylene glycol chain) an alkyl chain substituted with one halogen, preferably a chlorine, group. In still other embodiments, the alkylene (e.g., methylene) group is an amino acid side chain group, e.g., the side chain group of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, hydroxybenzoate ... It may be substituted with leucine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

[0072] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with an H. Thus, a range of carbon atoms that is C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, an H is present in place of the carbon.

[0073] The terms "substituted" or "optionally substituted" are intended to mean, independently (i.e., when more than one substituent occurs, each substituent is selected independently of another substituent) one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, more preferably 1 or 2 substituents) on a moiety in a compound of the present disclosure, which may themselves include substituents which may be further substituted at a carbon (or nitrogen) anywhere on a molecule herein, possible substituents including hydroxyl, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably 1, 2, or 3 halogens, particularly alkyl, especially halogen on a methyl group such as trifluoromethyl), alkyl group (preferably C1-C2), alkyl ... 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl, or aryl, including phenyl and substituted phenyl), thioethers (preferably C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), esters or thioesters (preferably C1-C6 alkyl or aryl), including alkylene esters (such that the bond is on the alkylene group rather than the ester function, which is preferably substituted with a C1-C6 alkyl or aryl group), halogens (preferably F or Cl), amines (including 5- or 6-membered cyclic alkylene amines, and optionally substituted with a polyethylene glycol chain further attached to an alkyl group containing a single halogen, preferably chlorine, substituent; hydrazine; amide, preferably substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups); alkanol (preferably C1-C6 alkyl or aryl); or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents of the present disclosure may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as otherwise described herein, and R3 is H or a C1-C6 alkyl group, preferably R1, R2, and R3 together are a C1-C3 alkyl group (including an isopropyl or t-butyl group). Each of the above groups may be directly linked to the substituted moiety, or the substituent may be an optionally substituted -(CH2) m - or optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) mThe alkylene group -(CH) may be linked via a - group to a substituted moiety (preferably in an aryl or heteroaryl moiety), which may be substituted with any one or more of the substituents described above. m -or-(CH2) n -group, or other chains such as the ethylene glycol chains identified above, may be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chains of amino acids as otherwise described herein, and optionally substituted amide (preferably the substituted carboxamide described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) ... The moiety is optionally substituted with up to five substituents, preferably up to three substituents. Most often, the substituted moiety is substituted with one or two substituents.

[0074] The term "substituted" (each substituent independent of any other substituent) is also intended to mean, within the context of its use, C-C alkyl, C-C alkoxy, halogen, amido, carboxamide, sulfone (including sulfonamide), keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane-OC(O)-NR1R2, or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C-C alkylene-NR1R2, including mono- or di-C-C alkyl-substituted amines optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms unless the context indicates otherwise. In certain embodiments, preferred substituents, depending on the context of the substituent's use, include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (where m and n are 1, 2, 3, 4, 5 or 6, in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (RS is C1-C6 alkyl or -(CH2) m The alkylene groups may also be substituted with an optionally substituted C-C alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl being preferred, thus providing a chiral center), the side chain of an amino acid group as described elsewhere herein, an amide group as described herein above, or a urethane group O-C(O)-NR-R group, where R and R are as described elsewhere herein, although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with more than two substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds at certain positions in the molecule, where substitution is required (primarily due to valence) but no substitution is indicated, that substituent is interpreted or understood to be H, unless the context of the substitution suggests otherwise.

[0075] The term "aryl" or "aromatic," in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical (e.g., a 5- to 16-membered ring) having a single ring (e.g., benzene, phenyl, benzyl, or a 5-, 6-, 7-, or 8-membered ring) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, a 10- to 16-membered ring, etc.), which can be attached to the compounds of this disclosure at any available stable position on the ring or as otherwise shown in the provided chemical structure. Other examples of aryl groups include: may, in context, include heterocyclic aromatic ring systems, "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above. Heteroaryl groups which may be mentioned in particular are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanacene, oxadiazole, benzimidazoline, aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoleoxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0076] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or multiple fused rings, at least one of which is aromatic, and the ring is substituted with one or more substituents. For example, an aryl group can be: -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) nand / or at least one of F, Cl, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), an optionally substituted phenyl group (the phenyl group itself is preferably attached to the PTM group (including a 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 positions of the phenyl ring, preferably the para position), an optionally substituted naphthyl group, an optionally substituted heterocyclic ... Aryl, preferably optionally substituted isoxazoles including methyl substituted isoxazoles, optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methyl imidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyl diazole groups, optionally substituted triazole groups including methyl substituted thiazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl substituted pyridine groups or oxapyridine groups (the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans. , optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0077] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where these generic substituents have the same meaning as the corresponding groups defined herein.

[0078] The terms "heteroaryl" or "hetaryl" include, but are not limited to, 5- to 16-membered heteroaryl (e.g., 10- to 16-membered heteroaryl having a 5-, 6-, 7-, or 8-membered monocyclic ring or multiple fused rings), optionally substituted quinoline (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2-, 3-, or 4-azaindolizine), optionally substituted benzimidazoline, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted -(CH2) m -O-C1-C6 alkyl group, or optionally substituted -(CH2) m It may also refer to a 1,2,3-triazole substituted with a —C(O)—O—C1-C6 alkyl group), an optionally substituted pyridine (2-, 3, or 4-pyridine), or a group according to the following chemical structure: [ka] During the ceremony, S c But CHR SS , N.R. URE or O, RHET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a and R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; Y C But N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR aand R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0079] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both aryl and / or heteroaryl, respectively, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems as defined above.

[0080] The term "arylalkyl," as used herein, refers to an aryl group, as defined above, appended to an alkyl group, as defined above. An arylalkyl group is attached to the parent moiety via an alkyl group, the alkyl group being 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as defined above.

[0081] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as O, N, or S, and can be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included within the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described above. Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolyl, and isothiazolyl. Examples include azolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thirane.

[0082] Heterocyclic groups include alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cycloalkenyl ... The heterocyclic groups may be optionally substituted with a member selected from the group consisting of anhydrous, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, and N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is fused to a benzene or cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0083] The term "cycloalkyl" can refer to, but is not limited in any manner to, a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., e.g., a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring. The term "substituted cycloalkyl" can refer to, but is not limited to, a monocyclic or polycyclic alkyl group, which can be substituted with one or more substituents, e.g., amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, with these generic substituents having the same meaning as the definition of the corresponding group defined in this Legend.

[0084] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, and which contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these common substituents have the same meaning as the definition of the corresponding group defined in this Legend.

[0085] Embodiments of the present disclosure provide compounds useful for regulating protein activity. The compounds preferably comprise an E3 ubiquitin ligase binding moiety and a protein targeting moiety linked or conjugated together via a chemical linking group, wherein the E3 ubiquitin ligase binding moiety recognizes an E3 ubiquitin ligase such as cereblon, VHL, or IAP, and the protein targeting moiety 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: PTM-L-ULM or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof; During the ceremony, ULM is a small molecule E3 ubiquitin ligase-binding moiety that binds to E3 ubiquitin ligases; PTMs are small molecules that contain a tau protein targeting moiety that degrades tau protein, L is a bond or chemical linking moiety that connects the ULM and the PTM.

[0086] In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety targets a member of the group consisting of von Hippel-Lindau (VLM), cereblon (CLM), and IAP (ILM).

[0087] In one aspect, the present description 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, [ka] [ka] During the ceremony, A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between rings indicates ring fusion and overlapping rings indicate a spirocyclic ring; L PTM is a bond, an alkyl, alkenyl, or alkynyl (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) optionally interrupted by one or more rings, or -O-, -S-, -NR 1PTM -(In the formula, R 1PTMis selected from H or alkyl), and one or more functional groups selected from -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, optionally located at either terminus of the linker.

[0088] In any aspect or embodiment described herein, the PTM is represented by Formula I, II, III, IV, XII, XIII, XIV, and XV: [ka] [ka] During the ceremony, A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between rings indicates ring fusion and overlapping rings indicate a spirocyclic ring; L PTM is a bond, an alkyl, alkenyl, or alkynyl (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) optionally interrupted by one or more rings, or -O-, -S-, -NR 1PTM one or more functional groups selected from -, -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, optionally located at either terminus of the linker; R 1PTM is selected from H, alkyl, or fluoroalkyl, and the PTM is attached via a chemical linking group (L) to the ULM 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).

[0089] In any aspect or embodiment described herein, the PTM is represented by Formula I, II, III, IV, XII, XIII, XIV, and XV: [ka] [ka] During the ceremony, A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between rings indicates ring fusion and overlapping rings indicate a spirocyclic ring; L PTM is a bond, the group -O-, NR 1PTM -, -C(O)-, optionally at either terminus of the linker; R 1PTM is selected from H, alkyl, or fluorolkyl.

[0090] In any aspect or embodiment described herein, the aryl and heteroaryl rings of A, B, C, D, E, and F of PTM are optionally substituted with 1 to 8 (e.g., 1 to 3) substituents each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, and the alkyl and alkenyl groups are optionally further substituted.

[0091] In any aspect or embodiment described herein, at least one ring of A, B, C, F, or a combination thereof is selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring.

[0092] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I, wherein: the A, B, and C rings are independently 5- or 6-membered fused aryl or heteroaryl rings; L PTM is selected from a bond or alkyl; D is selected from a 6-membered aryl, heteroaryl, or heterocycloalkyl; wherein A, B, C, and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0093] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I, wherein: A and C are phenyl or a 6-membered heteroaryl ring; B is a 5-membered heteroaryl ring; L PTM is a bond, D is a 6-membered heteroaryl or 6-membered heterocycloalkyl ring; wherein each A, B, C, and D is independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano, and no nitrogen atom in any of the A, B, C, and D rings is directly linked to a heteroatom or carbon atom to which another heteroatom is directly linked.

[0094] 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, and L PTM is selected from a bond or alkyl, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, and A, B, C, D, and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0095] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I or III, wherein: 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 to 3 substituents independently selected from optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano; L PTM is a bond, an alkyl, alkenyl, or alkynyl (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) optionally interrupted by one or more rings, or -O-, -S-, -NR 1 -(In the formula, R 1 - is selected from H or alkyl), and one or more functional groups which may include -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, optionally located at either terminus of the linker (i.e., immediately adjacent to the C or D ring).

[0096] In any aspect or embodiment described herein, the PTM is [ka] [ka] and wherein the compound is represented by a chemical structure selected from the group consisting of: During the ceremony, 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; XPTM6 is CH or N, R 1 But H, C 1-4 alkyl (e.g., methyl), or C 1-3 fluoroalkyl (e.g., -CHCF, -CHF); Each R 7 independently (i) if the atom to which it is attached is carbon, H, halogen, C 1-4 alkyl (e.g., methyl), or C 1-3 fluoroalkyl (e.g., —CF), or (ii) absent when the atom to which it is attached is nitrogen; R 7a But H, halogen, C 1-4 alkyl (e.g., 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) if the atom to which it is attached is carbon, H, halogen (e.g., F, Cl, Br), C 1-C4 Alkyl (e.g., methyl), C 1-3 fluoroalkyl (e.g., —CF), or —CN, or (ii) absent if the atom to which it is attached is nitrogen; [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM; During the ceremony, One R 7 or R 7a Only halogens, C 1-4 Alkyl, or C 1-3 is a fluoroalkyl; Two or fewer R's (e.g., 0, 1, or 2) 9 is halogen or -CN, X PTM3 , X PTM4 , X PTM5 , and XPTM6 0, 1, or 2 of them are N.

[0097] In any aspect or embodiment described herein, the PTM is [ka] [ka] and wherein the compound is represented by a chemical structure selected from the group consisting of: During the ceremony, X PTM7 and X PTM8 are independently nitrogen or carbon; Each R 7 are independently H or halogen (e.g., F, Cl, Br); Each R 9 independently (i) a halogen, H, or C when the atom to which it is attached is carbon 1-3 fluoroalkyl (e.g., —CF), or (ii) absent when the atom to which it is attached is nitrogen; [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0098] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, X PTM9 or X PTM10 one of which is nitrogen and the other is CH2, X PTM11 is nitrogen or CH, R 1 But H, C 1-4Alkyl (e.g., methyl), C 1-3 fluoroalkyl (e.g., -CHCF, -CHF); R 7 is (i) H when the atom to which it is attached is carbon, or (ii) C alkyl when the atom to which it is attached is nitrogen; R 9 is H, halogen, halogens (e.g., F, Cl, Br), or C 1-2 fluoroalkyl (-CF3), [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0099] In any aspect or embodiment described herein, the PTM is [ka] [ka] and wherein the compound is represented by a chemical structure selected from the group consisting of: During the ceremony, each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen to complete the valence, and X PTM12 and X PTM13 one of which is nitrogen, X PTM14 is nitrogen or CH, L PTM But, bond, C 1-3 Alkyl, C 2-3 alkynyl (e.g., C alkynyl), wherein a carbon of the alkyl is optionally replaced with O or C(=O); L PTM1 But C 1-C4 is alkyl, R 1 But H, C 1-4Alkyl (e.g., methyl), C 1-3 fluoroalkyl (e.g., -CHCF, -CHF); R 7 But H, halogen, C 1-4 alkyl (e.g., methyl), or C 1-3 fluoroalkyl (e.g., —CF), Each R 9 are independently H or halogen (e.g., F, Cl, Br); [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0100] In any aspect or embodiment described herein, the PTM is [ka] [ka] and wherein the compound is represented by a chemical structure selected from the group consisting of: During the ceremony, X PTM7 and X PTM8 are independently nitrogen or carbon; Each R 7 are independently H or halogen (e.g., F, Cl, Br); Each R 9 is independently (i) a halogen or H when the atom to which it is attached is carbon, or (ii) absent when the atom to which it is attached is nitrogen; [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0101] In any aspect or embodiment described herein, the PTM is [ka] [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, each X PTM12 and X PTM13 are independently nitrogen or carbon, with hydrogen to complete the valence, and X PTM12 and X PTM13 one of which 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); [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0102] In any aspect or embodiment described herein, the PTM is [ka] [ka] [ka] [ka] represented by a chemical structure selected from During the ceremony, X PTM14 is N or CH, R 10and R 11 is independently selected from water, methyl, and ethyl; R 12 and R 13 are independently 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 is 1 to 2 substituents independently selected from H, methyl, ethyl, and halogen; R 16 but H, OH, or C 1-3 alkoxyl (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 H, halogens (e.g., F, Cl, Br), C 1-2 haloalkyl (e.g., -CF), or -NH, 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; [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0103] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, X PTM17 , X PTM18 , and X PTM19 are each independently N or CH; X PTM15 and X PTM16 each of is N or C, R 21 but (i) if the atom to which it is attached is carbon, H or C 1-3 alkyl (e.g., methyl), or (ii) absent when the atom to which it is attached is nitrogen; R 22 is (i) H or halogen (e.g., F, Cl, Br) when the atom to which it is attached is carbon, or (ii) absent when the atom to which it is attached is nitrogen; Each R 23 is H or halogen (e.g., F, Cl, Br), Each R 24 is H or halogen (e.g., F, Cl, Br), R 25 is H or C 1-3 alkyl (e.g., methyl); [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM. In any aspect or embodiment described herein, the PTM has zero or one nitrogen per ring.

[0104] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, 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; R 7 and R 8 each independently represents one or two substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano; L PTM is a bond, the group -O-, -NR 1PTM C optionally interrupted by one or more functional groups selected from -, -C(O)- 1-3 Alkyl, C 2-3 Alkenyl, or C 2-3 alkynyl, said functional groups optionally being located at either terminus of the linker; [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0105] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, Each R 1 and R 7 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; Each R 8 and each R 9 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; each X PTMare independently C or N; [ka] is a single or double bond, [ka] is the attachment site to the chemical linking group (L).

[0106] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, Each R 1 and R 7 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; Each R 8 and each R 9 are independently H, halo, F, C1-3 alkyl, -CH(F2) , -CH2C(F3), CN; each X PTM are independently C or N; [ka] is a single or double bond, [ka] is the attachment site to the chemical linking group (L).

[0107] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, Each R 1 and R 7 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; Each R 8 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; each X PTM are independently C or N; [ka] is a single or double bond, [ka] is the attachment site to the chemical linking group (L).

[0108] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, Each R 21 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; each X PTM are independently C or N; [ka] is a single or double bond, [ka] is the attachment site to the chemical linking group (L).

[0109] In any aspect or embodiment described herein, the PTM is [ka] represented by a chemical structure selected from the group consisting of: During the ceremony, Each R 26 is H, an optionally substituted cyclic, heterocyclic, heterobicyclic, or [ka] A member selected from [ka] is the site of attachment to the pyrrolyl nitrogen, [ka] is the attachment site to the chemical linking group (L).

[0110] In one aspect, the present disclosure provides a compound having the structure: 1. A compound of PTM-L-ULM, wherein PTM is a tau protein targeting moiety, L is a chemical linking moiety, and ULM is an E3 ubiquitin ligase binding moiety; (i) The PTM is [ka] a structure selected from During the ceremony, Each R 1 and R 7 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; Each R 8 and each R 9 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; Each R 21 is independently selected from H, halo, F, C alkyl, —CH(F), —CHC(F), and CN; each X PTM are independently C or N, [ka] is a single bond or a double bond, [ka] is the attachment site to the chemical linking group (L); (ii) L is [ka] [ka] a structure selected from [ka] is the binding site for ULM or PTM, and (iii) ULM: [ka] The structure follows: During the ceremony, R is independently H, halo, methoxy, or a bonding site for a chemical linking group (L); and n is an integer selected from 1, 2, 3, or 4; wherein at least one R is a bonding site to a chemical linking group (L), or a pharmaceutically acceptable salt thereof.

[0111] In an aspect, the present disclosure provides a compound having the structure: 1. A compound of PTM-L-ULM, wherein PTM is a tau protein targeting moiety, L is a chemical linking moiety, and ULM is an E3 ubiquitin ligase binding moiety; (i) PTM is [ka] a structure selected from During the ceremony, Each R 26 is H, an optionally substituted cyclic, heterocyclic, heterobicyclic, or [ka] A member selected from [ka] is the site of attachment to the pyrrolyl nitrogen, [ka] is the attachment site to the chemical linking group (L). (ii) L is [ka] [ka] a structure selected from [ka] is the binding site for ULM or PTM, and (iii) ULM: [ka] The structure follows: During the ceremony, R is independently H, halo, methoxy, or a bonding site for a chemical linking group (L); and n is an integer selected from 1, 2, 3, or 4; wherein at least one R is a bonding site to a chemical linking group (L), or a pharmaceutically acceptable salt thereof.

[0112] In any aspect or embodiment described herein, the PTM is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is a chemical structure selected from the group consisting of During the ceremony, * and [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0113] In any aspect or embodiment described herein, the PTM is [ka] [ka] is a chemical structure selected from the group consisting of During the ceremony, [ka] is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM.

[0114] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] [ka] is represented by During the ceremony, R 1 , R 2 and R 3 is independently selected from H, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; R 4 and R 5 is independently selected from H, methyl, ethyl, halogen, haloalkyl, and cyano; R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl, and halogen; The PTM is attached to the ULM via L.

[0115] In any aspect or embodiment described herein, the PTM is covalently attached to one or more ULM (VLM or CLM) groups or a linker that attaches to one or more ULM (VLM or CLM) groups described herein.

[0116] In any aspect or embodiment described herein, the PTM has the chemical structure: [ka] [ka] [ka] [ka] is represented by During the ceremony, 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; R 7 , R 8 , R 9 , and R 10 is 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano; and P M is bonded to ULM (VLM or CLM) via L.

[0117] In any aspect or embodiment described herein, the PTM has the chemical structure: [ka] [ka] [ka] [ka] [ka] [ka]

[0118] In any aspect or embodiment described herein, the PTM is [ka] [ka] [ka] having a chemical structure selected from [ka] represents a linker group or point of attachment to a ULM as described herein.

[0119] In any aspect or embodiment described herein, the linker attachment point to the PTM is indicated by the dotted line: [ka]

[0120] In any aspect or embodiment described herein, the PTM is [ka] [ka] [ka] [ka] having a chemical structure selected from During the ceremony, each Z is N or CH; each of rings Z1, Z2, and Z3 is independently aryl or heteroaryl (e.g., each carbon of rings Z1, Z2, and Z3 is optionally replaced by a heteroatom such as N, O, or S); Ring Z4 is cycloalkyl or heterocycloalkyl (e.g., each carbon of ring Z4 is optionally replaced with a heteroatom such as N, O, or S); [ka] represents the point of attachment to a linker group or ULM (e.g., a CLM, VLM, ILM, or MLM) described herein.

[0121] In any aspect or embodiment described herein, ring Z1 is heteroaryl (e.g., ring Z1 has 1, 2, or 3 carbons substituted with N, O, or S).

[0122] In any aspect or embodiment described herein, ring Z2 is heteroaryl (e.g., ring Z2 has 1, 2, or 3 carbons substituted with N, O, or S).

[0123] In any aspect or embodiment described herein, ring Z3 is heteroaryl (e.g., ring Z2 has 1, 2, or 3 carbons substituted with N, O, or S).

[0124] In any aspect or embodiment described herein, ring Z4 is heteroalkyl (e.g., ring Z4 has 1, 2, or 3 carbons substituted with N, NH, O, or S).

[0125] Example VLM: In one embodiment, the ULM is a VHL E3 ubiquitin ligase binding moiety (VLM).

[0126] In any aspect or embodiment described herein, the ULM is a VLM and has the chemical structure: [ka] [ka] is represented by During the ceremony, R 14is R in any aspect or embodiment described herein 14 , R 14a , or R 14b as defined by R 15 is as defined in any aspect or embodiment described herein; R 16 is as defined in any aspect or embodiment described herein; o is as defined in any aspect or embodiment described herein; The dashed line indicates the site of attachment to the PTM via a chemical linking group (L), or alternatively, the attachment site is R 16 is located.

[0127] For example, in any aspect or embodiment described herein, the ULM is a VLM. and chemical structure: [ka] [ka] is represented by During the ceremony, R 14 is H, straight or branched C1-C3 alkyl (e.g., methyl), C 1-3 haloalkyl (e.g., fluoromethyl), or hydroxymethyl; R 15 is a 5-membered heteroaryl having 1 or 2 heteroatoms selected from N, S and O, optionally substituted with methyl; 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; o is an integer from 0 to 2 (e.g., 0, 1, or 2); The dashed line indicates the site of attachment to the PTM via a chemical linking group (L), or alternatively, the attachment site is R 16 is located.

[0128]

[0033] In any aspect or embodiment described herein, the VLM comprises: [ka] [ka] and is represented by a structure selected from where the dashed line indicates the site of attachment to the PTM via a chemical linker group (L).

[0129] In any aspect or embodiment described herein, the ULM is a VLM and is selected from the group ULM-a: [ka] and During the ceremony, The dashed line indicates the attachment of at least one PTM, another ULM or VLM or CLM or ILM (i.e., a ULM' or VLM' or CLM' or ILM'), or a chemical linker moiety linking at least one PTM, a ULM' or VLM' or CLM' or ILM' to a ULM; X in the formula ULM-a 1 and X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO; R in the formula ULM-a Y3 and R Y4 each independently represents a straight or branched chain C optionally substituted with H, one or more halo 1-6 Alkyl, optionally substituted C 1-6 Alkoxyl (e.g., 0 to 3 R Pand optionally substituted with a group; R in the formula ULM-a P are each independently a group H, halo, —OH, C 1-3 alkyl, C=O; Formula ULM-a W 3 is an optionally substituted T, an optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-biheteroaryl, optionally substituted -T-heterocycle, optionally substituted -T-biheterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle, X in the formula ULM-a 3 is C=O, R 1 , R 1a , R 1b and Each R in formula ULM-a 1 , R 1a , and R 1b are independently H, a straight 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, T of formula ULM-a is optionally substituted alkyl, —(CH) n - group, linear or branched -(CH2) n-O-C1-6 alkyl, or optionally substituted -(CH2) n -O-heterocyclyl, wherein each methylene group is selected from the group consisting of halogen, methyl, optionally substituted alkoxy, straight or branched C1-C6 alkyl group optionally substituted with one or more halogens, C(O)NR 1 R 1a , or NR 1 R 1a or R 1 and R 1a are linked to form an optionally substituted heterocyclyl, or an —OH group, or an optionally substituted amino acid side chain, Formula ULM-a W 4 is an optionally substituted -NR1-T-aryl, wherein the aryl group can be an optionally substituted 5- to 6-membered heteroaryl, or an optionally substituted aryl, an optionally substituted -NR1-T-heterocycle, wherein -NR1 is X 2 R1 is H or CH3, preferably H; In the formula ULM-a, n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

[0130] In any aspect or embodiment described herein, T is optionally substituted alkyl, —(CH) n - groups, wherein each methylene group is selected from the group consisting of halogen, methyl, optionally substituted alkoxy, straight or branched C1-C6 alkyl groups optionally substituted with one or more halogens, C(O)NR 1 R 1a , or NR 1 R 1a or R 1 and R 1a are connected to form an optionally substituted heterocycle, or an —OH group or an optionally substituted amino acid side chain, n is 0 to 6, often 0, 1, 2, or 3, and preferably 0 or 1.

[0131] In any aspect or embodiment described herein, W of formula ULM-a 4 teeth, [ka] wherein: W 5 is optionally substituted (e.g., W 5 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted 5-10 membered heteroaryl) (e.g., W 5 is optionally substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; R 14a , R 14b are each independently H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, 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 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms 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; o is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4); Each R 16is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy.

[0132] In any aspect or embodiment described herein, W 5 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted 5-10 membered heteroaryl (e.g., W 5 is selected from optionally substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; R 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14 a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.

[0133] In any aspect or embodiment described herein, the W of formula ULM-a for use in the present disclosure 4 Substituents may also be any of the W groups found in certain compounds disclosed herein. 4 These W groups are specifically included (and are not limited to the particular compounds disclosed). 4 Each of the substituents may be any number of W as also disclosed herein. 3 It may be used in conjunction with a substituent.

[0134] In any aspect or embodiment described herein, ULM-a may comprise one to three R in the pyrrolidine moiety. P groups, and each R P are independently H, halo, —OH, C1-3 alkyl, or C═O.

[0135] In any of the embodiments described herein, W 3 and W 4 can be independently covalently attached to a chemical linker group that is attached to one or more PTM groups;

[0136] In any aspect or embodiment described herein, the ULM is a VLM and has the structure: [ka] is represented by During the ceremony, W in formula ULM-b 3 is an optionally substituted aryl, an optionally substituted heteroaryl, or [ka] is selected from the group R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R in formula ULM-b 11 is an optionally substituted heterocyclyl, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, [ka] is selected from the group R in formula ULM-b12 is selected from the group of H or optionally substituted alkyl; R in formula ULM-b 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in formula ULM-b 14a and R 14b are each independently H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxylalkyl, 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 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms 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; W in formula ULM-b 5 is an optionally substituted phenyl or an optionally substituted 5- to 10-membered heteroaryl (e.g., W 5 is selected from the group of optionally substituted with one or more [e.g., 1, 2, 3, 4, or 5] halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy; R in formula ULM-b 15H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl; Each R in formula ULM-b 16 is independently selected from the group of H, CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o of formula ULM-b is 0, 1, 2, 3, or 4; R in formula ULM-b 18 is independently selected from the group of halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; p of the formula ULM-b is 0, 1, 2, 3, or 4; The dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM. Shows.

[0137] In any aspect or embodiment described herein, R 15 H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted dialkyl, or optionally substituted heterocyclyl; 26 are independently H, optionally substituted alkyl, or NR 27a R 27b Each R 27a and R 27b are independently H, optionally substituted alkyl, or R 27a and R 27b taken together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl.

[0138] In any aspect or embodiment described herein, R 15 teeth [ka] wherein: R 17 is H, halo, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl, and C 1-6 is haloalkyl, Xa is S or O.

[0139] In any aspect or embodiment described herein, R 17 is selected from the group of methyl, ethyl, isopropyl, and cyclopropyl.

[0140] In any aspect or embodiment described herein, R 15 is selected from the group consisting of: [ka]

[0141] In any aspect or embodiment described herein, R 11 is selected from the group consisting of: [ka]

[0142] In any aspect or embodiment described herein, R 14a , R 14b are each independently H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CHOR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms 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, and the spirocycloalkyl or spiroheterocyclyl itself is an alkyl, haloalkyl, or -COR 33 wherein R 33 is alkyl or haloalkyl, In the formula, R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl; R 26and R 27 However, as stated above.

[0143] In any aspect or embodiment described herein, R 15 H, halogen, CN , OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 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 the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from CHOR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 ,or [ka] wherein R 26 , R 27 , R 30 , and R 14 a is as described above.

[0144] In any aspect or embodiment described herein, R 14a , R 14b each independently represents H, optionally substituted haloalkyl, optionally substituted alkyl, CHOR 30 , CH2NHR30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocyclyl itself is not an alkyl, haloalkyl, or -COR 33 wherein R 33 is alkyl or haloalkyl, wherein R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl; R in formula ULM-b 15 H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 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 substitutions of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from CHOR 30 , CH2NHR 30 , CH2NCH3R30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 ,or [ka] wherein R 26 , R 27 , R 30 , and R 14 a is as described above.

[0145] In any aspect or embodiment described herein, the ULM comprises: [ka] During the ceremony, R1 of formulae 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; R for formulas ULM-c, ULM-d, and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R for formulas ULM-c, ULM-d, and ULM-e 15 is selected from the group consisting of H, halogen, CN, OH, NO, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; X of formula ULM-c, ULM-d, and ULM-e is C, CH, or C=O; R3 of formulae ULM-c, ULM-d, and ULM-e is absent or an optionally substituted 5- or 6-membered heteroaryl; Dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker group connecting at least one PTM or ULM', or both, to ULM (ULM-a).

[0146] In any aspect or embodiment described herein, ULM has the following chemical structure: [ka] R11 in the formula ULM-f is [ka] or optionally substituted heteroaryl; of the formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R in the formula ULM-f 12 is H, C=O, R in the formula ULM-f 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in the formula ULM-f 15 is H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, [ka] and selected from the group consisting of The dashed line in formula ULM-f indicates the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM (ULM-f).

[0147] In any aspect or embodiment described herein, the VLM may be an R group (e.g., 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 covalently attached via T to a PTM or chemical linker group (L).

[0148] In any aspect or embodiment described herein, the VLM may be 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 , W3 , W 4 , W 5 , X, X 1 , X 2 , X 3 , or covalently attached via T to a PTM or chemical linker group (L).

[0149] 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 covalently linked to a linker that independently connects to a linker and / or one or more PTM, ULM, and VLM groups.

[0150] In any aspect or embodiment described herein, ULM has the following structure: [ka] [ka] is selected from wherein the dashed lines indicate the attachment site for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0151] In any aspect or embodiment described herein, ULM has the following structure: [ka] [ka] is selected from wherein n is 0 or 1, and the dashed lines indicate the attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0152] In any aspect or embodiment described herein, ULM has the following structure: [ka] [ka] [ka] [ka] [ka] is selected from wherein the phenyl rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, and the dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM-a.

[0153] In any aspect or embodiment described herein, the phenyl rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 can be functionalized as esters to become part of a prodrug.

[0154] 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 each comprises an ester-linked prodrug moiety.

[0155] In any aspect or embodiment described herein, the ULM or VLM comprises: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R3 is an optionally substituted 5- to 6-membered heteroaryl; W 5 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted pyridinyl; R 14a and R 14b is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxylalkyl, 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 14bthe other of which is H; or R 14a , R 14b together with the carbon atoms 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; R 15 is CN, optionally substituted fluoroalkyl, [ka] [ka] , in the formula R 28a is halo, optionally substituted alkyl or fluoroalkyl), or [ka] and Each R 16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; Each R 26 are independently 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 form a 4- to 6-membered heterocyclyl; 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; o is 0, 1, or 2; Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM', or both, to ULM.

[0156] In any aspect or embodiment described herein, ULM has the following formula: [ka] It is of During the ceremony, X 4 , X 5 , and X 6 are each selected from CH and N, and no more than two are N; R 1 is C1-6 alkyl, R3 is an optionally substituted 5- to 6-membered heteroaryl; R 14a and R 14b one of which is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted 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 of which is H; or R 14a and R 14b together with the carbon atoms 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; Each R 27a and R 27b are independently H or C1-6 is alkyl, q is 1, 2, 3, or 4; R 15 but, [ka] , or CN, R 28 H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] and R 28C is H, methyl, fluoro, or chloro; R 16 But H, C 1-4 Alkyl, fluoro, chloro, CN, or C 1-4 is an alkoxy; Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0157] In any aspect or embodiment described herein, R 14a and R 14b is H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyloxyalkyl, C 1-4 Alkyl-NR 27a R 27b , and CONR 27a R 27b is selected from.

[0158] In any aspect or embodiment described herein, R 14a and R 14bAt least one of is H (e.g., R 14a and R 14b Both are H).

[0159] In any aspect or embodiment described herein, R 14a and R 14b at least one of which is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, 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 14b one of which is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkoxyheterocycloalkyl substituted with COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 and R 14a and R 14b The other of these is H.

[0160] In any aspect or embodiment described herein, R 14a and R 14b together with the carbon atoms to which they are attached, [ka] wherein R 23 But H, C1-4 Alkyl, -C(O)C 1-4 alkyl.

[0161] In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, each independently has the chemical structure: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is CH or N; R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R3 is an optionally substituted 5- to 6-membered heteroaryl; R 14a and R 14b is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxylalkyl, 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 of which is H; or R 14a , R 14b together with the carbon atoms 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; R 15 is CN, optionally substituted fluoroalkyl, [ka] [ka] , in the formula R 28a is halo, optionally substituted alkyl or fluoroalkyl), or [ka] and Each R 26 are independently 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 form a 4- to 6-membered heterocyclyl; 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; Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0162] In any of the aspects or embodiments described herein, R1 is C 1-6 It is alkyl.

[0163] In any of the aspects or embodiments 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 Alkylamines, 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 R 27b , (CH2) q NHCOC 1-6 Alkyl, C 3-6 Cycloalkyl, or NR 27a R 27b and each R 26 are independently H, C 1-6 Alkyl, or NR 27a R 27b and each R 27a and R 27b are independently H or C 1-6 alkyl, and q is 1, 2, 3, or 4.

[0164] In any of the aspects or embodiments described herein, R 14a and R 14 b One of them is H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, optionally substituted C 1-4 Alkylamines, (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 and each R 26 are independently H, C 1-4 Alkyl, or NR 27a R 27b and each R 27a and R27b are independently H or C 1-4 alkyl; and q is 1 or 2.

[0165] In any of the aspects or embodiments described herein, R 28 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, (CH2) q O.C. 1-6 Alkyl, (CH2) q OH, (CH2) q NR 27a R 27b , (CH2) q NHCOC 1-6 alkyl, or [ka] and R 29 But H, C 1-6 Alkyl, NR 27a R 27b or q NHCOC 1-6 is alkyl, In the formula, q is 1 or 2.

[0166] In any of the aspects or embodiments described herein, R 3 is isoxazolyl, 4-chloroisoxazolyl, 4-fluoroisoxazolyl, or pyrazolyl. In any of the aspects or embodiments described herein, X is CH.

[0167] In any aspect or embodiment described herein, ULM has the following formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R1, R 14a , and R 14b is as described herein; X is CH or N; R 30 is H, F, or Cl; R 16 But H, C 1-4 Alkyl, fluoro, chloro, CN, or C 1-4 is an alkoxy; R 28 H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] and Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM', or both, to ULM.

[0168] In any aspect or embodiment described herein, ULM has the following formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R1, R 14a , and R 14b is as described herein; R 30 is H, F, or Cl; Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM', or both, to ULM. Shows.

[0169] In any aspect or embodiment described herein, the VLM may comprise a PTM, or an R group (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 etc.), X, X 4 , X 5 , or X 6 is covalently bonded to the chemical linking group (L) via

[0170] In any aspect or embodiment described herein, the VLM may comprise a PTM, or an 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 is covalently bonded to the chemical linking group (L) via

[0171] 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 , R28a , R 28C , R 29 , R 30 , X, X 4 , X 5 , or X 6 can be independently covalently attached to a linker and / or a linker that attaches to one or more PTM, ULM, and VLM groups.

[0172] In any aspect or embodiment described herein, the ULM described herein (or ULM', if present) may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any aspect or embodiment described herein, the ULM described herein (or ULM', if present) may be attached to a PTM directly via a bond or by a chemical linker.

[0173] In any aspect or embodiment described herein, the ULM comprises: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0174] Example CLM: In any aspect or embodiment described herein, the present disclosure provides a method for the preparation of a medicament for the treatment of cereblon-associated leukemia. , and provides useful CLM for mobilization.

[0175]

[0023] In any aspect or embodiment described herein, the CLM has the chemical structure: [ka] [ka] is selected from the group consisting of During the ceremony, W of formulas (a1) through (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)) is independently selected from the group CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 in formula (a2) is C or N, each X in formulas (a) through (f) is independently selected from the group consisting of: absent, O, S, and CH; each Y in formulas (a1) through (fe) is independently selected from CH, —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; each Z in formulas (a1) through (e) is independently selected from absent, O, and S or CH2, provided that X and Z cannot both be CH2 or absent; each G and G' of formulas (a1) through (e) is independently selected from H, optionally substituted straight or branched chain alkyl (e.g., optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3, and Q4 in formulas (a1) to (e) represent N or a carbon C substituted with a group independently selected from H, R, N, and N-oxide; A in formulas (a1) through (e) is independently selected from H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; each n in formulas (a1) through (e) represents an integer independently selected from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); Each R in formulas (a1) to (e) is independently H, —C(═O)R′ (e.g., a carboxy group), —CONR′R″ (e.g., an amide group), —OR′ (e.g., OH), —NR′R″ (e.g., an amine group), —SR′, —SOR′, —SOR′, —SOR′, —CR′R″—, CR′NR′R″—, (—CR′O) n’R″, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted heteroaryl (e.g., optionally substituted 5-7 membered heteroaryl), unsubstituted or substituted straight or branched chain alkyl (e.g., C1-C6 straight or branched chain alkyl optionally substituted with one or more halogens, cycloalkyl (e.g., 3-6 membered cycloalkyl), or aryl (e.g., 5-7 membered aryl)), optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; alkoxyl can be substituted with one or more halogens, alkyl, haloalkoxy, fluoroalkyl, cycloalkoxy, cycloalkyl ... optionally substituted with alkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl), optionally substituted cycloalkyl (e.g., optionally substituted 3- to 7-membered cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 3- to 7-membered heterocyclyl), -P(O)(OR')R", -P(O)R", -OP(O)(OR')R", -OP(O)R", -Cl, -F, -Br, - and at least one W, X, Y, Z, G, G', R, R', R", Q1, Q2, Q3, Q4, or A is modified to covalently bond to a PTM, a chemical linker (L), a ULM, a CLM, or a combination thereof; R' and R" of formulas (a1) through (e) are each independently selected from a bond, H, optionally substituted straight or branched chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, -C(=O)R, and optionally substituted heterocyclyl; n' in formulas (a1) to (e) is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); [ka] represents a single or double bond, Equations (a1) to (e) [ka] independently represent a bond that is stereospecific ((R) or (S)) or non-stereospecific.

[0176] In any aspect or embodiment described herein, the CLM is [ka] [ka] and a chemical structure selected from the group consisting of: During the ceremony, each W of formulas (a1) through (e) (i.e., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)) is independently selected from the group CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 in formula (a2) is selected from C and N; each X in formulas (a1) through (e) is independently selected from the group consisting of: absent, O, S, and CH; each Y in formulas (a1) through (e) is independently selected from CH, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; each Z in formulas (a1) through (e) is independently selected from absent, O, S, and CH2, with the proviso that X and Z cannot both be CH2 or absent; each of G and G' of formulas (a1) through (e) is independently selected from H, optionally substituted straight or branched chain alkyl (e.g., optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3, and Q4 of formulas (a1) through (e) each independently represent nitrogen or a carbon substituted with a group independently selected from H, R, N, and N-oxide; A in formulas (a1) through (e) is independently selected from H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; n in formulas (a1) through (e) represents an integer independently selected from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulas (a1) to (e) is H, -C(=O)R' (e.g., a carboxy group), -CONR'R'' (e.g., an amide group), -OR' (e.g., OH), -NR'R'' (e.g., an amine group), -SR', -S02R', -S02NR'R'', -CR'R''-, CR'NR'R''-, (-CR'O) n’R″, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted heteroaryl (e.g., optionally substituted 5-7 membered heteroaryl), optionally substituted straight or branched chain alkyl (e.g., C1-C6 straight or branched chain alkyl optionally substituted with one or more halogens, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; alkoxyl may be substituted with one or more halogens, alkyls, haloalkoxy, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), optionally substituted cycloalkyl (e.g., optionally substituted C3- to -C6 cycloalkyl), optionally substituted heterocyclyl (e.g., optionally substituted 3- to 7-membered heterocyclyl), -P(O)(OR')R", -P(O)R", -OP(O)(OR')R", -OP(O)R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SONR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(= and at least one W, X, Y, Z, G, G', R, R', R", Q1, Q2, Q3, Q4, or A is covalently bonded to a PTM, chemical linker (L), ULM, CLM, or combination thereof (e.g., directly or indirectly via a functional group or an atom such as O, S, N, etc.); R' and R" of formulas (a1) through (e) are each independently selected from a bond, H, optionally substituted straight or branched chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, -C(=O)R, and optionally substituted heterocyclyl; n' in formulas (a1) to (e) is an integer selected from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); [ka] represents a single or double bond, Equations (a1) to (e) [ka] independently represent a bond that is stereospecific ((R) or (S)) or non-stereospecific.

[0177] In any aspect or embodiment described herein, the CLM or ULM has formula (g): [ka] and having the chemical structure During the ceremony, W of formula (g) is selected from CH2, O, C=O, NH, and N-alkyl; A in formula (g) is selected from H, methyl, or optionally substituted straight or branched chain alkyl; n' is an integer from 1 to 4, R of formula (g) is independently selected from H, O, OH, N, NH, NH, -Cl, -F, -Br, -I, methyl, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl), optionally substituted straight or branched chain alkoxy (e.g., optionally substituted straight or branched chain C1-C6 alkoxy), -alkyl-aryl (e.g., alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or combinations thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy), and at least one R or W is modified to covalently bond to a PTM, a chemical linking group (L), a ULM, a CLM, or combinations thereof; Each of the formulas (g) [ka] represents a bond that is stereospecific ((R) or (S)) or non-stereospecific.

[0178] In any aspect or embodiment described herein, the CLM or ULM is [ka] is selected from the group consisting of During the ceremony, Q1, Q2, Q3, Q4, and Q5 each independently represent nitrogen or a carbon substituted with a group independently selected from R, N, or N-oxide; W is selected from CH2 and C=O; A is H or straight or branched chain C 1-3 alkyl (e.g., methyl or ethyl); n is an integer selected from 1 to 4 (e.g., 1, 2, or 3, or 1 or 2); G is H or a straight or branched chain C 1-3 alkyl (e.g., methyl); Each R is independently H, O, OH, N, NH, NH2, -Cl, -F, -Br, straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl), straight or branched chain C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2), or linear or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy), wherein one R is modified to covalently attach to a PTM via a chemical linking group (L); each [ka] represents a bond that is stereospecific ((R) or (S)) or non-stereospecific.

[0179] In any aspect or embodiment described herein, the CLM or ULM has the chemical structure: [ka] is represented by During the ceremony, Q1, Q2, Q3, Q4, and Q5 each independently represent nitrogen or a carbon substituted with a group independently selected from R', N, or N-oxide; R 4 is H or halo, R' is H, halogen (e.g., F, Cl, Br), C 1-3 alkyl (e.g., methyl or ethyl), or C 1-3 alkoxyl (e.g., methoxy or ethoxy); [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific.

[0180] In any aspect or embodiment described herein, the CLM or ULM is [ka] [ka] [ka] [ka] is selected from the group consisting of During the ceremony, A is H or straight or branched chain C 1-3 alkyl (e.g., methyl or ethyl); G is H or linear 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 chain C 1-3 Alkyl (e.g., methyl or ethyl), straight or branched chain C 1-3 Fluoroalkyl (e.g., -CH 3 or CHF2), or linear or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy); R' is H, halogen (e.g., F, Cl, Br), C 1-3 alkyl (e.g., methyl or ethyl), or C 1-3 alkoxyl (e.g., methoxy or ethoxy); [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; N * is the point of attachment of the PTM to a chemical linking group (L) or directly to a ULM (e.g., N *is (i) covalently bonded to the PTM via a chemical linking group (L) having a H or methyl valency, or (ii) is a nitrogen atom shared with the chemical linking group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl of the chemical linking group (L)); [ka] is a single bond or a double bond, [ka] indicates the attachment site of the PTM via a chemical linker group.

[0181] In any aspect or embodiment described herein, the CLM or ULM is [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of During the ceremony, N * is the point of attachment of the PTM to a chemical linking group (L) or directly to a ULM (e.g., N *is (i) covalently bonded to the PTM via a chemical linking group (L) having a H or methyl valency, or (ii) is a nitrogen atom shared with the chemical linking group (L) (e.g., a heteroatom shared with an optionally substituted heterocycloalkyl of the chemical linking group (L)); [ka] indicates the attachment site of the PTM via a chemical linker group (L).

[0182] In any aspect or embodiment described herein, the CLM or ULM is [ka] is selected from the group consisting of During the ceremony, A is H or straight or branched chain C 1-3 alkyl (e.g., methyl or ethyl); G is H or linear or branched C 1-3 alkyl (e.g., methyl); Each R is independently H, OH, NH, -Cl, -F, -Br, straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl), or straight or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy); N * is a nitrogen atom covalently attached to the PTM via a chemical linker group (L) having a H or methyl valency, or shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl group of the chemical linker group (L)).

[0183] In any aspect or embodiment described herein, the CLM or ULM is [ka] is selected from the group consisting of During the ceremony, A is H or straight or branched chain C 1-3 alkyl (e.g., methyl or ethyl); G is H or a straight or branched chain C 1-3 alkyl (e.g., methyl); One R is hydrogen and the other R is H, OH, NH2, -Cl, -F, -Br, straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl), or straight or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy); N * is a nitrogen atom covalently attached to the PTM via a chemical linker group (L) having a H or methyl valency, or shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl group of the chemical linker group (L)).

[0184] In any aspect or embodiment described herein, the CLM or ULM is [ka] is selected from the group consisting of During the ceremony, A is H or straight or branched chain C 1-3 alkyl (e.g., methyl or ethyl); G is H or a straight or branched chain C 1-3 alkyl (e.g., methyl), preferably H; One R is hydrogen and the other R is H, -Cl, -F, -Br, straight or branched chain C 1-3 Alkyl (e.g., methyl or ethyl), or straight or branched chain C 1-3 alkoxy (e.g., methoxy or ethoxy); N *is a nitrogen atom covalently attached to the PTM via a chemical linker group (L) having a H or methyl valency, or shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl group of the chemical linker group (L)).

[0185] In any aspect or embodiment described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, or A of the CLM may independently be covalently attached to a linker and / or a linker that is attached to one or more PTM, ULM, or CLM groups.

[0186] In any aspect or embodiment described herein, R is selected from O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., an alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy.

[0187] In any aspect or embodiment described herein, at least one R (e.g., R groups) are selected from H, O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy, and W is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

[0188] In any aspect or embodiment described herein, n is an integer from 1 to 4, and each R on the aryl or heteroaryl of the CLM is independently selected from a functional group or atom, e.g., O, OH, N, —Cl, —F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, and optionally one of these is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

[0189] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules resulting from a combination of one or more of the different features shown in the molecules below, where at least one R or W is modified to covalently attach to a PTM, a chemical linker (L), a ULM, a CLM, or combinations thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0190]

[0033] In any aspect or embodiment described herein, the CLM is selected from the group: [ka] [ka] [ka] [ka] and During the ceremony, W is independently selected from O, CH, CHR, C═O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl (e.g., CH, CHR, C═O, SO, NH, and N-alkyl); Q1, Q2, Q3, Q4, and Q5 each independently represent nitrogen or a carbon substituted with a group independently selected from R', N, and N-oxide; R 1 is absent or selected from H, OH, CN, C1-C3 alkyl, and C=O; R 2 is absent or selected from the group H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2; R 3is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), and substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently selected from H, halogen, C(=O)R', CN, OH, and CF3; X is C, CH, C═O or N; X1 is C=O, N, CH, or CH2; R' is H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl; n is 0 to 4, [ka] is a single bond or a double bond, The CLM is covalently attached to the PTM by a covalent bond or via a chemical linking group (L).

[0191] In any aspect or embodiment described herein, the CLM may be a CLM having an R group (e.g., R, R 1 , R 2 , R 3 , R 4 , or R'), W, X, or Q group (Q1, Q2, Q3, Q4, or Q5), either directly or covalently attached to the PTM via a chemical linking group (L).

[0192]

[0033] In any aspect or embodiment described herein, the CLM may be any of W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R', Q1, Q2, Q3, Q4, and Q5, are covalently attached to the PTM either directly or via a chemical linker group (L).

[0193] In any aspect or embodiment described herein, W, X, R, R 1 , R 2 , R 3 , R 4 , R', Q1, Q2, Q3, Q4, or Q5 can independently be covalently attached to a linker that is attached to one or more PTM, ULM, or CLM groups.

[0194] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds that result from combining features of one or more of the following compounds: [ka] [ka] [ka] During the ceremony, W is independently selected from the group: CH, CHR, C=O, SO, NH, and N-alkyl; R 1 is absent or selected from H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl; R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R 4 is methyl or ethyl, R 5 is H or halo, R 6 is H or halo, n is an integer from 0 to 4, R and R' are independently H, a functional group or atom (e.g., H, a halogen (such as -Cl or -F), an amine, C 1-3 Alkyl, C 1-3 Alkoxyl, NR 2 R 3 , or C(=O)OR 2 ) or a point of attachment to a PTM or chemical linking group (L); Q1 and Q2 are each independently C or N substituted with a group independently selected from H and C1-C3 alkyl; [ka] is a single bond or a double bond,

[0195] In any of the embodiments described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, R, or R' can independently be covalently attached to a linker that attaches to one or more PTM groups.

[0196] In any of the embodiments described herein, R 1 , R 2 , Q1, Q2, Q3, Q4, R, and R' can independently be covalently attached to a linker that attaches to one or more PTM groups.

[0197] In any of the embodiments described herein, Q1, Q2, Q3, Q4, R, and R' can independently be covalently attached to a linker that attaches to one or more PTM groups.

[0198] In any aspect or embodiment described herein, R is modified to covalently attach to a linker group (L), or directly to a PTM, or a combination thereof.

[0199] In any aspect or embodiment described herein, the CLM is [ka] [ka] wherein R' is halogen and R 1 as described in any aspect or embodiment described herein.

[0200] In any aspect or embodiment described herein, a "CLM" can be an imide that binds to cereblon E3 ligase. These imides and linker attachment points can be, but are not limited to, the following structures: [ka] or [ka]

[0201] In any aspect or embodiment described herein, the CLM or ULM is [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of During the ceremony, N * is a nitrogen atom that is (i) covalently attached to the PTM via a chemical linker group (L) having a H or methyl valency, or (ii) shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl group of the chemical linker group (L)); CLM's [ka] indicates the point of attachment to the linker group or PTM.

[0202] In any aspect or embodiment described herein, the CLM is [ka] is selected from the group consisting of [ka] During the ceremony, N * is a nitrogen atom shared with the chemical linker group (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl group of the chemical linker group (L)); CLM's [ka] indicates the point of attachment to the linker group or PTM.

[0203] In any aspect or embodiment described herein, the CLM is [ka] [ka] [ka] is selected from the group consisting of During the ceremony, CLM's [ka] indicates the point of attachment to the linker group or PTM, N * is a nitrogen atom shared with a chemical linker group or a PTM; W, Q4, and Q5 are each as described in any aspect or embodiment described herein.

[0204] Exemplary ILM AVPI tetrapeptide fragment 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 chemical structures represented by ILM-I, ILM-II, ILM-III, and ILM-IV: [ka] During the ceremony, R of ILM-I, ILM-II, ILM-III, and ILM-IV 1 But H or C 1-3 alkyl (e.g., methyl or ethyl); R of ILM-I, ILM-II, ILM-III, and ILM-IV 2 But H or C 1-3 alkyl (e.g., methyl or ethyl); R for ILM-I, ILM-II, ILM-III, and ILM-IV3 is selected from cycloalkyl and heterocycloalkyl; R for ILM-I, ILM-II, ILM-III, and ILM-IV 5 is H, R for 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), bicyclic group optionally having 1, 2, or 3 heteroatoms such as O or N (e.g., 9-12 membered bicyclic group optionally having 1, 2, or 3 heteroatoms such as O or N), optionally further substituted with 1 to 3 substituents as described above; R for ILM-IV 4a But -(CH2) x -aryl (e.g., 5- to 7-membered aryl), -(CH2) x -heteroaryl (e.g., 5- to 7-membered heteroaryl), optionally further substituted with 1 to 3 substituents as defined above; x for ILM-IV is 0, 1, 2, or 3; ILM, R 4 , R 4a , R 5 is attached to a chemical linking group (L) or a PTM via

[0205] In any aspect or embodiment described herein, R for ILM-I, ILM-II, ILM-III, and ILM-IV 1 is a methyl group, R for ILM-I, ILM-II, ILM-III, and ILM-IV 2 is a methyl group, R for ILM-I, ILM-II, ILM-III, and ILM-IV 3 is C6 cycloalkyl or C6 heterocycloalkyl (e.g. [ka] ) and R for ILM-I, ILM-II, and ILM-III 4 is an 11-membered bicyclic group optionally containing one heteroatom, where the bicyclic group is the point of attachment of the ILM to a chemical linker group (L) or PTM, as described herein, or R of ILM-IV 4a But -CH2CH2-C 5-7 aryl, for example phenyl, 5-7 the aryl or phenyl is the point of attachment of the ILM to a chemical linking group (L) or PTM, as described herein; or At least one of these combinations.

[0206] In any aspect or embodiment described herein, R for ILM-I, ILM-II, and ILM-III 4 teeth, [ka] is.

[0207] In any aspect or embodiment described herein, the ILM or ULM may comprise: [ka] [ka] is selected from the group consisting of During the ceremony, [ka] indicates the attachment site of the PTM via a chemical linker group (L).

[0208] In any aspect or embodiment described herein, the ILM may have the structure of formula (XVII) (which is derived from the IAP ligand described in Cohen, F. et al., Antagonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010)), or a non-natural mimetic thereof: [ka] During the ceremony, R in formula (XVII) 1 but halogen (e.g., fluorine), cyano, [ka] is selected from the group X in formula (XVII) is selected from the group of O or CH2.

[0209]

[0033] In any aspect or embodiment described herein, the ILM of the composition comprises: [ka] is selected from the group consisting of:

[0210]

[0033] In any aspect or embodiment described herein, the ILM of the compound is [ka] is.

[0211]

[0033] In any aspect or embodiment described herein, the ILM of the compound is [ka] has a chemical structure selected from the group consisting of:

[0212] Exemplary Linkers In any aspect or embodiment described herein, the compounds described herein comprise a PTM chemically linked to a ULM (e.g., a CLM, a VLM, an ILM, or a combination thereof) via a chemical linker (L). In certain embodiments, the linker group L comprises one or more covalently attached structural units (e.g., -A L 1… (A L ) q -or-( A L ) q -) and A L 1 is a group attached to the PTM, (A L ) q is a group attached to ULM.

[0213] In any aspect or embodiment described herein, the connection of the linker (L) to a ULM (e.g., a VLM, an ILM, or a CLM) is a stable L-ULM bond. For example, in any aspect or embodiment described herein, when the linker (L) and a ULM are joined via a heteroatom (e.g., N, O, S), any additional heteroatom (if present) is separated by at least one carbon atom (e.g., —CH—), e.g., by an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and a ULM are linked via a heteroatom, the heteroatom is not part of an ester.

[0214] In any aspect or embodiment described herein, the linker group L is of the formula -(A L ) q-, where A is a chemical moiety as described in any aspect or embodiment described herein, and q is 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, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80), and L is covalently linked to the PTM and ULM and provides sufficient binding of the PTM to the protein target and of the ULM to the E3 ubiquitin ligase to achieve target protein ubiquitination.

[0215] In any aspect or embodiment described herein, the linker group L is of the formula -(A L ) q -, where A is a chemical moiety as described in any aspect or embodiment described herein; q is an integer between 6 and 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 L covalently attaches the PTM and ULM and provides sufficient proximity binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase to result in target protein ubiquitination.

[0216] In any aspect or embodiment described herein, the linker group (L) may be -(A L ) q - and During the ceremony, (A L ) q is a group that attaches a ULM (e.g., a CLM, an ILM, or a VLM) to a PTM; q of the linker is an integer of 1 or more, Each A L However, independently, combined, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , C=O, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocyclyl, 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 1 to 8 R L1 and / or R L2 C optionally substituted with a group 5-13 Spiroheterocycloalkyl, 1 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 1 to 6 R L1 and / or R L2 optionally substituted with a group and R is selected from the group consisting of: L1 or R L2 each independently optionally linked to other groups, and L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , RL2 , R L3 , R L4 and R L5 are each independently H, halo, 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-, 6-, 7-, or 8-membered aryl), heteroaryl (e.g., 5-, 6-, 7-, or 8-membered heteroaryl), C 3-11 Heterocyclyl, 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(C1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0217] In any aspect or embodiment described herein, q is an integer greater than or equal to 1.

[0218] In any aspect or embodiment described herein, for example, when the linker q is greater than 2, (A L ) q is A L 1 and (A L ) q and the linker connects the PTM to the ULM.

[0219] In any aspect or embodiment described herein, for example, when q of the linker is 2, (A L )2 is A L 1 and a group bound to ULM.

[0220] In any aspect or embodiment described herein, q of the chemical linking group (L) is 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, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 6, 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).

[0221] In any aspect or embodiment described herein, for example, when the linker q is 1, the linker group L has the structure -A L 1- and A L 1 is a group that attaches the ULM moiety to the PTM moiety.

[0222] In any aspect or embodiment described herein, the unit A of the linker (L) L teeth, -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(lower alkoxyl)-OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(cyclo Alkyl)-(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)-CH, and -N(R1R2)-(heterocyclyl)-CH, wherein: n of the linker can be 0 to 10; R of the linker can be H or lower alkyl; The linker R1 and R2 can form a ring with the N to which they are attached.

[0223] In any aspect or embodiment described herein, the linker (L) can be an optionally substituted C-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), and all subranges (e.g., C1-C10, C1-C20, C2-C10, C2-20, C10-C20, C10-C50, etc.) are included, where each carbon is optionally independently substituted or replaced with (1) a heteroatom selected from N, O, S, P, or Si atoms having the 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 a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not covalently linked or are not adjacently positioned).

[0224] In any aspect or embodiment described herein, the linker (L) may be an optionally substituted C-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 , C41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 alkyl), wherein Each carbon is CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , C=O, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 1 to 8 R L1 and / or R L2 C optionally substituted with a group 5 -13 Spiroheterocyclyl, 1 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 1 to 6 R L1 and / or R L2a group independently selected from heteroaryl optionally substituted with a group, optionally independently substituted or replaced by R L1 or R L2 each independently optionally linked to another group, and optionally 1 to 4 R L5 forming a cycloalkyl and / or heterocyclyl moiety substituted with a group, R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, 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- to 8-membered aryl (e.g., 5-, 6-, 7-, or 8-membered aryl), 5- to 8-membered heteroaryl (e.g., 5-, 6-, 7-, or 8-membered heteroaryl), C 3-11 Heterocyclyl, 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 1-8Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0225] In any aspect or embodiment described herein, the linker group may be an optionally substituted C-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 , C38 , 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 all subranges (e.g., C1-C10, C1-C20, C2-C10, C2-20, C10-C20, C10-C50, etc.) are included, where each carbon is optionally substituted or replaced with: The appropriate number of hydrogens, substitutions (e.g., OH, halo, C) to complete the valence 1~8 Alkyl, methyl, ethyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, C 1~8 alkoxy, or methoxy), or both with O, N, S, P or Si atoms; Optionally substituted aryl (e.g., optionally substituted 5- or 6-membered aryl) or bicyclic aryl (e.g., optionally substituted 9- to 20-membered bicyclic heteroaryl), e.g., OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 optionally substituted aryl or bicyclic aryl optionally substituted with alkoxy, or methoxy; Optionally substituted aryl (e.g., optionally substituted 5- or 6-membered heteroaryl) or bicyclic heteroaryl (e.g., optionally substituted 9- to 20-membered bicyclic heteroaryl), e.g., an appropriate number of hydrogens, substitutions (e.g., OH, halo, C) to complete the valence. 1~8 Alkyl, methyl, ethyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, C 1~8 Optionally substituted alkoxy, or methoxy) with one or more heteroatoms selected from O, N, S, P or Si atoms, or both heteroaryl or bicyclic heteroaryl; For example, OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 optionally substituted C1-C6 alkyl optionally substituted with alkoxy, or methoxy; For example, OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 optionally substituted C2-C6 alkenyl optionally substituted with alkoxy, or methoxy; For example, OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 optionally substituted C2-C6 alkynyl optionally substituted with alkoxy, or methoxy; Optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl) or bicyclic cycloalkyl (e.g., optionally substituted C5-C20 bicyclic cycloalkyl), such as OH, halo, C 1-8 Alkyl, methyl, ethyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 optionally substituted cycloalkyl or bicyclic cycloalkyl optionally substituted with alkoxy, or methoxy; Optionally substituted heterocycloalkyl (e.g., an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic group) or bicyclic heteroacycloalkyl (e.g., an optionally substituted 5- to 20-membered bicyclic heterocycloalkyl), e.g., an appropriate number of hydrogens, substitutions (e.g., OH, halo, C) to complete the valence; 1~8 Alkyl, methyl, ethyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, C 1~8Optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl having one or more heteroatoms independently selected from O, N, S, P, or Si atoms, having alkoxy, or methoxy, or both. In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted with one or more OH, halo, straight-chain or branched C1-C6 alkyl (e.g., methyl or ethyl), straight-chain or branched C1-C6 haloalkyl, straight-chain or branched C1-C6 hydroxyalkyl, or straight-chain or branched C1-C6 alkoxy (e.g., methoxy).

[0226] In any aspect or embodiment described herein, the linker (L) does not have a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not covalently linked or adjacently positioned).

[0227] 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 carbon or oxygen may be substituted or replaced with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens to complete the valence.

[0228] In any aspect or embodiment described herein, the linker (L) has the chemical structure: [ka] is represented by During the ceremony, Y L1 is a bond, O, or NH, C=O, or C1-C3 alkyl; WL2 is an optionally substituted 3- to 7-membered ring (e.g., 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl); Y L2 is a bond, O, unsubstituted or substituted straight or branched chain C1-C6 alkyl (e.g., 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 chain C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3 , methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight-chain or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have 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- to 7-membered ring (e.g., a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl), an 8- to 11-membered spirocycle, or an 8- to 11-membered non-aromatic bicyclic group, each having 0 to 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 groups, or C═O; Y L3is a bond, O, unsubstituted or substituted straight or branched chain C1-C6 alkyl (e.g., 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 chain C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3 , methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight-chain or branched C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have 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- to 7-membered ring (e.g., a 4- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl) or an 8- to 11-membered spiro ring, each having 0 to 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 groups, or C═O; Y L4is a bond, O, unsubstituted or substituted straight or branched chain C1-C4 alkyl (e.g., 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 chain C2-C4 alkenyl (e.g., optionally substituted C2-C3 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3 , methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight or branched C1-C4 alkynyl (e.g., optionally substituted C2-C3 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have one or more (e.g., 1, 2, or 3) C atoms replaced by O, NH, NCH3, or NCH(CH3)2; Y L5is a bond, O, unsubstituted or substituted straight or branched chain C1-C9 alkyl (e.g., 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 chain C2-C9 alkenyl (e.g., optionally substituted C2-C6 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3 , methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight-chain or branched C1-C6 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have one or more (e.g., 1, 2, or 3) C atoms replaced by O, NH, NCH3, or NCH(CH3)2; Y L6is a bond, O, unsubstituted or substituted straight or branched chain C1-C8 alkyl (e.g., 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 chain C2-C8 alkenyl (e.g., optionally substituted C2-C6 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3 , methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight-chain or branched C1-C8 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have 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 chain C1-C10 alkyl (e.g., 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 chain C2-C10 alkenyl (e.g., optionally substituted C2-C8 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl , C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), or unsubstituted or substituted straight or branched C1-C10 alkynyl (e.g., optionally substituted C2-C8 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF3, methyl, ethyl, isopropyl, or C=O), wherein the alkyl, alkenyl, and alkyl each have 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 group, or C═O), wherein the alkyl has one or more (e.g., 1, 2, or 3) C atoms replaced by O, NH, NCH3, or NCH(CH3)2; [ka] indicates the binding site for PTM or ULM.

[0229]

[0037] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from: [ka] During the ceremony, U L and U L1 is independently selected from a bond or O; X L1 , X L2 , Y L1 , and Y L2 is independently selected from N or CH, with the proviso that XL1 If N, then U L is a bond and Y L2 If N, then U L1 is the bond, n1 and n2 are each independently 0 or 1; L1 and X L2 When both are N, n1 is 1 and n2 is 1, m1 and m2 are each independently 0 or 1; Y L1 and Y L2 Both are N When m1 is 1 and m2 is 1, R L1 and R L2 are each methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN; halogen (e.g., F), OH, and CN substituents represent one or two substituents; halogen (e.g., F), OH, and CN substituents represent one or two substituents; and halogen (e.g., F), OH, and CN substituents represent one or two substituents; L1 If N, then X L1 does not exist on the carbon atom adjacent to X L2 If N, then X L2 is not present on the carbon atom adjacent to Y L1 If N, then Y L1 is not present on the carbon atom adjacent to Y L2 If N, then Y L2 not present on adjacent carbon atoms, M L is selected from the following: [ka] In the formula, M L However, methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 optionally substituted with 1 or 2 substituents independently selected from (fluoroalkyl), OH and CN, provided that said F, OH and CN substituents are not present on the carbon atom adjacent to a heteroatom; ZL and Z L1 each independently represents O or NR 3 is selected from R L3 is H, methyl, ethyl, or isopropyl; p is 0, 1, or 2; U L and U L1 is the binding site for PTM or ULM.

[0230]

[0037] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from: [ka] During the ceremony, U L and U L1 is independently selected from a bond or O; X L1 , X L2 , Y L1 , and Y L2 is independently selected from N or CH, with the proviso that X L1 If N, then U L is a bond and Y L2 If N, then U L1 is the bond, n1 and n2 are each independently 0 or 1; L1 and X L2 When both are N, n1 is 1 and n2 is 1, m1 and m2 are each independently 0 or 1; Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1; R L1 and R L2 are each methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN; and the halogen (e.g., F), OH, and CN substituents are independently selected from XL1 If N, then X L1 does not exist on the carbon atom adjacent to X L2 If N, then X L2 is not present on the carbon atom adjacent to Y L1 If N, then Y L1 is not present on the carbon atom adjacent to Y L2 If N, then Y L2 not present on adjacent carbon atoms, M L is selected from the following: [ka] In the formula, M L However, methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 optionally substituted with 1 or 2 substituents independently selected from (fluoroalkyl), OH and CN, provided that said F, OH and CN substituents are not present on the carbon atom adjacent to a heteroatom; Z L and Z L1 each independently represents O or NR L3 is selected from R L3 is H, methyl, ethyl, or isopropyl; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5, and Y L2 is N, q is not 0 or 1, U L and Z L is the binding site for PTM or ULM.

[0231]

[0037] In any aspect or embodiment described herein, the linker (L) comprises a chemical structure selected from: [ka] [ka] During the ceremony, U L and U L1 is independently selected from a bond or O; X L1 , X L2 , Y L1 , and Y L2 is independently selected from N or CH, with the proviso that X L1 If N, then U L is a bond and Y L2 If N, then U L1 is the bond, n1 and n2 are each independently 0 or 1; L1 and X L2 When both are N, n1 is 1 and n2 is 1, m1 and m2 are each independently 0 or 1; Y L1 and Y L2 When both are N, m1 is 1 and m2 is 1; R L1 and R L2 are each methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C 1-3 represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN; and the halogen (e.g., F), OH, and CN substituents are independently selected from X L1 If N, then X L1 does not exist on the carbon atom adjacent to X L2 If N, then X L2 is not present on the carbon atom adjacent to Y L1 If N, then Y L1 is not present on the carbon atom adjacent to Y L2 If N, then Y L2 On adjacent carbon atoms Without W L1 and W L2 are each independently selected from N or CH; W L2 If N, then U L1 is the bond, r1 is 1 or 2, r2 is 0, 1 or 2, and WL1 and W L2 are both N, then r1 is 2 and r2 is 1 or 2; R L3 However, methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN; and the halogen (e.g., F), OH, and CN substituents are independently selected from X L1 If N, then X L1 does not exist on the carbon atom adjacent to X L2 If N, then X L2 is not present on the carbon atom adjacent to Y L1 If N, then Y L1 is not present on the carbon atom adjacent to Y L2 If N, then Y L2 not present on adjacent carbon atoms, M L1 is selected from the following: [ka] In the formula, M L1 However, methyl, halogen (e.g., F), fluoroalkyl (e.g., C 1-3 optionally substituted with 1 or 2 substituents independently selected from (fluoroalkyl), OH and CN, provided that said F, OH and CN substituents are not present on the carbon atom adjacent to a heteroatom; Z L and Z L1 each independently represents O or NR 3 is selected from p is 0, 1, or 2; U L and U L1 is the binding site for PTM or ULM.

[0232] In any aspect or embodiment described herein, the linker (L) is [ka]

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[0233] In any aspect or embodiment described herein, the linker (L) is [ka] [ka] [ka] [ka] [ka]

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[0234] In any aspect or embodiment described herein, the linker (L) is [ka] [ka] is selected from During the ceremony, each * is the binding site for PTM or ULM.

[0235] In any aspect or embodiment described herein, the linker (L) may have the following chemical structure: [ka] Including, During the ceremony, W L1 and W L2 are each independently absent or optionally R Q and each R Qare independently H, halo, OH, CN, CF, optionally substituted straight or branched chain C-C alkyl, optionally substituted straight or branched chain C-C alkoxy, or two R Q groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 each independently represents a bond, an optionally substituted straight or branched chain C1-C6 alkyl, and optionally one or more C atoms are O or NR YL1 optionally substituted C1-C6 alkene, optionally having one or more C atoms replaced by O; optionally substituted C1-C6 alkyne, optionally having one or more C atoms replaced by O; or optionally substituted straight or branched C1-C6 alkoxy; R YL1 is H or optionally substituted straight or branched chain C 1-6 is alkyl, n is 0 to 10, [ka] indicates the point of attachment to the PTM or ULM moiety.

[0236] In any aspect or embodiment described herein, the linker (L) may have the structure shown below: [ka] and During the ceremony, W L1 and W L2 are each independently absent or optionally R Q Piperazine, piperidine, and morpholine substituted with R Qare independently H, -Cl-, -F-, OH, CN, CF3, optionally substituted straight or branched chain C1-C6 alkyl (e.g., methyl, ethyl), optionally substituted straight or branched chain C1-C6 alkoxy (e.g., methoxy, ethoxy); Y L1 each independently represents a bond, an optionally substituted straight or branched chain C1-C6 alkyl, and optionally one or more C atoms are O or NR YL1 optionally substituted C1-C6 alkene, optionally having one or more C atoms replaced by O; optionally substituted C1-C6 alkyne, optionally having one or more C atoms replaced by O; or optionally substituted straight or branched C1-C6 alkoxy; R YL1 is H or optionally substituted straight or branched chain C 1-6 alkyl (e.g., methyl, ethyl); n is 0 to 10, [ka] indicates the point of attachment to the PTM or ULM moiety.

[0237] In any aspect or embodiment described herein, the linker (L) may have the structure shown below: [ka] and During the ceremony, W L1 and W L2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclic, C 1-6 Alkyl and optionally one or more C atoms are O or NR YL1 What has been replaced by C 1-6 Alkenes and optionally one or more C atoms replaced by O, C 1-6Alkynes and optionally one or more C atoms replaced by O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with RQ, where each RQ is independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH2, NR YL1 R YL2 , CN or two R Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system having 0-4 heteroatoms; Y L1 each independently represents a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms replaced by O, optionally substituted linear or branched C1-C6 alkoxy; Q L is optionally bridged, and optionally has 0 to 6 R Q and each R is a 3- to 6-membered alicyclic, bicyclic, or aromatic ring having 0 to 4 heteroatoms, substituted with Q are independently H, optionally substituted straight or branched chain C 1-6 Alkyl (e.g., one or more halo, C 1-6 optionally substituted by alkoxyl) or two R Q the groups, together with the atoms to which they are attached, form a 3- to 8-membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 each independently represents H, OH, an optionally substituted straight or branched chain C 1-6 Alkyl (e.g., one or more halo, C 1-6optionally substituted by alkoxyl) or R YL1 , R YL2 together with the atoms to which they are attached form a 3-8 membered system containing 0-2 heteroatoms, n is 0 to 10, [ka] indicates the point of attachment to the PTM or ULM moiety.

[0238] In any aspect or embodiment described herein, the linker (L) may have the structure shown below: [ka] and During the ceremony, W L1 and W L2 are each independently absent, cyclohexane, cyclopentane, piperazine, piperidine, morpholine, C 1ー6 alkyl and optionally one or more C atoms are O or NR YL1 What has been replaced by C 1-6 Alkenes, optionally with one or more C atoms replaced by O, C 1-6 Alkenes, optionally with one or more C atoms replaced by O, or C 1-6 Alkynes in which one or more C atoms are replaced by O, each of which is R Q and each R Q is H, -Cl, -F, OH, CN, CF, hydroxyl, optionally substituted straight or branched chain C-C alkyl (e.g., methyl, ethyl), or optionally substituted straight or branched chain C-C alkoxy; Y L1 each independently represents a bond, NR YL1 , O, C.R. YL1 R YL2 , C=O, optionally substituted straight or branched chain C1 -C 6 alkyl and optionally one or more C atoms are O or NR YL1 replaced by an optionally substituted C 1-6 Alkenes, optionally with one or more C atoms replaced by O, optionally substituted C 1-6 alkyne, optionally with one or more C atoms replaced by O, or optionally substituted linear or branched C1-C6 alkoxy; Q L However, 0 to 6 R Q and each R is a 3- to 6-membered heterocyclic, heterobicyclic, or heteroaryl ring substituted with Q are independently H or optionally substituted straight or branched chain C 1-6 Alkyl (e.g., one or more halo, C 1-6 optionally substituted by alkoxyl; R YL1 , R YL2 each independently represents H, an optionally substituted straight or branched chain C 1-6 Alkyl (e.g., methyl, ethyl, C optionally substituted with one or more halo) 1-6 alkoxyl), n is 0 to 10, [ka] indicates the point of attachment to the PTM or ULM moiety.

[0239] In any aspect or embodiment described herein, the linker group may be 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.). The linker may be an optionally substituted (poly)ethylene glycol having 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 interdispersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker can be asymmetric or symmetric.

[0240] In any aspect or embodiment described herein, the linker group can be any suitable moiety as 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, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0241] In any aspect or embodiment described herein, the linker (L) can be an optionally substituted C-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 , C17 , 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), each carbon of which is optionally substituted with (1) a heteroatom selected from N, S, P, or Si atoms having the 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 a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not a covalent linker or are not adjacently positioned).

[0242] In any aspect or embodiment described herein, the linker (L) can be an optionally substituted C1-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12, C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 alkyl), where each carbon is L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , C 3-11Cycloalkyl (0 to 6 R L1 and / or R L2 optionally substituted with a group), C 5-13 Spirosik alkyl (0 to 9 R L1 and / or R L2 optionally substituted with a group), C 3-11 Heterocyclyl (0 to 6 R L1 and / or R L2 optionally substituted with a group), C 5-13 Spiroheterocyclyl (0 to 8 R L1 and / or R L2 aryl (optionally substituted with 0 to 6 R L1 and / or R L2 heteroaryl (optionally substituted with 0 to 6 R L1 and / or R L2 optionally substituted with R L1 or R L2 each independently optionally linked to other groups, and 0 to 4 R L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , R L2 , R L3 , R L4 , and R L5 are each independently H, halo, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 In any aspect or embodiment described herein, the linker (L) does not have a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not covalently bonded or are not adjacently positioned).

[0243] In any aspect or embodiment described herein, the linker (L) comprises about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, wherein carbon or oxygen may be replaced with a heteroatom selected from N, S, P, or Si atoms bearing the appropriate number of hydrogens to complete the valence. For example, in any aspect or embodiment described herein, the linker (L) may be [ka] [ka] wherein carbon or oxygen may be optionally replaced with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens to complete the valence, and each m, n, o, p, q, r, and s is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0244] In some embodiments, L is an optionally substituted polyethyleneoxy group containing 1 to 10 units.

[0245] In any aspect or embodiment described herein, the linker (L) is an optionally aryl- or phenyl-substituted polyethylene group comprising 1 to 10 ethylene glycol units.

[0246] In any of the embodiments, the compound comprises multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[0247] While the ULM and PTM groups can be covalently attached to the linker group via any group that is appropriate and stable for the linker chemistry, in preferred embodiments of the present disclosure, the linkers are independently covalently attached to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, and each group can be inserted anywhere on the ULM and PTM groups to provide maximal coupling between the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself.) In certain embodiments, the linker can be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, an aryl group, or a heterocyclic group on the ULM and / or PTM group.

[0248] Exemplary Tau-Bifunctional Degrading Compounds As noted above, in certain embodiments, the descriptions provide bifunctional compounds comprising at least one PTM group described herein, a linker, and at least one ULM (VLM or CLM) group.

[0249] 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.

[0250] 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.

[0251] In any aspect or embodiment described herein, the compound is selected from Formulas CI-CV: [ka] [ka] During the ceremony, R 101 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano; R 102 is selected from H, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl; R 103 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano; R 104 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano; R 105 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano; R 106 , R 107 , R 109 , R 110 , R 111 , R 112 , R 113 , R 114 , R 116 , R 117 , R 120 , R 121 , R 126 , R 127 , R 122 , and R 123 are each independently selected from H, alkyl, halogen, or haloalkyl; R 108 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, cyano, or methoxy; R 115 is selected from H, alkyl, and haloalkylalkyl; R 118 and R 119 is independently selected from H, alkyl, halogen, or haloalkyl, or R 118 and R 119together with the carbon atom to which they are attached represent a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, such as cyclopropane or oxetane; R 124 and R 125 is 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- to 6-membered cycloalkyl or heterocycloalkyl ring, such as cyclopropane or oxetane; G is phenyl or a 5- or 6-membered heteroaryl ring; Z is CH2 or C=O.

[0252] In any aspect or embodiment described herein, R 101 is H, F, or Cl; R 102 is H, CH3, or CF2H, R 103 is H or F, R 104 is H, CH3, F, or CN; R 105 is H, CN, CH3, or CF3, R 106 and R 107 are each independently H, F, or CH3; R 108 is H, F, or CHO, R 109 and R 110 are each independently H, CH3, R 111 and R 112 are each independently H, F, or CH3; R 113 and R 114 are each independently H, CH3, R 115 is H or CH3, R 116 and R117 are each independently H, CH3, R 118 and R 119 are each independently H, CH3, F, or R 118 and R 119 together with the carbon atom to which they are attached represent a cyclopropane or oxetane ring; R 120 and R 121 are each independently H, CH3, R 122 and R 123 are each independently H, CH3, R 124 and R 125 are each independently H, CH3, F, or R 124 and R 125 together with the carbon atom to which they are attached represent a cyclopropane or oxetane ring; R 126 and R 127 are each independently H, CH3, A is pyridine or pyrimidine; Z is CH2 or C=O, or At least one of these combinations.

[0253] therapeutic composition The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one bifunctional compound described herein in combination with a pharmaceutically acceptable carrier, excipient, or vehicle.

[0254] In a further aspect, the present description provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition provides targeted protein degradation in a patient or subject, e.g., an animal such as a human, and can be used to treat or ameliorate a disease state or condition regulated by degrading the target protein. In certain embodiments, the therapeutic composition as described herein can be used to provide protein degradation to treat or ameliorate a tau-related disease or disorder, such as tau protein accumulation or aggregation or a neurodegenerative disease associated with tau accumulation and / or aggregation. In any aspect or embodiment described herein, the disease or disorder includes at least one of the following: acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Adie pupil, Adie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Alcardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, hemangiomatosis, anoxia, aphasia, aplaxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, cerebellar ataxia / spinocerebellar degeneration, hyperactivity syndrome, autism, autonomic dysfunction, back pain, Barth syndrome, Barth syndrome, Martens disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Ross syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, birth injury of the brachial plexus, birth injury of the brachial plexus, brachial plexus injury, Bradbury-Eggleston syndrome, cerebrospinal tumor, cerebral aneurysm, brain injury , Brown-Sequard syndrome, Spinal-bulbar muscular atrophy, Canavan disease, Carpal tunnel syndrome, Burning pain, Cavernous tumor, Cavernous hemangioma, Cavernous malformation, Central pain syndrome, Encephalopathy, Cerebellar degeneration, Cerebellar hypoplasia, Cerebral aneurysm, Cerebral arteriosclerosis, Cerebral atrophy, Cerebral beriberi, Cerebral gigantism, Cerebral hypoxia, Cerebral-oculofacial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, Chorea, Acanthocytic chorea,Chronic inflammatory demyelinating polyneuropathy (CIDP), chronic stereotactic intolerance, chronic pain cocaine syndrome type II, Coffin-Lowry syndrome, COFS, posterior horn enlargement, coma and persistent vegetative state, complex regional pain syndrome, congenital ophthalmoplegia, congenital myasthenia, congenital myopathy, congenital vascular cavernous angioma, malformations, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Do Son's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, Dejerine-Krampke palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, dentatocerebellar ataxia, dentato-nuclear cerebellar ataxia, dentato-nuclear atrophy, dermatomyositis, developmental disorders, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic neuropathy, dysgraphia, dysphagia, dyspraxia, dyspraxia, myoclonic cerebellar dyssynergia, progressive cerebellar dyssynergia, dystonia, early infantile epileptic encephalopathy, Empty-Sella syndrome, encephalitis lethargica, encephalocele, encephalopathy, Trigeminal angiomatosis, epilepsy, Erb and Krampke brachial plexopathy, Erb's palsy, Fabry's disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangiomas, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paraplegia, febrile convulsions, Fisher's syndrome, hypotonic infantile syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, bulbar cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallerforder's syndrome Spitz disease, head injury, headache, persistent hemicrania, hemifacial spasm, alternating hemiplegia, meniscal spastic paraplegia, hereditary neuropathy, hereditary spastic paraplegia, polyneuropathy-type hereditary ataxia, herpes zoster, varicella-zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydranencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelia, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotonia, infantile type, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy,, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, foramen occipitalis prolapse, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Joubert's syndrome, Kearns-Sayre's syndrome, Kennedy's disease, Kinsbourne's syndrome, Klein-Levin's syndrome, Klippel-Feil's syndrome, Klippel-Trenaunay's syndrome (KTS), Klüva-Buchy's syndrome, Korsakoff amnesic syndrome, Krabbe's disease, Kugelberg-Welander's disease, Kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner's syndrome, lateral femoral cutaneous nerve Strangulation, Lateral medullary syndrome, Learning disability, Leigh's 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, Megaencephalopathy, Manic mania, Megalencephaly, Melkerson-Rosenthal syndrome, Meningitis, Meningoencephalitis, Menkes disease, Lateral femoral cutaneous neuralgia, Metachromatic leukodystrophy, Microcephaly, Migraine, Miller-Fisher syndrome, Mild stroke, Mitochondrial dystrophy Doria myopathy, Moebius syndrome, lateral crural muscular atrophy, 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, myeloblastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, neurodegeneration with cerebral iron accumulation, neurofibromatosis, neuroleptic malignant syndrome, encephalopathy Neurological complications of rheumatoid arthritis, Neurological complications of Lyme disease, Neurological effects of cytomegalovirus infection, Neurological manifestations of Pompe disease, Neurological sequelae of lupus, Neuromyelitis optica, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorders, Hereditary neuropathies, Neurosarcoidosis, Neurotoxicity, Cotton wool nevus, Niemann-Pick disease, Normal pressure hydrocephalus, Occipital neuralgia, Obesity, Sequelae of latent spinal dysraphism, Otahara syndrome, Olivopontocerebellar atrophy, Opsoclonus-myoclonus, Orthostatic hypotension, O'Sullivan-McLeod syndrome, Overuse syndrome, Chronic painPain, pantothenate kinase-related neurodegeneration, paraneoplastic syndromes, paralysis, Parkinson's disease, paroxysmal choroidopathy, paroxysmal migraine, Parry-Romberg disease, Pelizaeus-Merzbacher disease, Penaschokeil II syndrome, perineural cyst leucomalasia, persistent vegetative state, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, prosencephaly, postherpetic neuralgia, postinfectious encephalomyelitis, postpolio, tachycardia syndrome, postural tachycardia syndrome, primary dentate atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease , progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear paralysis, 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, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Riley-Day syndrome, sacral nerve root cyst, St. Vitus's dance, salivary gland disease, Sandhoff's disease, Schilder's disease, schizophrenia, Seitelberger's disease, Seizure disorder, Semantic dementia, Septo-optic dysplasia, Shaken baby syndrome, Single-Shy Draeger syndrome, Shogren's syndrome, Sleep apnea, Sleeping sickness, Sotos syndrome, Spasticity, Spinocerebellar degeneration, Spinal cord infarction, Spinal cord injury, Spinal cord tumor, Spinal muscular atrophy, Spinocerebellar atrophy, Spinocerebellar degeneration-Richardson-Olszewski syndrome, Stiff-Person syndrome, Striatonigral degeneration, Stroke, Sturge-Weber syndrome, Subacute sclerosing panencephalitis, Subcortical arteriosclerotic encephalopathy, SUNCT headache, Generalized spinocerebellar degeneration, Syndemic chorea, Syncope, Syphilis Spinal sclerosis, syringomyelia, syringomyelia, systemic lupus erythematosus, gait ataxia, tardive dyskinesia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen myotonia, thoracic outlet syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, infectious cavernous trigeminal neuralgia, transverse myelitis, traumatic brain injury, tuberculous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, von Economo disease, von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome,Werdnig, Hoffmann's disease, Wernicke-Korsakoff syndrome, West syndrome, Williams syndrome, Wilson's disease, X-linked spinal and bulbar muscular atrophy, or Zellweger syndrome. For example, in any aspect or embodiment described herein, the disease or disorder is a neurological disease having at least one of the following: Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, injury to the spinal cord and brain, seizure disorder, epilepsy, brain tumor, meningitis, autoimmune disease such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory impairment, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumor, and stroke. For example, in any aspect or embodiment described herein, the disease or disorder is at least one of the following: primary tauopathies (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, injuries to the spinal cord and brain, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, and stroke.

[0255] In an alternative aspect, the present disclosure relates to a method for treating a disease state or ameliorating one or more symptoms of a disease or condition in a subject in need thereof by degrading tau protein, the method comprising administering to the patient or subject an effective amount of at least one compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally co-administered with an additional bioactive agent, wherein the composition is effective for treating or ameliorating a disease or disorder or a symptom thereof in the subject. Methods according to the present disclosure can be used to treat certain disease states, conditions, or symptoms, including neurological diseases or disorders, such as neurodegenerative diseases or disorders, by administering an effective amount of at least one compound described herein. For example, methods according to the present disclosure can be used to treat conditions causally associated with the accumulation and / or aggregation of tau protein, such as neurological / neurodegenerative diseases or disorders.

[0256] The present disclosure further includes pharmaceutical compositions that include pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein.

[0257] The acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned compounds useful according to this embodiment are, among many, those which 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, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3 naphthoate)] salts, among many others.

[0258] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of compounds or derivatives according to the present disclosure.Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds are those that form non-toxic base salts with the compounds.Such non-toxic base salts include, but are not limited to, water-soluble amine addition salts, such as alkali metal cations (e.g., potassium and sodium), and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or N-methylglucamine (meglumine), as well as lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0259] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide, other prodrug group, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound.

[0260] According to the present disclosure, the therapeutically effective compounds described herein can be administered orally, parenterally, or topically in single or divided doses. Administration of the active compound can range from continuous administration (intravenous infusion) to multiple administrations per day (e.g., QID), and includes oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Enteric-coated oral tablets can be used to enhance the bioavailability of the compound from oral administration. The most effective dosage form will depend on the pharmacokinetics of the specific drug selected, as well as the type, location, or severity of the disease, condition, or symptom, and the patient's health status.

[0261] The compound according to the present disclosure can also be administered as spray, mist or aerosol for intranasal, intratracheal or intrapulmonary administration.Therefore, the present disclosure also relates to a pharmaceutical composition comprising an effective amount of the compound described herein or its pharmaceutically acceptable salt, optionally combined with pharmaceutically acceptable carrier, additive or excipient.The compound according to the present disclosure can be administered in intermediate release or sustained release or controlled release form.The sustained release or controlled release form is preferably administered orally, but can also be administered in suppository and transdermal or other topical form.Intramuscular injection in liposome form or depot preparation can also be used to control or sustain the release of the compound at the injection site.

[0262] Compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in controlled-release formulations.The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum protein, such as human serum albumin, buffer substances, such as phosphate, 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 salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymer, polyethylene glycol and wool fat, and combinations thereof.

[0263] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, dimethyl sulfoxide (DMSO), beta-cyclodextrin and its derivatives, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also be used in combination with long-chain alcohol diluents or distillers. A powder such as Ph. Helv or similar alcohol may also be included.

[0264] 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 aqueous solutions.For tablets for oral use, commonly used carriers include, among others, lactose and corn starch, which are known in the art.For oral administration in capsule form, useful diluents include lactose and corn starch.When aqueous suspension is required for oral use, active ingredient can be combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or coloring agents can also be added.Lubricants such as magnesium stearate are also typically added.

[0265] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration.These can be prepared by mixing the drug with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and thus melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycol.

[0266] The pharmaceutical compositions described herein can also be administered topically.For topical application, pharmaceutical compositions can be either a reservoir patch or a matrix patch, which contains active compound combined with one or more carriers, buffers, absorption enhancers, and can be formulated into a transdermal patch, which provides continuous administration for 1 day to 2 weeks.

[0267] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated into suitable ointment, which contains the active ingredient suspended or dissolved in one or more carriers.The carrier for topically administering the compound of the present disclosure includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0268] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0269] Alternatively, the pharmaceutical composition of the present disclosure can be formulated for ophthalmic use.For example, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride.Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated into an ointment such as petrolatum.

[0270] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation.Such compositions can be prepared according to the techniques well known in the field of pharmaceutical formulation, and can be prepared as a solution in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0271] The amount of active pharmaceutical ingredient in the pharmaceutical compositions described herein that can be combined with a carrier material to produce a single dosage form will vary depending on the subject and disease, pathological or symptomatic state being treated, the particular mode of administration, and the condition of the subject. Preferably, the composition contains from about 0.05 milligrams to about 750 milligrams or more, more preferably from about 1 milligram to about 6 The active ingredient should be formulated to contain about 100 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with another compound according to the present disclosure.

[0272] It is also understood that the specific dosage and treatment regimen for any particular patient will depend on the judgment of the treating physician based on a variety of factors, including the activity and bioavailability of the particular compound employed, age, body weight, general health, sex, dietary restrictions, time of administration, rate of excretion, drug combination, and the severity of the particular disease or condition being treated.

[0273] Patients or subjects in need of therapy using the compounds 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.

[0274] 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 to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects to the patient being treated. Preferred active compound doses for all of the conditions mentioned herein are in the range of about 10 nanograms per kilogram (ng / kg) to 300 mg per kilogram (mg / kg) per day, preferably 0.1 to 100 mg / kg, e.g., 0.5 to about 25 mg per kilogram of recipient / patient body weight per day.

[0275] In any aspect or embodiment described herein, the compound is conveniently administered in any suitable unit dosage form, including, but not limited to, those 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 dosage of about 25 mg to 250 mg is often convenient.

[0276] In certain embodiments, the active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 millimolar (mM), preferably about 0.1 to 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 by administration as a bolus of the active ingredient. Oral administration can also be suitable to produce effective plasma concentrations of the active agent.

[0277] The concentration of active compound in the drug 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 dosage values ​​will also vary depending on the severity of the condition to be alleviated.It should be further understood that the specific dosage regimen for any particular subject should be adjusted over time according to individual needs and the professional judgment of the doctor who administers or supervises the administration of the composition, and the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed compositions.The active ingredient can be administered at once or divided into several smaller doses that are administered at various time intervals.

[0278] Oral compositions generally contain an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition.

[0279] Tablets, pills, capsules, lozenges, etc. contain the following ingredients: microcrystalline cellulose, tragacanth It can contain binders such as corn gum or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or sterols; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate or orange flavoring, or any of the compounds of similar nature.When the dosage unit is a capsule, it can contain liquid carriers such as fatty oils in addition to the above-mentioned materials.In addition, dosage unit can contain various other materials that modify the physical form of the dosage unit, for example, sugar, shellac or enteric coating.

[0280] 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, colorings, and flavors.

[0281] The active compounds or pharmaceutically acceptable salts thereof can also be mixed with other active substances that do not impair the desired action, or substances that complement the desired action, such as, among others, anti-neurodegenerative agents, 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 bioactive agent, such as an anti-neurodegenerative agent, as described elsewhere herein.

[0282] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical use can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0283] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0284] In any aspect or embodiment, active compound is prepared with carrier that can prevent compound from rapid excretion from body, for example, controlled release formulations, including implant and microencapsulated delivery system.Biodegradable biocompatible polymers can be used, for example, ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester and polylactic acid.The method of preparing such formulations will be clear to those skilled in the art.

[0285] Liposomal suspensions can also be pharmaceutically acceptable carriers.They can be prepared according to methods known to those skilled in the art, for example, the method described in U.S. Patent No. 4,522,811 (incorporated herein in its entirety by reference).For example, liposomal preparations can be prepared by dissolving suitable lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, aracadyl phosphatidylcholine and cholesterol) in an inorganic solvent, and then evaporating it to leave a thin film of dry lipid on the surface of the container.Then, an aqueous solution of active compound is introduced into the container.Then, the container is swirled by hand to release lipid material from the side of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0286] Treatment method In an additional aspect, the description provides a method of treatment comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier. In any aspect or embodiment described herein, the composition further comprises an effective or synergistic amount of another bioactive agent that is not a bifunctional degradable compound.

[0287] The term "bioactive agent" is used to describe an agent other than the bifunctional compounds described herein, which is used in combination with the present compounds as a biologically active agent to assist in achieving the intended therapy, inhibition, and / or prophylaxis / prevention regimen for which the present compounds are used. Preferred bioactive agents for use herein include agents that assist in achieving the intended therapy, such as P-gp inhibitors or agents with pharmacological activity similar to that for which the present compounds are used or administered, including, for example, anti-neurodegenerative agents.

[0288] 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 for achieving targeted exposure with therapeutic drugs. P-gp is expressed in barrier tissues (e.g., the blood-brain barrier) and secretory / absorptive tissues (e.g., the gastrointestinal tract) to sanctuary sites (Cordon-Cardo et al., 1989, 1990). This protein influences the overall pharmacokinetic profile of numerous drugs by functioning as a cytoprotective agent, actively exporting drugs from the intracellular environment (efflux) and reducing drug penetration through barrier tissues. In particular, P-gp efflux can reduce drug permeability across gastrointestinal membranes, resulting in reduced systemic drug exposure. P-gp efflux also reduces drug access across the blood-brain barrier. P-gp inhibitors may indirectly contribute to efficacy by increasing the exposure of bifunctional compounds, particularly in the CNS.

[0289] The term "additional anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that may be combined with a bifunctional compound according to the present disclosure to treat a neurodegenerative disease.

[0290] In any aspect or embodiment described herein, the bifunctional compound is used in conjunction with a P-gp inhibitor.

[0291] In any aspect or embodiment described herein, the P-gp inhibitor is selected from the group consisting of amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, elacridar, and verapamil.

[0292] The therapeutic methods are useful for effecting protein degradation in a patient or subject in need thereof, e.g., an animal such as a human, to treat or ameliorate a disease state, condition, or associated symptom that can be treated by targeted protein degradation.

[0293] In another aspect, the disclosure provides a method of modulating 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 described herein or a composition comprising an effective amount of a heterobifunctional compound, wherein the compound or composition comprising the compound is effective to modulate protein ubiquitination and protein degradation in the subject. In certain embodiments, the protein is tau protein.

[0294] In certain embodiments, the description provides a method for modulating the protein activity of tau protein by denaturing tau aggregates in a patient in need thereof, comprising administering to the patient a quantity of The present invention provides a method for treating a rheumatoid arthritis, comprising administering a compound described herein to a patient having rheumatoid arthritis.

[0295] In yet further embodiments, the description provides a method of treating a disease state or condition in a patient in which dysregulated protein activity (tau aggregation and accumulation) contributes to the disease state or condition, the method comprising administering to the patient an effective amount of a compound described herein to modulate the protein activity in the patient. In certain embodiments, the protein is tau.

[0296] Terms such as "treat," "treating," and "treatment," as used herein, refer to any action that provides benefit to a patient to which the compounds may be administered, including treatment of any disease state, condition, or symptom associated with the protein to which the compounds bind. Disease states or conditions, including neurological and neurodegenerative diseases or disorders, that can be treated using compounds according to the present disclosure are described above.

[0297] The present description provides a therapeutic method for causing the degradation of a target protein to treat or improve a disease, such as a neurological disease or neurodegenerative disease or disorder. Accordingly, in another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In any aspect or embodiment described herein, the method comprises administering a bifunctional compound of the present disclosure. The control or reduction of specific protein levels in a subject's cells provided by the present disclosure provides treatment for a disease state, pathology, or symptom. In any aspect or embodiment, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0298] In additional embodiments, the present description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound described herein or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0299] In any aspect or embodiment described herein, the disease or disorder is associated with tau accumulation or aggregation in a subject, e.g., a cell, tissue, mammal, or human patient.

[0300] In any aspect or embodiment described herein, the disease or disorder is a neurological disorder, including, but not limited to, septum pellucidum defect, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Adie's pupil, Adie's syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Alcardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, cerebellar ataxia Symptoms of tonicity / spinocerebellar degeneration, hyperactivity syndrome, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Ross syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus birth injury, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome, cerebrospinal tumor, cerebral aneurysm, brain injury, Brown-Sequard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, burning pain, cavernoma, cavernous angiomas, cavernous malformations, central pain syndrome, encephalopathy, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-ocular-facial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orientation intolerance, chronic pain cocaine syndrome type II, Coffin-Lowry syndrome, COFS, posterior ventricular horn enlargement, coma and persistent vegetative state, complex regional pain syndrome, congenital ophthalmoplegia, congenital myasthenia gravis, Congenital myopathy, congenital vascular cavernous angioma, malformation, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, megacytoplasmic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, Dejerine-Klumpke palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, dentatocerebellar ataxia, dentato-nuclear cerebellar ataxia, dentato-nuclear atrophy, skin Dermatomyositis, Developmental disorders, Devic's syndrome, Diabetic neuropathy, Diffuse sclerosis, Autonomic neuropathy, Dysgraphia, Dyslexia, Dysphagia, Syndromes, Myoclonic cerebellar dyssynergia, Progressive cerebellar dyssynergia, Dystonia, Early infantile epileptic encephalopathy, Empty-Sella syndrome, Encephalitis lethargica, Encephalopathy, Trigeminal angiomatosis, Epilepsy, Erb and Krampke brachial plexopathy, Erb's palsy, Fabry's disease, Fahr's syndrome, Syncope, Familial autonomic neuropathy, Familial hemangioma, Familial idiopathic basal ganglia calcification, Familial periodic paralysis, Familial spasticity Paraplegia, febrile convulsions, Fisher syndrome, hypotonic infantile syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion body disease, bulbar cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, head injury, headache, persistent hemigraine, hemifacial spasm, alternating hemiplegia, meniscal spastic paraplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary polyneuropathy, hereditary ataxia, shingles, shingles, Hirayama syndrome,Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydranencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelia, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotonia, infantile, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, foramen occipitalis prolapse, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy's disease, Kin Zborn syndrome, Klein-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Klüva-Buchy syndrome, Korsakoff amnesic syndrome, Krabbe disease, Kugelberg-Welander syndrome, Kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment, lateral bulbar syndrome, learning disability, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage disease, lissencephaly, entrapment syndrome group, Lou Gehrig's disease, lupus - neurological sequelae, Lyme disease - neurological complications, Machado-Joseph disease, encephalopathy, manic mania, megalencephaly, Melkerson-Rosenthal syndrome, meningitis, meningoencephalitis, Menkes disease, lateral femoral cutaneous neuralgia, metachromatic leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mild stroke, mitochondrial myopathy, Moebius syndrome, lateral crural muscular atrophy, motor neuron disease, moyamoya disease, mucolipidosis, mucopolysaccharidosis, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension Myasthenia, muscular dystrophy, congenital myasthenia, myasthenia gravis, myeloblastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, congenital myotonia, narcolepsy, neuroacanthocytosis, neurodegeneration with cerebral iron accumulation, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological effects of cytomegalovirus infection, neurological symptoms of Pompe disease, neurological sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder,hereditary neuropathies, , neurosarcoidosis, neurotoxicity, cotton wool nevus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, secondary to latent spinal dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, pain, pantothenate kinase-associated neurodegeneration, paraneoplastic syndrome, paralysis, Parkinson's disease, paroxysmal choroidopathy, paroxysmal migraine, Parry-Romberg disease, Pelizaeus-Merzbacher disease, Penaschokeil II syndrome, perineural cysts, leukomalasia, persistent Nutritional status, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, prosencephaly, postherpetic neuralgia, postinfectious encephalomyelitis, postpolio, tachycardia syndrome, postural tachycardia syndrome, primary dentate atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear, paralytic Ramsay Hunt syndrome I (formerly known as Ramsay Hunt syndrome II (formerly known as Rasmussen's encephalitis), reflex sympathetic dystrophy Lee's syndrome, Refsum's disease, infantile Refsum's disease, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Riley-Day syndrome, sacral nerve root cyst, St. Vitus's dance, salivary gland disease, Sandhoff's disease, Schilder's disease, schizophrenia, Seitelberger's disease, seizure disorder, semantic dementia, septo-optic dysplasia, shaken baby syndrome, Singlet-Shy-Drager syndrome, Shogren's syndrome, sleep apnea, sleeping sickness, Sotos syndrome, spasticity, spinocerebellar degeneration, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinal cord Cerebellar atrophy, Spinocerebellar degeneration - Richardson-Olszewski syndrome, Stiff-Person syndrome, Striatonigral degeneration, Stroke, Sturge-Weber syndrome, Subacute sclerosing panencephalitis, Subcortical arteriosclerotic encephalopathy, SUNCT headache, Systemic spinocerebellar degeneration, Syndemic chorea, Syncope, Syphilitic spinal sclerosis, Hydromyelia, Syringomyelia, Systemic lupus erythematosus, Gait ataxia, Tardive dyskinesia, Tarlov cyst, Tay-Sachs disease, Temporal arteritis, Tethered spinal cord syndrome, Thomsen myotonia, Thoracic outlet syndrome, Thyrotoxic myopathy, Trigeminal neuralgia,Neurological disorders include, but are not limited to, Todd's palsy, Tourette's syndrome, transient ischemic attacks, infectious cavernous trigeminal neuralgia, transverse myelitis, traumatic brain injury, tuberculous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, von Economo disease, von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, Williams syndrome, Wilson's disease, X-linked spinal and bulbar muscular atrophy, or Zellweger syndrome.

[0301] 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, injury to the spinal cord and brain, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, and stroke.

[0302] In any aspect or embodiment describe herein, the disease or disorder is Alzheimer's disease.

[0303] In another aspect, the present disclosure provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0304] In another aspect, the description provides a process for making a molecule that can cause degradation of tau protein in a cell (e.g., in vivo or in vitro), comprising the steps of: (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) coupling the small molecule of step (i) to a tau protein via a chemical linking group (L). and (ii) covalently binding ULM to form a compound that binds to both the E3 ubiquitin ligase and tau protein in cells, thereby bringing the E3 ubiquitin ligase into proximity with the tau protein and ubiquitinating the bound tau protein, thereby resulting in the subsequent degradation of the ubiquitinated tau.

[0305] In another aspect, the description provides a method for detecting whether a molecule can trigger the degradation of tau protein in a cell (e.g., in vivo or in vitro), the method comprising: (i) providing a molecule to be detected for its ability to trigger the degradation of tau protein in a cell, the molecule comprising the structure: ULM-L-PTM (wherein ULM is an E3 ubiquitin ligase binding moiety that can bind to an E3 ubiquitin ligase in the cell, where ULM is as described herein (e.g., CLM, VLM, or ILM); PTM is a protein targeting moiety that is a small molecule that binds to tau protein, wherein the tau has 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 linking group that covalently attaches the ULM to the PTM to form the molecule); (ii) incubating a tau protein-expressing cell in the presence of the molecule of step (i); and (iii) detecting whether the tau protein in the cell has been degraded.

[0306] 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.

[0307] In another embodiment of said treatment, the present disclosure provides a method of treating a human patient in need of said treatment for a disease state, condition, or symptom causally linked to tau protein (e.g., expression, overexpression, mutation, aggregation, accumulation, misfolding, or dysregulation), where degradation of tau protein would result in 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 bioactive agent.

[0308] The disease state, condition, or symptom may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by the expression, overexpression, mutation, misfolding, or dysregulation of tau protein leading to the disease state, condition, or symptom.

[0309] In another aspect, the disclosure provides a method of treating or ameliorating at least one symptom of a disease or condition in a subject, the method comprising the steps of providing a subject identified as having symptoms of a disease or condition causally related to expression, overexpression, mutated, misfolded, or dysregulation of Tau protein in the subject, wherein the symptoms of the disease or condition are treated or ameliorated by degrading Tau protein in the subject's cells; and administering a therapeutically effective amount of a compound comprising a small molecule of the invention to the subject such that Tau protein is degraded, thereby treating or ameliorating at least one symptom of the disease or condition in the subject.

[0310] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and degradation of one or more proteins in the patient can provide beneficial therapy or symptom relief to a patient in need thereof. In certain cases, the disease state or condition can be cured.

[0311] Disease states or conditions that may be treated using compounds according to the present disclosure include neurological / nervous abnormalities or diseases, such as neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, injuries to the spinal cord and brain, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, and stroke.

[0312] As used herein, the term "neurological disorder" or "neurological disorder" refers to any disorder, disease, and / or syndrome resulting from or resulting from neurological, psychiatric, psychological, and / or cerebrovascular conditions or origins. The term "neurological disorder" or "neurological disorder" as used herein also refers to a disease, disorder, or condition of the brain and nervous system, or a psychiatric disorder or condition. Neurological disorders include, but are not limited to, septum pellucidum defect, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Addie's pupil, Addie's syndrome, adrenoleukodystrophy, and aplasia. Acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, Addie pupil, Addie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Alcardi syndrome, AIDS-neurological complications, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cyst , arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, dyspraxia, telangiectasia, cerebellar ataxia / spinocerebellar degeneration, hyperactivity syndrome, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Ross syndrome, Binswang - disease, blepharospasm, Bloch-Sulzberger syndrome, birth injury of brachial plexus, birth injury of brachial plexus, brachial plexus injury, Bradbury-Eggleston syndrome, cerebrospinal tumor, cerebral aneurysm, brain injury, Brown-Sequard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, burning pain, cavernoma, cavernous hemangioma, cavernous malformation, central pain syndrome, brain damage, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral artery Sclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-oculofacial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orientation intolerance, chronic pain cocaine syndrome type II, Coffin-Lowry syndrome, COFS, posterior ventricular horn enlargement, coma and persistent vegetative state, complex regional pain syndrome, congenital ophthalmoplegia,Congenital myasthenia, congenital myopathy, congenital vascular cavernous angioma, malformations, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, Dejerin- Krampke's palsy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, dentatocerebellar ataxia, dentato-nuclear cerebellar ataxia, dentato-nuclear atrophy, dermatomyositis, developmental disorders, Devic's syndrome, diabetic neuropathy, diffuse sclerosis, autonomic neuropathy, dysgraphia, dyslexia, dysphagia, syndromic movement disorder, myoclonic cerebellar dyssynergia, progressive cerebellar dyssynergia, dystonia, early Infantile epileptic encephalopathy, Empty-Sella syndrome, encephalitis lethargica, encephalocele, encephalopathy, trigeminal angiomatosis, epilepsy, Erb and Krampke brachial plexopathy, Erb's palsy, Fabry disease, Fahr's syndrome, syncope, familial dysautonomia, familial hemangiomas, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paraplegia, febrile convulsions, Fisher syndrome, hypotonic infantile syndrome, Friedreich's ataxia syndrome, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion body disease, bulbar cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, head injury, headache, persistent hemigraine, hemifacial spasm, alternating hemiplegia, meniscal spastic paraplegia, hereditary neuropathy, hereditary spastic paraplegia, multiple sclerosis, Transinflammatory hereditary ataxia, shingles, herpes zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydranencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotonia, infantile type, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile hypotonia, infantile neuroaxonal dystrophy, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, foramen occipitalis, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Hubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klein-Levin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay syndrome (KTS), Klüva-Buchy syndrome, Korsakoff amnesic syndrome, Krabbe disease, Kugelberg-Welander syndrome, Kuru, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment, lateral bulbar syndrome, learning disability, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome 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, megaencephalopathy, manic mania, megalencephaly, Melkerson-Rosenthal syndrome, meningitis, meningoencephalitis, Menkes disease, lateral femoral cutaneous neuralgia, metachromatic leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mild stroke, mitochondrial myopathy, Moebius syndrome, lateral crural muscular atrophy, motor neuron disease, moyamoya disease, mucolipidosis, mucopolysaccharidosis, multifocal motor neuropathy, multi-infarct cognitive impairment Disease, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, congenital myasthenia, myasthenia gravis, myeloblastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, congenital myopathy, thyrotoxic myopathy, myotonia, myotonia congenita, narcolepsy, neuroacanthocytosis, neurodegeneration with cerebral iron accumulation, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological effects of cytomegalovirus infection, neurological symptoms of Pompe disease, neurological sequelae of lupus, neuromyelitis optica,Neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, hereditary neuropathies, neurosarcoidosis, neurotoxicity, cotton wool nevus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, secondary to latent spinal dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, pain, pantothenate kinase-related neurodegeneration, paraneoplastic syndrome, paralysis, Parkinson's disease, paroxysmal choroidopathy, paroxysmal migraine, Parry-Romberg disease, peliosis S-Merzbacher disease, Penascocaine II syndrome, perineural cyst leukomalasia, persistent nutritional status, pervasive developmental disorder, phytanic acid storage disease, Pick's disease, pinched nerve, piriformis syndrome, pituitary tumor, polymyositis, Pompe disease, prosencephaly, postherpetic neuralgia, postinfectious encephalomyelitis, postpolio, tachycardia syndrome, postural tachycardia syndrome, primary dentate atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing polydystrophy, progressive supranuclear paralysis, 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, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Riley-Day syndrome, sacral nerve root cyst, St. Vitus's dance, salivary gland disease, Sandhoff's disease, Schilder's disease, schizophrenia, Seitelberger's disease, seizure disorder, semantic dementia, septo-optic dysplasia, shaken baby syndrome, single-shy Draeger syndrome, Shogren's syndrome, sleep apnea, sleeping sickness, So Toth syndrome, spasticity, spinocerebellar degeneration, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache, generalized spinocerebellar degeneration, syndromic chorea, syncope, syphilitic spinal sclerosis, syringomyelia, syringomyelia, systemic lupus erythematosus, gait ataxia, tardive dyskinesia, Tarlov cyst, Tay-Sachs disease, temporal arteritis,Tethered spinal cord syndrome, These conditions include, but are not limited to, Thomsen myotonia, thoracic outlet syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attacks, infectious cavernous trigeminal neuralgia, transverse myelitis, traumatic brain injury, tuberculous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, von Economo disease, von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, Williams syndrome, Wilson's disease, X-linked spinal and bulbar muscular atrophy, or Zellweger syndrome.

[0313] The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the present compound as a biologically active agent to help achieve the intended therapeutic, inhibitory, and / or prophylactic / preventative method for which the present compound is used.

[0314] The term "pharmaceutically acceptable salt" is used throughout this specification to describe one or more salt forms of the compounds described herein, which are provided to increase the solubility of the compound in the gastric acid of the patient's gastrointestinal tract, where applicable, to promote the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases, and, where applicable, acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, among many acids and bases well known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure. [Example]

[0315] The bifunctional compounds of the present disclosure are effective in degrading tau. Exemplary compounds are presented in Table 1, which includes data on several exemplary compounds. In vivo, in vivo, and ex vivo studies showing the degradation of tau protein are shown in the figures.

[0316] General methods of chemical synthesis The synthesis of the claimed chimeric compounds can be carried out according to general synthetic procedures known in the literature. The synthetic route shown in the schemes of the present disclosure is described as one method that can be used to obtain the desired compounds. Other methods can also be used by those skilled in the art of synthesis. The ULM and PTM shown in the schemes represent only one of many ULMs and PTMs in this application.

[0317] LC-MS method for purity analysis (quality control) LCMS method Instrumentation: Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer The analysis is carried out on a Poroshell 120 EC C18 column (50 mm id x 3.0 mm, 2.7 μm packing diameter) at 45°C. The solvent used is A = 0.1 v / v% formic acid solution in water. B = 0.1% v / v formic acid in acetonitrile. The gradients used are as follows: [Table 1] UV detection is the average signal from wavelengths between 210 nm and 350 nm, and mass spectra are recorded using electrospray ionization in positive mode on a mass spectrometer.

[0318] Abbreviation: ACN: acetonitrile Boc2O: di-tert-butyl dicarbonate DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide EA: Ethyl acetate HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC: High-performance liquid chromatography LC-MS: Liquid chromatography-mass spectrometry Min: minutes MTBE: Methyl tert-butyl ether PE: Petroleum ether RT: room temperature SPB: Sodium perborate tBu: tert-butyl TBACl: tetra-butylammonium chloride TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: trimethylsilyl t R :Holding time TsCl: p-toluenesulfonyl chloride

[0319] Ubiquitin E3 ligase targeting moiety (ULM) and protein targeting moiety (PTM) intermediates 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). [ka] Step 1: Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere, 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 at room temperature. The resulting mixture was heated to 150 °C and stirred at this temperature for 5 h, at which time LC-MS indicated completion of the reaction. The mixture was cooled to room temperature, diluted with 1 L of water, and extracted with ethyl acetate (300 mL × 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 give the title compound (yield: 91%) as a white solid.

[0320] Step 2: Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL), LiAlH (20 g, 526.32 mmol) was added portionwise over 10 minutes at 0° C. under a nitrogen atmosphere. The resulting mixture was then stirred at 60° C. for 3 hours, at which time LC-MS indicated the reaction was complete. The mixture was cooled to 0° C. and then quenched by adding water (20 mL, slowly added), aqueous NaOH (15%, 20 mL), and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL×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 give the title compound (yield: 56%) as a yellow oil.

[0321] 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 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) was 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) at room temperature. The resulting mixture was stirred at room temperature overnight, at which point LC-MS indicated completion of the reaction. The reaction mixture was then diluted with 20 mL of water and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the crude residue, which was purified by flash silica gel column chromatography. The residue was purified by column chromatography (eluent: dichloromethane / methanol (v:v=20:1)) to give the title compound (yield: 56%) as a yellow solid.

[0322] Step 4: Preparation of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride To a 1 L round-bottom flask containing 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) in dioxane was added hydrogen chloride in dioxane (4 N, 300 mL). The resulting solution was stirred at room temperature for 2 hours. The solid was collected by filtration to give the title product (yield: 98%) as a yellow solid.

[0323] 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 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) 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) at room temperature.

[0324] The resulting solution was stirred at room temperature for 16 hours, and 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 × 3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (50 mL × 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 give the title compound (yield: 51%) as a yellow solid.

[0325] Step 6: (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) 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 (4 N, 80 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours, at which time LC-MS showed completion of the reaction. The precipitated solid was collected by filtration to give the title product (yield: 48%) as a yellow solid.

[0326] d: 48%) as a yellow solid. 1 HNMR(400MHz, CD3OD):δ 9.84-9.82(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 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) [ka]

[0327] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate To a mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) and NaHCO (1.24 g, 14.8 mmol) in HO (10 mL) and ethyl acetate (10 mL) was added (Boc)O (5.20 g, 23.8 mmol) at 5 °C. The reaction was allowed to continue for 2 h. TLC showed the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 mL) and HO (10 mL) for 0.5 h. The mixture was filtered, and the solid was collected and dried in an oven at 50 °C to give the title compound as a white solid (5.9 g, 98.7%). 1 HNMR (400MHz, DMSO-d6): δ 1.28 (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).

[0328] Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride 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. for 18 hours under N. After cooling to ambient temperature, the reaction mixture was filtered. To the filtrate was added HO (50 mL), 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 give (S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g, 82.3%) as a gray solid. 1HNMR (400MHz, DMSO-d6): δ 1.33(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

[0329] This solid material (1.9 g, 6.0 mmol) was dissolved in 4 N hydrochloride salt 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 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 pale green solid. 1 HNMR (400MHz, DMSO-d6):δ 1.56(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

[0330] Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylic acid 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) under nitrogen at 0 °C. The mixture was stirred at ambient room temperature for 18 h. TLC indicated completion of the reaction. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic layers were washed with 5% citric acid (10 mL × 2), saturated NaHCO3 solution (10 mL × 2), brine (10 mL × 2), and dried over Na2SO4. The organic solution was filtered and concentrated to give (2S,4R)-methyl 1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylate as a pale yellow oil (1.93 g, 100% yield). This crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were added to THF (20 mL) and HO (10 mL). The resulting mixture was stirred at ambient room temperature for 18 hours. The 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 HO (6 mL × 2). The solid was collected by filtration and dried in an oven at 50 °C to give the title compound as a white solid (1.4 g, 75% yield over two steps). 1 HNMR (400MHz, DMSO-d6): δ 6.50 (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).

[0331] 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) 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) at 0° C. The resulting mixture was warmed to ambient temperature and continued stirring for 2 hours. TLC showed 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 placed in methanol (10 mL) and activated carbon (150 mg) was added. The mixture was heated to 80°C and stirred for 1 hour. The mixture was filtered while hot. Water (5 mL) was added to the filtrate at 80°C. 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 give 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-oxobutan-2-yl-carbamate as a white solid (1.41 g, 74.2%). 1H NMR (400MHz, CDCl3):δ 1.05(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, 1H), 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).

[0332] This solid (1.04 g, 1.9 mmol) was dissolved in 4 N hydrogen chloride in methanol (3.0 mL), and the mixture was stirred at ambient temperature for 3 hours. TLC showed the reaction was complete. The reaction mixture was concentrated to remove all volatiles under reduced pressure to give a pale 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%). 1 H NMR (400 MHz, DMSO-d): δ 1.03(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), 3.88-3.90(m, 1H), 4.3 1(br, 1H), 4.56(t, J=8.4Hz, 1H), 4.89-4.95(m, 1H), 7.41(d, J=8.4Hz, 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):δ 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) [ka]

[0333] Step 1: Preparation of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile 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 dry NMP (125 mL) was stirred at 110 °C for 6 h under a nitrogen atmosphere. TLC showed the reaction was complete. The mixture was first cooled to room temperature and then partitioned between EtOAc and water. The combined organic fractions were filtered, and the filtrate was washed with water, brine, dried over anhydrous NaSO, and concentrated. The residue was dissolved in toluene (100 mL) and re-evaporated to give the 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 give the title compound as a pale yellow solid (10.5 g, 64%). LC / MS: 217.2 [M+1] + . 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).

[0334] Step 2: Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol To a solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (2.9 g, 13.41 mmol) in dry THF (150 mL) was added LiAlH (1.5 g, 40.23 mmol) portionwise at 0 °C. The resulting mixture was stirred at 50 °C for 3 h under a nitrogen atmosphere. TLC showed that the reaction was complete. The mixture was cooled in an ice-water bath, and then NaSO 10H O (5 g) was carefully added and stirred at this temperature for 1 h. The mixture was filtered, and the filter cake was washed four times with 10% MeOH in DCM. The combined filtrate was concentrated to give crude 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol as a pale yellow solid (2.0 g, 68%), which was used in the next step without further purification. LCMS: 221.2 [M+H] + . 1 HNMR (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).

[0335] Step 3: Preparation of (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid L-Valine (4.37 g, 37.3 mmol) was added to a solution of phthalic acid dicarboxaldehyde (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 give (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid as a white solid (6.45 g, 74%). 1HNMR (400MHz, DMSO-d6):δ 0.85(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).

[0336] Step 4: Preparation of (2S,4R)-methyl 4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate To a solution containing 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 dry DMF (15 mL) was added HATU (3.8 g, 10 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. 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 hexane as the eluent to give the title compound as a pale yellow solid (1.21 g, 67.6%). LCMS:361.3[M+1] + .

[0337] Step 5: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid A mixture containing (2S,4R)-methyl 4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate (1.2 g, 3.33 mmol), LiOH HO (559 mg, 13.32 mmol) in THF (20 mL) and HO (10 mL) was stirred at room temperature for 2 h. TLC showed the reaction was complete. The reaction mixture was acidified to pH 1-2 with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the title compound as a pale yellow solid (1.05 g, 91% yield). 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).

[0338] Step 6: (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisopropyl)benzyl) Preparation of indolin-2-yl)butanoyl)pyrrolidine-2-carboxamide To a solution containing (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) was added HATU (2.2 g, 5.77 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography using 2-5% MeOH in DCM to give the title compound as a pale yellow solid (650 mg, 43% yield). LCMS: 549.2 [M+H] + 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). 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) [ka]

[0339] 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):δ 1.14(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, 1H), 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 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) [ka]

[0340] Step 1: Synthesis of 2-(4-bromophenyl)oxirane 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 warmed to 55 °C for 4 h. 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 removal of the organic solvent under reduced pressure and used in the next reaction without purification. 1 H NMR (400MHz, CDCl3) δ 2.74 (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).

[0341] Step 2: Synthesis of 2-azido-2-(4-bromophenyl)ethanol 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 give 2-azido-2-(4-bromophenyl)ethanol (5.5 g, 90.2%) as a pale yellow oil. The crude product was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ 1.94 (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).

[0342] Step 3: Synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride To a solution of 2-azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) in tetrahydrofuran (20.0 mL) and water (5.00 mL) was added triphenylphosphine (4.35 g, 16.6 mmol). 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 give 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.5 g, 72.1% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 3.70(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 / MS 216.2[M+H] + .

[0343] Step 4: Synthesis of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine To a solution of 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.80 g, 7.17 mmol) in dichloromethane (50 mL) was added imidazole (1.95 g, 2.87 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.63 g, 10.8 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 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-butyldimethylsilyloxy)ethanamine (1.50 g, 63.6%) as a white solid. LC / MS: 330.1 [M+H] +

[0344] Step 5: Synthesis of tert-butyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate To a solution of 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine (1.50 g, 4.56 mmol) in tetrahydrofuran (20 mL) was added triethylamine (0.69 g, 6.84 mmol) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with ethyl acetate (50 mL × 3) and washed with brine. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the 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 pale yellow oil. 1 H NMR (400MHz, CDCl3) δ 0.01 (6H, d, J=9.6Hz), 0.86 (9H, s), 1.42 (9H, s), 3.65-3.70 (2H, m), 4.60-4.6 3(1H, m), 7.34(2H, d, J=8.0Hz), 7.39(1H, d, J=8.8Hz), 7.56(2H, d, J=8.4Hz).

[0345] Step 6: Synthesis of tert-butyl 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamate 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), and 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 h. The resulting mixture was then diluted with water. The aqueous phase was extracted with ethyl acetate (50 mL × 3) and washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude compound, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give tert-butyl 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (1.30 g, 41.8%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J=6.0Hz), 4.55-4.58 (1H, m), 4.84 (1 LC / MS 335.2[M+H] + ;Rt=1.859 minutes

[0346] Step 7: Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride 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 give 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.

[0347] Step 8: 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) 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 × 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 give 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) as a pale yellow oil 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.

[0348] ULM-5-A: 1 H NMR (400MHz, CDCl3) δ 0.93 (9H, s), 1.39 (9H, s), 1.77-1.83 (1H, m), 2.01-2.06 (1H, 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

[0349] ULM-5-B: 1 H NMR (400MHz, CDCl3) δ 0.87(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 / MS 561.2[M+H] + ;Rt=1.887 minutes 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) [ka]

[0350] This key intermediate was prepared using the synthetic route described above. The required 3-methylisoxazole-5-acetic acid was prepared according to the literature (J. Org. Chem. 66, 6595-6603, 2001). The alkylation with 2-iodopropane is described in the literature. The desired ULM-6 was prepared using the same synthetic method as described in the preparation of intermediate ULM-3.

[0351] 1 H NMR (400MHz, CDCl3):δ 9.33(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. LC-MS 436.1[M+1] + ;Rt=3.57 minutes.

[0352] PTM synthesis: Preferred PTM embodiments of the present disclosure can be prepared according to the synthetic routes in the following schemes, which can be modified and adapted to the synthesis of specific PTM embodiments using general methods known to those skilled in the art. [ka] [ka]

[0353] The above general approach also applies when ring C is absent and the tricyclic fused ring system of ABC is instead represented by the bicyclic fused ring system of AB, and also when monocyclic ring D is instead represented by the fused bicyclic ring system DE.

[0354] Those skilled in the art will appreciate that the above approach is illustrated in the following examples and may be applicable to other examples. It will be recognized that this may include cases where the heterobifunctional linker is already pre-attached to ring D or ring E (with or without the presence of ULM), such that: [ka]

[0355] Additionally, the complete heterobifunctional molecule can be assembled using other series of steps. For example, the PTM can be connected to the remainder of the molecule using a functional group on Ring D that reacts with a functional group on a heterobifunctional linker previously attached to the ULM in a process of nucleophilic substitution or reductive amination, as shown in the scheme below. [ka]

[0356] Alternatively, the functional groups on the PTM and ULM fragments can be reversed, as shown in the scheme below. [ka]

[0357] Alternatively, the sequence of steps can be reversed, with one end of the PROTAC linker first attached to a PTM, and then the functional group on the other end of the linker can be reacted with ULM via one of the non-limiting approaches shown in the schemes below, depending on the exact nature of the ULM group. Those of skill in the art will understand that certain protecting group manipulations may be required during these transformations. [ka]

[0358] Preferred embodiments of the present invention can be prepared using approaches previously described in US2018 / 0125821, as well as approaches further detailed in the following schemes.

[0359] In particular, preferred PTMs of the present invention can be prepared as described below. [ka] [ka]

[0360] The most preferred PTMs of the present invention are detailed below. [ka] [ka]

[0361] Additional synthetic routes that can be utilized to prepare exemplary PTMs of the present disclosure are provided below. [ka] [ka]

[0362] Exemplary Bifunctional Compound Synthesis: Intermediate 1 [ka]

[0363] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione [ka] 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 h. After cooling to room temperature, the reaction was quenched with HO (10 mL), and the mixture was extracted with EtOAc (10 mL × 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).

[0364] Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde [ka] 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 h. After cooling to room temperature, the mixture was filtered through Celite and the filtrate was concentrated to give the 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.

[0365] Intermediate 2 [ka] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (10 g, 36.2 mmol) in NMP (70 mL) was added tert-butyl piperazine-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 EArOAc (300 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=100 to 2 / 1) to give 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.

[0366] Synthetic scheme for exemplary compound 51 Step 1: 3-(4-bromophenyl)-4-nitropyridine [ka] 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) and water (100 ml), tetrakis(triphenylphosphine)palladium (14.8 g, 12.8 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was degassed with nitrogen three times. The resulting mixture was stirred at 50°C overnight. TLC showed the reaction was complete. The solid was removed by filtration and washed with ethyl acetate (100 ml x 3). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (400 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel pad (eluted with 10% to 33% ethyl acetate in hexane) to give 3-(4-bromophenyl)-4-nitropyridine (89 g, 65% yield) as a yellow solid.

[0367] Step 2: 7-Bromo-5H-pyrido[4,3-b]indole [ka] A mixture of 3-(4-bromophenyl)-4-nitropyridine (20.0 g, 71.7 mmol) in triethyl phosphate (400 ml) was stirred at 110° C. under a nitrogen atmosphere for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure to give a residue that was purified by recrystallization (me...

Claims

1. Chemical structure: PTM-L-ULM, A bifunctional compound having the formula: or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, During the ceremony, (a) the PTM is represented by Formula I, II, III, IV, XII, XIII, XIV, and XV: 【Chemistry 1】 During the ceremony, A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between the rings indicates ring fusion and overlapping rings indicate a spirocyclic ring; L ＰＴＭ is a bond, an alkyl, alkenyl or alkynyl (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) optionally interrupted by one or more rings, or -O-, -S-, -NR １ＰＴＭ -, -N=N-, -S(O)-, -SO ２ -, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO ２ one or more functional groups selected from -, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, said functional groups optionally being located at either terminus of the linker; R １ＰＴＭ is selected from H, alkyl, or fluoroalkyl, and said PTM is attached to a ULM via a chemical linking group (L) via at least one of A, B, C, D, E, or F; (b) a small molecule E3 ubiquitin ligase, wherein the ULM binds to an E3 ubiquitin ligase; a binding moiety, and (i) a cereblon E3 ubiquitin ligase binding moiety (CLM) selected from: 【Chemistry 2】 During the ceremony, Q １ , Q ２ , Q ３ , Q ４ , Q ５ each independently represents a nitrogen or carbon substituted with a group independently selected from R′, N, or N-oxide; W is CH ２ or C=O; A is H or a 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 a straight or branched chain C １－３ alkyl (e.g., methyl); Each R and R' is independently H, O, OH, N, NH, NH ２ , -Cl, -F, -Br, linear or branched chain C １－３ Alkyl (e.g., methyl or ethyl), straight or branched chain C １－３ Fluoroalkyl (e.g., —CH ３ Or CHF ２ ), or linear or branched C １－３ alkoxy (e.g., methoxy or ethoxy), where one R is modified to be covalently attached to the PTM via a chemical linking group (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 alkoxyl (e.g., methoxy or ethoxy); 【Chemistry 3】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and (ii) a Von Hippel-Lindau E3 ubiquitin ligase binding moiety (VLM) selected from: 【Chemistry 4】 During the ceremony, R １４ H, linear 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 having 1 or 2 heteroatoms selected from N, S and O, optionally substituted with methyl; 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; o is an integer from 0 to 2 (e.g., 0, 1, or 2); the Von Hippel-Lindau E3 ubiquitin ligase binding moiety (VLM), where the dashed line indicates the site of attachment to the PTM via a chemical linker (L); (iii) an inhibitor of apoptosis protein E3 ubiquitin ligase binding moiety (ILM) selected from: 【Chemistry 5】 During the ceremony, R for ILM-I, ILM-II, ILM-III, and ILM-IV １ is H or C １－３ alkyl (e.g., methyl or ethyl); R for ILM-I, ILM-II, ILM-III, and ILM-IV ２ is H or C １－３ alkyl (e.g., methyl or ethyl); R for ILM-I, ILM-II, ILM-III, and ILM-IV ３ is selected from cycloalkyl and heterocycloalkyl; R for ILM-I, ILM-II, ILM-III, and ILM-IV ５ is H, R for 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), bicyclic groups optionally having 1, 2, or 3 heteroatoms such as O or N (e.g., 9-12 membered bicyclic groups optionally having 1, 2, or 3 heteroatoms such as O or N), optionally further substituted with 1 to 3 substituents as described above; R for ILM-IV ４ａ But -(CH ２ ) ｘ -aryl (e.g., 5- to 7-membered aryl), -(CH ２ ) ｘ -heteroaryl (e.g., 5- to 7-membered heteroaryl); x for ILM-IV is 0, 1, 2, or 3; The ILM is R ４ , R ４ａ , or R ５ to a chemical linking group (L) or PTM via an inhibitor of apoptosis protein E3 ubiquitin ligase binding moiety (ILM) attached to said (c) A compound, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, wherein L is a bond or chemical linking group (L) connecting a ULM and a PTM.

2. PTM, 【Chemistry 6】 and During the ceremony, A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between the rings indicates ring fusion and overlapping rings indicate a spirocyclic ring; L ＰＴＭ is a bond, a group -O-, -NR １ＰＴＭ is selected from alkyl, alkenyl or alkynyl, optionally interrupted by one or more functional groups selected from -, -C(O)-, said functional groups being optionally located at either terminus of said linker; R １ＰＴＭ 3. The compound of claim 1 or 2, wherein is selected from H, alkyl, or fluorolkyl.

3. at least one of A, B, C, F, or combinations thereof is selected from an optionally substituted 5- 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, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, said alkyl and alkenyl groups being optionally further substituted; or 3. The compound according to claim 1 or 2, which is at least one of:

4. the PTM is of formula I or III, and 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 to 3 substituents independently selected from optionally substituted straight or branched chain alkyl, optionally substituted straight or branched chain alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano; L ＰＴＭ is a bond, an alkyl, alkenyl or alkynyl (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) optionally interrupted by one or more rings, or -O-, -S-, -NR １ - (wherein, R １ is selected from H or alkyl), -S(O)-, -SO ２ -, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO ２ 4. The compound of claim 3, wherein the functional groups are selected from one or more functional groups which may include -, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, optionally located at either terminus of the linker (i.e. immediately adjacent to the C or D ring).

5. The PTM is 【Chemistry 7】 represented by a chemical structure selected from the group consisting of: During the ceremony, X ＰＴＭ１ and X ＰＴＭ２ one of which is N and the other is C; X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ is independently C or N; X ＰＴＭ６ is CH or N; R １ But, H, C １－４ Alkyl (e.g., methyl), or C １－３ Fluoroalkyl (e.g., —CH ２ CF ３ , -CHF ２ ) and Each R ７ independently, (i) when the atom to which it is attached is carbon, H, halogen, C １－４ Alkyl (e.g., methyl), or C １－３ fluoroalkyl (e.g., —CF3), or (ii) is absent when the atom to which it is attached is nitrogen; R ７ａ is H, halogen, C １－４ Alkyl (e.g., methyl), or C １－３ Fluoroalkyl (e.g., -CF ３ ) and 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, H, halogen (e.g., F, Cl, Br), C １－Ｃ４ Alkyl (e.g., methyl), C １－３ Fluoroalkyl (e.g., -CF ３ ), or —CN, or (ii) is absent when the atom to which it is attached is nitrogen; 【Chemistry 8】 is the point of attachment of the PTM to a chemical linker group (L) or directly to a ULM; During the ceremony, One R ７ Or R ７ａ Only halogen, C １－４ Alkyl, or C １－３ is a fluoroalkyl; Two or less (e.g., 0, 1, or 2) R ９ is a halogen or -CN, X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ , and X ＰＴＭ６ The compound according to any one of claims 1 to 4, wherein 0, 1 or 2 of are N.

6. The PTM is 【Chemistry 9-1】 【Chemistry 9-2】 represented by a chemical structure selected from the group consisting of: During the ceremony, X ＰＴＭ７ and X ＰＴＭ８ are 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, a halogen, H or C １－３ Fluoroalkyl (e.g., -CF ３ or (ii) is absent when the atom to which it is attached is nitrogen; 【Chemistry 10】 is the point of attachment of said PTM to a chemical linking group (L) or directly to a ULM.

7. The PTM is 【Chemistry 11-1】 【Chemistry 11-2】 or, 【Chemistry 12】 During the ceremony, X ＰＴＭ９ Or X ＰＴＭ１０ One of them is nitrogen and the other is CH ２ and X ＰＴＭ１１ is nitrogen or CH; R １ But, H, C １－４ Alkyl (e.g., methyl), C １－３ Fluoroalkyl (e.g., —CH ２ CF ３ , -CHF ２ ) and R ７ is (i) H when the atom to which it is attached is carbon, or (ii) H or C1-3 alkyl when the atom to which it is attached is nitrogen; R ９ is H, halogen, halogen (e.g., F, Cl, Br), or C １－２ Fluoroalkyl (-CF ３ ) and 【Chemistry 13】 is the point of attachment of the PTM to a chemical linking group (L) or directly to a ULM.

8. The PTM is 【Chemistry 14】 represented by a chemical structure selected from the group consisting of: During the ceremony, Each X ＰＴＭ１２ and X ＰＴＭ１３ are independently nitrogen or carbon with hydrogen atoms to complete the valence; X ＰＴＭ１２ and X ＰＴＭ１３ at least one of is nitrogen; X ＰＴＭ１４ is nitrogen or CH; L ＰＴＭ is bond, C １－３ Alkyl, C ２－３ alkynyl (e.g., C alkynyl), wherein a carbon of the alkyl is optionally replaced with O or C(=O); L ＰＴＭ１ But, C １－Ｃ４ is alkyl, R １ But, H, C １－４ Alkyl (e.g., methyl), C １－３ Fluoroalkyl (e.g., —CH ２ CF ３ , -CHF ２ ) and R ７ H, halogen, C １－４ Alkyl (e.g., methyl), or C １－３ Fluoroalkyl (e.g., -CF ３ ) and Each R ９ is independently H or a halogen (e.g., F, Cl, Br); 【Chemistry 15】 is the point of attachment of the PTM to a chemical linking group (L) or directly to a ULM.

9. The PTM is 【Chemistry 16】 represented by a chemical structure selected from the group consisting of: During the ceremony, Each X ＰＴＭ１２ and X ＰＴＭ１３ are independently nitrogen or carbon with hydrogen atoms to complete the valence; X ＰＴＭ１２ and X ＰＴＭ１３ at least one of is nitrogen; Each R ７ is independently H or a halogen (e.g., F, Cl, Br); Each R ９ is independently H or a halogen (e.g., F, Cl, Br); 【Chemistry 17】 is the point of attachment of the PTM to a chemical linking group (L) or directly to a ULM.

10. The PTM is 【Chemistry 18-1】 【Chemistry 18-2】 represented by a chemical structure selected from the group consisting of: During the ceremony, X ＰＴＭ１４ is N or CH; R １０ and R １１ is independently selected from H, methyl, and ethyl; R １２ and R １３ are independently 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 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen; R １６ is H, OH, or C １－３ alkoxyl (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., -CF ３ ) and R １９ is H, halogen (e.g., F, Cl, Br), C １－２ Haloalkyl (e.g., -CF ３ ), or -NH ２ , N(R ２０ ) ２ and 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 linking group (L) or directly to the ULM; 【Chemistry 19】 is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

11. The PTM is 【Chemistry 20】 represented by a chemical structure selected from the group consisting of: During the ceremony, X ＰＴＭ１７ , X ＰＴＭ１８ , and X ＰＴＭ１９ each is independently N or CH; X ＰＴＭ１５ and X ＰＴＭ１６ is N or C; R ２１ (i) if the atom to which it is attached is carbon, H or C １－３ alkyl (e.g., methyl), or (ii) absent when the atom to which it is attached is nitrogen; R ２２ is (i) H or halogen (e.g., F, Cl, Br) when the atom to which it is attached is carbon, or (ii) absent when the atom to which it is attached is nitrogen; Each R ２３ is H or a halogen (e.g., F, Cl, Br); Each R ２４ is H or a halogen (e.g., F, Cl, Br); R ２５ is H or C １－３ alkyl (e.g., methyl); 【Chemistry 21】 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 the PTM has 0 or 1 nitrogen per ring.

13. The PTM is 【Chemistry 22】 represented by a chemical structure selected from the group consisting of: During the ceremony, 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; R ７ and R ８ each independently represents one or two substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano; L ＰＴＭ is a bond, a group -O-, -NR １ＰＴＭ C optionally interrupted by one or more functional groups selected from -, -C(O)- １－３ Alkyl, C ２－３ alkenyl, or C ２－３ alkynyl, said functional groups being optionally located at either terminus of said linker; 【Chemistry 23】 is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

14. The PTM is 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 represented by a chemical structure selected from the group consisting of: During the ceremony, 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; R ７ , R ８ , R ９ , and R １０ is 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano.

15. The PTM is 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 【Chemistry 25-6】 【Chemistry 25-7】 【Chemistry 25-8】 represented by a chemical structure selected from the group consisting of: In the formula, ＊ and 【Chemistry 26】 is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

16. The PTM is 【Chemistry 27-1】 【Chemistry 27-2】 represented by a chemical structure selected from the group consisting of: During the ceremony, 【Chemistry 28】 is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM.

17. The compound according to any one of claims 1 to 16, wherein the ULM is a VLM.

18. The VLM is 【Chemistry 29-1】 【Chemistry 29-2】 and wherein the structure is selected from 17. The compound of any one of claims 1 to 16, wherein the dashed line indicates the site of attachment to a PTM via a chemical linking group (L).

19. The compound according to any one of claims 1 to 16, wherein the ULM is a CLM.

20. The CLM is 【Chemistry 30-1】 【Chemistry 30-2】 【Chemistry 30-3】 having a chemical structure represented by During the ceremony, A is H or a straight or branched chain C １－３ alkyl (e.g., methyl or ethyl); G is H or a linear or branched chain C １－３ alkyl (e.g., methyl); One R is hydrogen and the other R is H, O, OH, N, NH, NH ２ , -Cl, -F, -Br, linear or branched chain C １－３ Alkyl (e.g., methyl or ethyl), straight or branched chain C １－３ Fluoroalkyl (e.g., —CH ３ Or CHF ２ ), or linear or branched C １－３ alkoxy (e.g., methoxy or ethoxy); R' is H, halogen (e.g., F, Cl, Br), C １－３ Alkyl (e.g., methyl or ethyl), or C １－３ alkoxyl (e.g., methoxy or ethoxy); 【Chemistry 31】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; N ＊ is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM; 【Chemistry 32】 is a single bond or a double bond, The above 【Chemical 33】 The compound according to any one of claims 1 to 16 and 19, wherein: represents the attachment site of a PTM via a chemical linking group.

21. The CLM is 【Hua 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 【Chemistry 34-4】 having a chemical structure selected from During the ceremony, N ＊ is the point of attachment of the PTM to the chemical linking group (L) or directly to the ULM; The above 【Chemistry 35】 represents the attachment site of a PTM via a chemical linking group (L).

22. The compound according to any one of claims 1 to 16, wherein the ULM is an ILM.

23. R for ILM-I, ILM-II, ILM-III, and ILM-IV １ is a methyl group, R for ILM-I, ILM-II, ILM-III, and ILM-IV ２ is a methyl group, R for ILM-I, ILM-II, ILM-III, and ILM-IV ３ is C6 cycloalkyl or C6 heterocycloalkyl (e.g. 【Chemical 36】 ) and R for ILM-I, ILM-II, and ILM-III ４ is an 11-membered bicyclic group optionally containing one heteroatom, wherein said bicyclic group is the point of attachment of said ILM to a chemical linking group (L) or a PTM, as described herein, or R ４ａ But -CH ２ CH ２ -C ５－７ aryl, for example phenyl; ５－７ aryl or phenyl is said point of attachment of the ILM to a chemical linking group (L) or a PTM, as described herein; or 23. The compound according to any one of claims 1 to 16 or 22, which is at least one of:

24. R for ILM-I, ILM-II, and ILM-III ４ but, 【Chemical 37】 24. The compound of any one of claims 1 to 16, 22, or 23, wherein

25. The ULM is 【Chemical Formula 38】 and 【Chemical Formula 39】 represents the attachment site of a PTM via a chemical linking group (L).

26. The linker (L) has the chemical structure: 【Chemistry 40】 is represented by During the ceremony, Y Ｌ１ is a bond, O, or NH, C═O, or C1-C3 alkyl; W Ｌ２ is an optionally substituted 3- to 7-membered ring (e.g., 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl); Y Ｌ２ is a bond, O, unsubstituted or substituted straight or branched chain C1-C6 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O), unsubstituted or substituted straight or branched chain C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), or unsubstituted or substituted straight or branched chain C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with 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 spirocycle, or an 8-11 membered non-aromatic bicyclic group, each having 0-4 heteroatoms and optionally one or more (e.g., 1, 2, or 3) of halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O; Y Ｌ３ is a bond, O, unsubstituted or substituted straight or branched chain C1-C6 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O), unsubstituted or substituted straight or branched chain C2-C6 alkenyl (e.g., optionally substituted C-C4 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), or unsubstituted or substituted straight or branched chain C1-C6 alkynyl (e.g., optionally substituted C2-C4 alkynyl and / or one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with 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 one or more (e.g., 1, 2, or 3) of halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O; Y Ｌ４ is a bond, O, unsubstituted or substituted straight or branched chain C1-C4 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), unsubstituted or substituted straight or branched chain C2-C4 alkenyl (e.g., optionally substituted C2-C3 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl groups, or C=O), or unsubstituted or substituted straight or is a branched C1-C4 alkynyl (e.g., an optionally substituted C2-C3 alkynyl, and / or one or more (e.g., 1, 2, or 3) of halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with Y Ｌ５ is a bond, O, unsubstituted or substituted straight or branched chain C1-C9 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O), unsubstituted or substituted straight or branched chain C2-C9 alkenyl (e.g., optionally substituted C2-C6 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), or unsubstituted or substituted straight or branched chain C1-C6 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with Y Ｌ６ is a bond, O, unsubstituted or substituted straight or branched chain C1-C8 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), unsubstituted or substituted straight or branched chain C2-C8 alkenyl (e.g., optionally substituted C2-C6 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C═O), or unsubstituted or substituted straight or branched chain C1-C8 alkynyl (e.g., optionally substituted C2-C6 alkynyl and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ has one or more (e.g. 1, 2 or 3) C atoms replaced with Y Ｌ７ is a bond, O, unsubstituted or substituted straight or branched chain C1-C10 alkyl (e.g., one or more (e.g., 1, 2, or 3) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O), unsubstituted or substituted straight or branched chain C2-C10 alkenyl (e.g., optionally substituted C2-C8 alkenyl, and / or one or more (e.g., 1, 2, or 3) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C═O), or unsubstituted or substituted straight or branched chain C1-C10 alkynyl (e.g., optionally substituted C2-C8 alkynyl and / or one or more (e.g., 1, 2, or 3) halogen, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, —CF ３ , methyl, ethyl, isopropyl, or C=O, wherein each of the alkyl, alkenyl, and alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with Y Ｌ７ is a bond, O, or unsubstituted or substituted straight or branched chain C1-C25 alkyl (e.g., unsubstituted or substituted straight or branched chain C1-C25 alkyl, and and / or one or more (e.g., 1, 2, or 3) halogen (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, -CF ３ , methyl, ethyl, isopropyl, or C=O, wherein the alkyl is O, NH, NCH ３ , or NCH(CH ３ ) ２ Optionally, one or more (e.g., one, two or three) C atoms are replaced with The above 【Chemistry 41】 represents the binding site of a PTM or a ULM.

27. The linker (L) is 【Chemistry 42-1】 【Chemistry 42-2】 is represented by a chemical structure selected from During the ceremony, U Ｌ and U Ｌ１ is independently selected from a bond or O; X Ｌ１ , X Ｌ２ , Y Ｌ１ , and Y Ｌ２ is independently selected from N or CH, with the proviso that X Ｌ１ If N, then U Ｌ is a bond, and Y Ｌ２ If N, then U Ｌ１ is a bond, n1 and n2 are each independently 0 or 1; 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; Y Ｌ１ and Y Ｌ２ When both are N, m1 is 1 and m2 is 1; R Ｌ１ and R Ｌ２ are each independently methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C １－３ represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN, and the halogen (e.g., F), OH, and CN substituents are each independently selected from X Ｌ１ If N, then X Ｌ１ does not exist on the carbon atom adjacent to X Ｌ２ If N, then X Ｌ２ is not present on the carbon atom adjacent to Y Ｌ１ If N, then Y Ｌ１ is not present on a carbon atom adjacent to Y Ｌ２ If N, then Y Ｌ２ is not present on the carbon atom adjacent to M Ｌ is selected from: 【Chemistry 43】 In the formula, M Ｌ is methyl, halogen (e.g., F), fluoroalkyl (e.g., C １－３ fluoroalkyl), OH and CN, with the proviso that said F, OH and CN substituents are not present on a carbon atom adjacent to a heteroatom; Z Ｌ and Z Ｌ１ each independently represents O or NR ３ is selected from R Ｌ３ is H, methyl, ethyl, or isopropyl; p is 0, 1, or 2; U Ｌ and U Ｌ１ is the binding site for a PTM or a ULM.

28. The linker (L) is 【Chemistry 44】 is represented by a chemical structure selected from During the ceremony, U Ｌ and U Ｌ１ is independently selected from a bond or O; X Ｌ１ , X Ｌ２ , Y Ｌ１ , and Y Ｌ２ is independently selected from N or CH, with the proviso that X Ｌ１ If N, then U Ｌ is a bond, and Y Ｌ２ If N, then U Ｌ１ is a bond, n1 and n2 are each independently 0 or 1; 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; Y Ｌ１ and Y Ｌ２ When both are N, m1 is 1 and m2 is 1; R Ｌ１ and R Ｌ２ are each independently methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C １－３ represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN, and the halogen (e.g., F), OH, and CN substituents are each independently selected from X Ｌ１ If N, then X Ｌ１ does not exist on the carbon atom adjacent to X Ｌ２ If N, then X Ｌ２ is not present on the carbon atom adjacent to Y Ｌ１ If N, then Y Ｌ１ is not present on a carbon atom adjacent to Y Ｌ２ If N, then Y Ｌ２ is not present on the carbon atom adjacent to M Ｌ is selected from: 【Chemistry 45】 In the formula, M Ｌ is methyl, halogen (e.g., F), fluoroalkyl (e.g., C １－３ fluoroalkyl), OH and CN, with the proviso that said F, OH and CN substituents are not present on a carbon atom adjacent to a heteroatom; Z Ｌ and Z Ｌ１ each independently represents O or NR Ｌ３ is selected from R Ｌ３ is H, methyl, ethyl, or isopropyl; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5; Y Ｌ２ is N, q is not 0 or 1, U Ｌ and Z Ｌ is the binding site for a PTM or a ULM.

29. The linker (L) is 【Chemistry 46-1】 【Chemistry 46-2】 is represented by a chemical structure selected from During the ceremony, U Ｌ and U Ｌ１ is independently selected from a bond or O; X Ｌ１ , X Ｌ２ , Y Ｌ１ , and Y Ｌ２ is independently selected from N or CH, with the proviso that X Ｌ１ If N, then U Ｌ is a bond, and Y Ｌ２ If N, then U Ｌ１ is a bond, n1 and n2 are each independently 0 or 1; 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; Y Ｌ１ and Y Ｌ２ When both are N, m1 is 1 and m2 is 1; R Ｌ１ and R Ｌ２ are each independently methyl, halogen (e.g., F, Cl, Br), fluoroalkyl (e.g., C １－３ represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN; The substituent is X Ｌ１ If N, then X Ｌ１ does not exist on the carbon atom adjacent to X Ｌ２ If N, then X Ｌ２ is not present on the carbon atom adjacent to Y Ｌ１ If N, then Y Ｌ１ is not present on a carbon atom adjacent to Y Ｌ２ If N, then Y Ｌ２ is not present on the carbon atom adjacent to W Ｌ１ and W. Ｌ２ are each independently selected from N or CH; W Ｌ２ If N, then U Ｌ１ is a bond, r1 is 1 or 2, r2 is 0, 1 or 2, W Ｌ１ and W. Ｌ２ are both N, then r1 is 2 and r2 is 1 or 2; R Ｌ３ is methyl, halogen (e.g., F), fluoroalkyl (e.g., C １－３ represents any one or two substituents independently selected from halogen (e.g., F), OH, and CN, and the halogen (e.g., F), OH, and CN substituents are each independently selected from X Ｌ１ If N, then X Ｌ１ does not exist on the carbon atom adjacent to X Ｌ２ If N, then X Ｌ２ is not present on the carbon atom adjacent to Y Ｌ１ If N, then Y Ｌ１ is not present on a carbon atom adjacent to Y Ｌ２ If N, then Y Ｌ２ is not present on the carbon atom adjacent to M Ｌ１ is selected from: 【Chemistry 47】 In the formula, M Ｌ１ is methyl, halogen (e.g., F), fluoroalkyl (e.g., C １－３ fluoroalkyl), OH and CN, with the proviso that said F, OH and CN substituents are not present on a carbon atom adjacent to a heteroatom; Z Ｌ and Z Ｌ１ each independently represents O or NR ３ is selected from p is 0, 1, or 2; U Ｌ and U Ｌ１ is the binding site for a PTM or a ULM.

30. The linker (L) is 【Chemistry 48-1】 【Chemistry 48-2】 【Chemistry 48-3】 【Chemistry 48-4】 【Chemistry 48-5】 【Chemistry 48-6】 【Chemistry 48-7】 【Chemistry 48-8】 【Chemistry 48-9】 【Chemistry 48-10】 【Chemistry 48-11】 【Chemistry 48-12】 【Chemistry 48-13】 【Chemistry 48-14】 【Chemistry 48-15】 【Chemistry 48-16】 is selected from the group consisting of During the ceremony, each ＊ and 【Chemistry 49】 is the binding site for a PTM or a ULM.

31. The linker (L) is 【Chemistry 50-1】 【Chemistry 50-2】 【Chemistry 50-3】 【Chemistry 50-4】 【Chemistry 50-5】 【Chemistry 50-6】 【Chemistry 50-7】 【Chemistry 50-8】 【Chemistry 50-9】 【Chemistry 50-10】 【Chemistry 50-11】 【Chemistry 50-12】 【Chemistry 50-13】 【Chemistry 50-14】 【Chemistry 50-15】 【Chemistry 50-16】 is selected from the group consisting of During the ceremony, each ＊ and 【Chemistry 51】 is the binding site for a PTM or a ULM.

32. The linker (L) is 【Chemistry 52-1】 【Chemistry 52-2】 is selected from the group consisting of During the ceremony, each ＊ is the binding site for a PTM or a ULM.

33. 2. The bifunctional compound of claim 1, wherein the compound is selected from the group consisting of compounds 332, 335, 337-586, and 589-686 in Table 1 or a pharma- ceutically acceptable salt thereof.

34. 34. The compound of claim 33, wherein the compound demonstrates greater than 50% tau proteolysis as measured in CHOK1 tau P301L cells treated with 1 μM of the compound for 48 hours compared to untreated cells.

35. 34. The compound of claim 33, wherein the compound demonstrates 50% or less 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. 34. The compound of claim 33, wherein the compound demonstrates tau protein degradation in an in vivo tauopathy mouse model (e.g., Tg2508).

37. 34. The compound of claim 33, wherein said compound demonstrates tau proteolysis of seed-competent 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 pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

39. 36. The composition of claim 35, wherein the composition further comprises at least one of an additional bioactive agent, another bifunctional compound of any one of claims 1-37, or a combination thereof.

40. 40. The composition of claim 39, wherein the additional bioactive agent is an anti-neurodegenerative agent.

41. 40. The composition of claim 39, wherein the additional bioactive agent is a P-gp inhibitor.

42. 42. The composition of claim 41, wherein the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, elacridar, or verapamil.

43. 40. A composition comprising a pharma- ceutically acceptable carrier and an effective amount of at least one compound of any one of claims 1-37 for use in a method of treating a tau-associated disease or disorder in a subject, said method comprising administering said composition to a subject in need thereof, wherein said compound is effective to treat or ameliorate at least one symptom of said disease or disorder.

44. 44. The composition of claim 43, wherein the disease or disorder is associated with tau accumulation and aggregation.

45. 45. The composition of claim 43 or 44, wherein the disease or disorder is a neurodegenerative disease associated with tau accumulation and aggregation.

46. 46. ​​The composition of any one of claims 43 to 45, wherein the disease or disorder is at least one of primary tauopathies (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, injuries to the spinal cord and brain, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal tumors, and stroke.

47. The composition of any one of claims 43 to 45, wherein the disease or disorder is Alzheimer's disease.

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