Tau Protein-Targeting PROTACs and Related Methods of Use

Abstract

Bifunctional compounds are provided that find utility as modulators of tau protein. [Solution] The present disclosure provides bifunctional compounds containing a VHL or cereblon ligand that binds to E3 ubiquitin ligase on one end and a moiety that binds to tau protein on the other end, thereby placing tau protein in proximity to ubiquitin ligase, resulting in tau degradation (and inhibition). The present disclosure exhibits a wide range of pharmacological activities related to tau protein degradation / inhibition. Diseases or disorders resulting from tau protein aggregation or accumulation can be treated or prevented using the compounds and compositions of the present disclosure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to U.S. Provisional Application No. 62 / 415,830, filed November 1, 2016. No. 60 / 699,999, filed on Oct. 1, 2007, which application is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference U.S. Patent Application No. 15 / 230,354, filed August 5, 2016; U.S. Patent Application No. 62 / 406,888, filed October 11, 2016; U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; U.S. Patent Application No. 14 / 686,640, filed July 6, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; U.S. Patent Application No. 14 / 792,414, published as U.S. Patent Application Publication No. 2016 / 0058872; 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, all of which 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. Technical Field The present disclosure provides a method for the intracellular ubiquitination and subsequent degradation of target polypeptides and proteins, particularly Tau proteins. Sensuality The present disclosure relates to a compound. The compound places the target protein / polypeptide in proximity to the ubiquitin ligase, resulting in the ubiquitination and degradation (and inhibition) of the tau protein.

[0004] 2. Background technology Most small molecule drugs bind closely and in well-defined pockets to enzymes or receptors, while other small molecule compounds can be used to target protein-protein interactions. E3 ubiquitin ligases, of which several hundred are known in humans, are notoriously difficult to target because of the large protein contact surfaces and the shallow groove-like or flat interfaces involved. These compounds confer substrate specificity to E3 ligases. Therefore, they are specific for specific protein substrates and are more attractive therapeutic targets than general proteasome inhibitors. The development of ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds targeting E3 ligases have been reported, but the field remains largely unexplored.

[0005] One E3 ligase with attractive therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is a substrate recognition subunit of the E3 ligase complex VCB. This complex is further composed 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 angiogenic growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low levels of oxygen. The first small molecule ligand of von Hippel-Lindau (VHL) to the substrate recognition subunit of VHL has been prepared and its crystal structure obtained, demonstrating that this compound is a key substrate of VHL, the transcription factor HIF. It was confirmed that it mimics the binding mode of -1α.

[0006] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon binds damaged DNA-binding protein 1 ( DDB1, Cullin-4A (CUL4A), and Regulator of Cullins1 (ROC1), form an E3 ubiquitin ligase complex that binds many other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates, for example, the formation of limbs and otic vesicles. It has been conclusively concluded that this ubiquitin ligase complex is important for limb outgrowth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0007] Tau protein is an abundant protein in the central nervous system, primarily present in neurons, while other cells in the central nervous system express tau at low levels. In healthy neurons, tau binds to microtubules and regulates their stability, which is important for axonal elongation and neuroplasticity. Pathologically altered tau molecules are unable to stabilize microtubules and are prone to forming insoluble aggregates. The formation of insoluble tau aggregates within cells leads to cellular dysfunction, impaired axonal transport, and neuronal loss. The accumulation of abnormal tau aggregates in neurons is a key pathological feature of several neurodegenerative disorders, including Alzheimer's disease. In certain pathological conditions, tau aggregation leads to the formation of paired-helical filaments (PHFs), straight filaments (SFs), and / or neurofibrillary tangles (NFTs). The accumulation of PHFs and NFTs in neurons directly correlates with microtubule dysfunction and neurodegeneration. Neurons containing tau PHFs, SFs, and / or NFTs may be mediated by diverse cellular mechanisms. When activated, they attempt to clear the cells of abnormal protein aggregates.

[0008] More recent studies suggest that soluble tau oligomers, rather than large insoluble filaments, may play a more important role in the development and progression of disease before the onset of PHF- or NFT-induced neurotoxicity. Oligomeric tau may act as seeds for the aggregation of native tau, thereby promoting neurotoxic tau aggregates. Accumulating evidence indicates that tau aggregates can be transmitted from one cell to another by propagation in a prion-like manner.

[0009] Alterations and dysfunction of tau, as well as widespread neuronal loss, have long been associated with several neurodegenerative diseases, now collectively referred to as tauopathies.

[0010] The term "tauopathy" as used herein refers to certain neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Examples of tauopathies include, but are not limited to, AD, Down's syndrome, frontotemporal lobular dementia (FTLD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

[0011] Due to its pathological significance in numerous neurodegenerative diseases, tau is an important therapeutic target. Preventing tau aggregation may be a strategy for treating tau-associated neurodegenerative disorders. Significant efforts have been made to identify the molecular mechanisms of tau aggregation and to find therapeutic approaches to halt the progression of neurodegeneration.

[0012] Tau aggregation inhibitors that have shown promising preclinical data have been shown to be ineffective in recent clinical trials for the treatment of various tauopathies. Thus, there is a need in the art for effective treatments for diseases and conditions associated with tau aggregation, e.g., in neurodegenerative disorders such as tauopathies. Summary of the Invention

[0013] This disclosure provides two Sensuality This disclosure describes compounds, compositions containing such compounds, and methods of using them, which function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation. Sensuality

[0003] The present disclosure provides proteolytic or proteolytic targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination and degradation of tau protein aggregates. The present disclosure also provides methods of using an effective amount of the compounds described herein to treat or ameliorate conditions resulting from the accumulation or aggregation of tau protein, such as tauopathies. These diseases or disorders include, but are not limited to, neurological or neurodegenerative disorders.

[0014] Thus, in one embodiment, the present disclosure provides compounds that function to recruit endogenous proteins, such as tau, to an E3 ubiquitin ligase for ubiquitination and degradation.

[0015] In any embodiment, the compound has the following general structure: PTM-L-ULM.

[0016] In certain embodiments, the compound has the following general structure (A): PTM-L-VLM (A) In certain embodiments, the compound has the following general structure (B):

[0017] PTM-L-CLM (B) where PTM represents a protein targeting moiety and ULM represents an E3 ubiquitin ligase targeting moiety, including but not limited to VLM (VHL ligase binding moiety) and CLM (cereblon ligase binding moiety). and L represents a linker, such as a bond or a chemical linker moiety. As will be appreciated, the two methods described herein Sensuality The functional compounds can be synthesized so that the number and location of each functional moiety can be varied as desired.

[0018] In certain embodiments, the PTM of structure (A) is a ligand that binds to tau as well as VHL E3 ubiquitin ligase.

[0019] In certain embodiments, the PTM of structure (B) is a ligand that binds to tau as well as CLM E3 ubiquitin ligase.

[0020] In certain embodiments, the compounds described herein comprise multiple ULMs, multiple PTMs, multiple In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to regulate protein degradation in a patient or subject, e.g., an animal such as a human, and treat or ameliorate a disease state or condition regulated via the degraded protein. In certain embodiments, the therapeutic composition described herein can be used to cause degradation of a target protein for the purpose of treating or ameliorating a disease, e.g., a neurological disease. In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method involves using two ubiquitin-binding domains described herein, including a ULM and a PTM, which can be linked via a linker moiety. Sensuality and administering a compound to a subject, wherein ULM is linked to a PTM, as otherwise described herein, and wherein ULM is linked to a ubiquitin pathway protein, e.g., an E3 ubiquitin ligase, more preferably Preferably, the PTMs recognize ubiquitin ligases such as VLM and CLM, and the PTMs recognize target proteins (TBMs) such that degradation of the target protein (e.g., tau) occurs when the target protein is brought into proximity with the ubiquitin ligase, thereby causing degradation of the target protein, inhibiting its action and resulting in control of protein levels. In another embodiment, the target protein is tau. The present disclosure provides for the treatment of disease states or conditions through control of protein levels, i.e., by reducing the levels of the protein (e.g., tau protein) in patient cells through degradation.

[0021] In particular, PTM is a molecule that binds to tau protein (TBM), and ULM is a molecule that binds to VHL E3 A molecule that binds to ubiquitin ligases and / or CLM E3 ubiquitin ligases and has the following general structure: TBM-L-VLM / CLM The PTMs (protein targeting moieties) of the PROTACs of the present disclosure are represented by the general formulas I, II, III, IV, V, VI, VII, VIII, XI, X, and XI:

[0022] [ka]

[0023] During the ceremony: A, B, C, D, E, and F are each independently selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between the rings indicates ring fusion; and L PTM is selected from a bond, alkyl, alkenyl, or alkynyl, and is optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) or one or more functional groups, such as —O—, —S—, —NR 1 PTM - (where R 1 PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, wherein said functional groups can be optionally located at either end of the linker (i.e., A, B, C, D, E, or F rings). (It may be directly adjacent to the

[0024] The aryl and heteroaryl rings described above can be optionally substituted with 1 to 3 substituents each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups can be further substituted.

[0025] In any aspect or embodiment described herein, at least one of A, B, C, F, or a combination thereof is selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring.

[0026] In certain embodiments of the present disclosure, the PTM is represented by Formula I and / or Formula II, 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 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, trifluoromethyl, or cyano.

[0027] In other embodiments, the PTM is represented by Formula I and / or Formula II, 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; D and E are 5- or 6-membered fused aryl or heteroaryl rings; and wherein A, B, C, D, and E are alkyl, haloalkyl, Optionally substituted with halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

[0028] In certain other embodiments of the present disclosure, the PTM is represented by Formula I, wherein A is a phenyl or a 6-membered heteroaryl ring, B is a 5-membered heteroaryl ring, C is a phenyl or a 6-membered heteroaryl ring, and L PTM is a bond and D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl ring, wherein each of A, B, C and D is optionally and independently and optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, provided that rings A, B, and C are independently substituted. and any nitrogen atom in the D ring is L PTM is not directly attached to a heteroatom or carbon atom of , to which another heteroatom is directly attached.

[0029] 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.

[0030] In further embodiments, the present specification provides compounds having a structure selected from the group consisting of Examples 1-330 (e.g., compounds selected from Tables 1 and 2). Sensuality The present invention provides compounds, their salts, polymorphs, and prodrugs.

[0031] In further embodiments, the present disclosure provides compounds having a structure selected from Table 1 or Table 2 (e.g., a chemical structure selected from Compounds 1-330). Sensuality The present invention provides compounds, their salts, polymorphs, and prodrugs.

[0032] In another aspect, the present disclosure provides compositions comprising a compound described herein and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound described herein and an acceptable carrier. In certain embodiments, the therapeutic or pharmaceutical composition is a therapeutic agent, such as an agent effective in treating a neurological disorder. Contains an additional bioactive agent.

[0033] In any of the aspects or embodiments described herein, the therapeutic compositions comprising the compounds described herein may be configured to be delivered in any suitable dosage form, e.g., solid or liquid, and by any suitable route, e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

[0034] In another aspect, the description provides a method for modulating the ubiquitination and degradation of tau protein 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 the ubiquitination and degradation of tau in the subject.

[0035] In yet another aspect, the description provides methods of treating or ameliorating symptoms of a disease associated with tau activity in a subject, e.g., a cell, tissue, mammal, or human patient, comprising administering to a subject in need thereof 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 the disease associated with tau activity in the subject. In certain embodiments, the disease to be treated is a neurological or neurodegenerative disease, e.g., Alzheimer's disease, Parkinson's disease, dementia, etc.

[0036] In a preferred embodiment, the subject is a human. In an additional aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0037] Where applicable or unless specifically excluded, it is anticipated 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. Therefore, the foregoing general description of utility is presented for illustrative purposes only and is 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 apparent to those skilled in the art in light of the claims, detailed description, and examples. For example, the various aspects and embodiments of the present disclosure can be used in many combinations, all of which are expressly contemplated by this specification. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to describe the background of the disclosure and, in certain cases, to provide additional details regarding the implementation are incorporated by reference.

[0038] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0039] [Figure 1] Figure 1 shows total tau levels in hippocampal homogenates. Data are displayed as scattered dot blots. Statistically significant differences between test item (TI)-treated and vehicle control groups by one-way ANOVA followed by Dunneett's Multiple Comparison Test are indicated by asterisks: ** p<0.01, * p<0.05. DETAILED DESCRIPTION OF THE INVENTION

[0040] The following is a detailed description provided to assist those skilled in the art in implementing the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned herein are expressly incorporated by reference in their entirety.

[0041] The present specification relates to the surprising and unexpected discovery that an E3 ubiquitin ligase protein can ubiquitinate a target protein when the two proteins are brought into close proximity by a chimeric construct (e.g., a PROTAC) described herein, and the chimeric construct can bind to an E3 ubiquitin ligase protein (e.g., VHL and Selen). lebron) binds a target protein, such as tau. Accordingly, the present specification provides compounds, compositions containing such compounds, and related methods of use, directed to the ubiquitination and degradation of selected target proteins.

[0042] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in connection with its use in describing this disclosure.

[0043] Where a range of values ​​is provided, unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated range, or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, as are any specifically excluded limits in the stated range. When 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.

[0044] As used herein, the articles "a" and "an" are used interchangeably with "a" and "an" unless the context clearly dictates otherwise. Unless otherwise indicated, the articles "a" and "b" 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 in question. By way of example, "an element" means one element or more than one element.

[0045] 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. That is, in some instances, the elements are present conjunctivly and in other instances, they are present disjointly. Multiple elements listed with "and / or" should be construed in the same manner, that is, "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause can optionally be present, whether related or not to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can, in one embodiment, refer only to A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), and in yet another embodiment to both A and B (optionally including other elements).

[0046] 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" shall be interpreted as inclusive, i.e., any number of elements or any number of a list of elements. "Any combination of any of the following is inclusive of one, but also includes a plurality, and optionally includes additional unlisted items. Only terms clearly indicating 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" should be construed to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by exclusive terms, such as "either," "one of," "only one of," or "exactly one of."

[0047] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrase "consisting essentially of" is definite or semi-definite, respectively. The term "patentable" is a transitional phrase, as set forth in Section 2111.03 of the United States Patent Examining Guidelines. It is being done.

[0048] 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 elements in the list of elements, but not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. Furthermore, this definition allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or not to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "A and In one embodiment, "at least one of A and / or B" refers to at least one A, optionally including multiple A, and no B (optionally including elements other than B). In the embodiment, it refers to at least one B, optionally including multiple Bs, and A is absent (optionally). In yet another embodiment, it refers to at least one A, optionally including multiple As, and at least one B, optionally including multiple Bs (optionally including other elements). ).

[0049] In certain methods described herein that include multiple steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context indicates otherwise.

[0050] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and, where appropriate, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof, where appropriate in the context. Within its use in context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or mixtures enriched for a specific enantiomer. The term also refers, in context, to prodrug forms of compounds modified to facilitate administration and delivery of the compound to the active site. Note that in describing the present compounds, many substituents and, particularly, variables associated therewith are described. It will be understood by those of skill in the art that the molecules described herein are stable compounds, as outlined below.

[0051] join

[0052] [ka]

[0053] is shown, both double and single bonds are represented within the context of the compound shown.

[0054] 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 an infection, condition, or pathology specific to a particular animal, e.g., a human patient, the term patient refers to the particular animal, including domestic animals, e.g., dogs or cats, or agricultural animals, e.g., horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by the context in which the term is used.

[0055] The term "effective," when used within the context of its intended use, is used to describe an amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms that are otherwise described or used in this application.

[0056] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, together with or alone with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to lysine on a target protein, thereby targeting the specific protein substrate for proteasomal degradation. Thus, either in a complex with an E2 ubiquitin-conjugating enzyme or alone, an E3 ubiquitin ligase is involved in the transfer of ubiquitin to a targeted protein. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks a protein for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation, but may instead change their cellular location or function, for example, through binding to other proteins that contain domains that can bind ubiquitin. To further complicate the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is degraded by the proteasome. It is the lysine used to generate polyubiquitin, which is recognized by

[0057] The term "protein targeting moiety" or "PTM" refers to a target protein or other molecule of interest. The term "target protein binding moiety" is used to describe a small molecule that binds to a protein or polypeptide and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include compounds that target tau protein.

[0058] The term "target protein" as used herein below refers to a protein to which the disclosed compounds bind, ULM is used to describe proteins or polypeptides that are targets for degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding moieties are linked to a ULM group via a linker group.

[0059] The tau protein target may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the disclosed compounds, the activity level of the protein may be altered for therapeutic end results.

[0060] The term "pathology or condition" is used to describe any pathology or condition in which dysregulation of the protein occurs (i.e., the amount of protein expressed in the patient is increased) and in which degradation of the patient's tau protein provides beneficial treatment or symptomatic relief to a patient in need thereof. In certain instances, the pathology or condition may be treated.

[0061] Disease states or conditions that may be treated using compounds according to the present disclosure include, for example, 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.

[0062] As used herein, the term "neurological disorder" refers to any disorder, disease, and / or syndrome caused by or resulting from neurological, psychiatric, psychological, and / or cerebrovascular manifestations or origins. The term "neurological disorder" as used herein also refers to a disease, disorder, or condition of the brain and nervous system, or a mental disorder or condition. Neurological disorders include, but are not limited to, the following: septum pellucidum defect, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Adie pupil, Adie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, AIDS-neurological complications, Alexander disease, Alpers syndrome, alternating hemiplegia of childhood, 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, Ataxia, Telangiectasia, Ataxia and cerebellar degeneration / Spinocerebellar degeneration, Attention deficit hyperactivity disorder, Autism, Autonomic dysfunction, Back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, Benign essential blepharospasm, Benign focal muscular atrophy, Benign intracranial hypertension, Bernhard-Troth syndrome, Binswanger's disease, Eye Blepharospasm, Bloch-Sulzberger syndrome, brachial plexus birth trauma, traumatic brachial plexus palsy, pure autonomic dysfunction, brain and spinal cord tumors, cerebral aneurysms, cerebral trauma, Brown-Séquard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernoma, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, head injury, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral megalomania encephalomyelitis, cerebral hypoxia, cerebral palsy, cerebro-oculo-facial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic hypotension, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, agenesis of the corpus callosum, coma and persistent vegetative state, complex regional pain syndrome, congenital bilateral facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformation, corticobasal ganglia abnormalities Neuropathy, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disease, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, opsoclonus-myoclonus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, brachial plexus neuropathy, dementia, multi-infarct cognition dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, myoclonic cerebellar synergy disorder, dentatorubral atrophy, dermatomyositis, developmental dyspraxia, Debi Schneider's disease, diabetic neuropathy, diffuse sclerosis, dysautonomia, dysgraphia, dyslexia, dysphagia, dyspraxia, myoclonic dyssynergia, progressive cerebellar dyssynergia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis lethargica, encephalopathy, trigeminal angiomatosis, epilepsy, upper and lower paralysis, Erb's palsy, Fabry's disease, Fahr's disease, syncope, familial dysautonomia disease, familial hemangioma, familial basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Haller-Farber syndrome Ludden-Spatz disease, head injury, headache, persistent hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, polyneuropathy-type hereditary ataxia, herpes zoster, otic varicella, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotonia - infancy , hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, childhood hypotonia, childhood neuroaxonal dystrophy, childhood phytanic acid storage disease, childhood Refsum's disease, childhood seizures, inflammatory myopathy, foramen occipitalis prolapse, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy's disease, opsoclonus-myoclonus syndrome (Kinsbourne syndrome), Kleine-Lewin syndrome, Klippel-Feil syndrome syndrome, Klippel-Trenaunay-Weber syndrome (KTS), Klüber-Büssel syndrome - syndrome, Korsakoff amnesic syndrome, Krabbe disease, Kugelberg-Welander disease, Kuhl-, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment , Lateral Cord 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 Erythematosus-Neuropathy, Sequelae, Lyme Disease-Neuropathy, Complications, Machado-Joseph Disease, Encephalopathy, Mania, Megaloencephaly, Melkerson-Rosenthal Syndrome, Meningitis, Meningitis and Encephalitis, Menkes Disease, Dysesthesias Femoral Neuralgia, Metachromatic Type, Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Minor Stroke, Mitochondrial Myopathy, Moebius Syndrome, Hirayama Disease, Motor Neuron Disease, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidosis, Multifocal Motor Neuropathy, Multi-Infarct Cognitive Disorders Disease, Multiple Sclerosis, Multiple System Atrophy, Multiple System Atrophy with Orthostatic Hypotension, Muscular Dystrophy, Myasthenia - Congenital, Myasthenia Gravis, Demyelinating Diffuse Sclerosis, Myoclonic Encephalopathy of Childhood, Myoclonus, Myopathy, Myopathy - Congenital, Myopathy - Thyrotoxicity, 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 Manifestations of Pompe Disease, Neurological Sequelae of Lupus Erythematosus, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration Disorders, Neuropathy - Hereditary, Neurosarcoidosis, Neurotoxicity, Nevus Cavernous Cavernosus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, split spinal cord, Ohtahara syndrome, olivopontocerebellar atrophy, ocular myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome Syndrome), Overuse Syndrome, Chronic Pain, Pain, Pantothenate Kinase-Related Neurodegeneration, Paraneoplastic Syndrome, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Migraine, Facial Hemiatrophy, Pelizaeus-Merzbacher Disease, Pena-Shocker Syndrome Type II, Perineural Cyst, Periodic Paralysis, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorder, Phytanic Acid Storage Disease, Pick's Disease, Stiff Neck, Piriformis Syndrome, Pituitary Tumor, Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postpolio Syndrome, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, Orthostatic Tachycardia Syndrome, Primary Dentatum Atrophy, Primary Dentatum Atrophy Neurosclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive gait ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (previous name), Ramsay Hunt syndrome II ( (previous name), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Refsum's disease, Refsum's disease-childhood type, repetitive movement disorder, repetitive strain injury, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Relay-Day syndrome, sacral nerve root cyst, Chorea, salivary gland disease, Sandhoff disease, Schilder's disease, schizencephaly, Seitelberger disease, seizure disorders, semantic dementia, septo-optic dysplasia, shaken baby syndrome, shingles, Scheid-Rager syndrome, Sjogren's syndrome, sleep apnea syndrome, African sleeping sickness, Sotos disease, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosis Metastatic panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT Headache Swallowing Disorders, Sydenham chorea, syncope, syphilitic spinal sclerosis, syringomyelia, syringomyelia, systemic lupus erythematosus, tabes dorsalis, tardive dyskinesia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tethered cord syndrome, Thomsen's myotonia, thoracic outlet syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular erectile tumor, vasculitis-induced Conducting temporal arteritis (Vasculitis including Temporal Arteritis), von Echonomo disease , von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury, Whipple disease, Williams syndrome, Wilson disease, X-linked spinal-bulbar muscular atrophy atrophy, or Zellberger syndrome.

[0063] The term "bioactive agent" is used to describe an agent other than a compound of the present disclosure, which is used in combination with a compound of the present disclosure as an agent having biological activity to aid in the therapeutic, inhibitory, and / or preventative / preventative effects for which the compound is used.

[0064] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, where appropriate, one or more salt forms of the compounds described herein, which salt forms increase the solubility of the compound in the gastric juices of a patient's digestive tract, facilitating the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0065] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrug groups, etc.) which, upon administration to a patient, yields, directly or indirectly, the compound, or an active metabolite of the compound.

[0066] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0067] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0068] The term "alkyl" shall mean, within its context, a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical or group of alkyl, preferably C-C 10 , more preferably C1-C6 or C1-C3 alkyl groups, which may be optionally substituted. 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, cyclo ... Propyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl.

[0069] The term "lower alkyl" means an alkyl group having six or fewer carbon atoms. The term "unsubstituted" shall 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 from C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with H replacing the carbon for C0. The terms "substituted" or "optionally substituted" shall be used within the context. One or more substituents (independently up to five substituents, preferably up to three substituents, often one or two substituents, on a moiety in a compound according to the present disclosure, which may include substituents that may themselves be further substituted) independently at any carbon (or nitrogen) position on the molecule. (i.e., when there are multiple substituents, each substituent is independent of the other substituents), and the substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (especially alkyl, especially methyl, such as trifluoromethyl), a halogen atom, preferably 1, 2, or 3 halogen atoms on the alkyl group; an alkyl group (preferably C1-C 10 ,Yo more preferably C1-6), aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl; phenyl and and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl), alkylene ester (the attachment is on the alkylene group rather than the ester functionality and is preferably substituted with a C1-C6 alkyl or aryl group), preferably containing a C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including 5- or 6-membered cyclic alkylene amines, C1-C6 alkylamines or C1-C6 dialkylamines), the alkyl group may be substituted with one or two hydroxyl groups), or or optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) group (which may be optionally substituted with a polyethylene glycol chain to which is further attached an alkyl group containing one halogen, preferably chlorine, substituent); hydrazine; amide, which preferably has one or two C1-C6 alkyl groups (including carboxamide, which is optionally substituted with one or two C1-C6 alkyl groups); alkanol (preferably C1-C6 alkyl or aryl); or alkanoic acid (preferably Preferably, the substituted aryl group is C1-C6 alkyl or aryl. The substituents may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as defined herein. and R3 is H or a C1-C6 alkyl group, preferably in this context R1, R2, R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly attached 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 to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via a - group, which may be substituted with any one or more of the above-mentioned substituents. m -or-(CH2) n - groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen, or C1-C6 (preferably C1-C3) These include alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or an amino acid side chain as otherwise described herein, and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often one or more or two C0-C6 alkyl substituents, which may also be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or an amino acid side chain as otherwise described herein. Moieties in the molecules disclosed herein may be optionally substituted with up to five substituents, preferably up to three substituents. In most cases, substituted moieties in the disclosed embodiments are substituted with one or two substituents.

[0070] The term "substituted" (each substituent being independent of any other substituent) includes, within the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane -O-C(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C1-C6 alkylene-NR1R2, mono or or di-C1-C6 alkyl substituted amines with one or two hydroxyl groups Each of these groups contains 1 to 6 carbon atoms, unless otherwise indicated within the context. In certain embodiments, depending on the context in which the substituent is used, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (wherein m and n are 1, 2, 3, 4, 5 or 6, depending on the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 Rukill, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogens (F, Cl, Br , I, preferably F or Cl). R1 ​​and R2 may each be, in context, H or a C1-C6 alkyl group (one or two hydroxyl groups, or up to three halogens). The term "substituted" is also intended to mean, within the chemical context of the compound specified and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. Alkylene groups may also be substituted as otherwise disclosed herein, and are preferably optionally substituted C1-C6 alkyl groups (methyl, The substituents may be substituted with aryl, aryl, aryl groups, aryls ... Please note that this may occur.

[0071] The terms "aryl" or "aromatic," in context, refer to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenylphenyl, phenanthrenyl, etc.), which may be attached to a compound in accordance with the present disclosure at any available stable position on the ring or as otherwise specified in the provided chemical structure. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a ring (single ring) of heteroaromatic ring systems, such as imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, etc., among others. Among the heteroaryl groups that 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, imidazoline, benzophenone ... pyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen. Included are heterocycles such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0072] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, i.e., O, N, or S, and may be aromatic (heteroaryl) or non-aromatic. Heteroaryl moieties are therefore encompassed under the definition of heterocycle, depending on the context of their use. Exemplary heteroaryl groups are described herein above. Exemplary non-aromatic heterocyclic groups for use in the present disclosure include, for example, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide, among others, as described herein.

[0073] The term "co-administration" or "combination therapy" is intended to mean that at least two compounds or compositions are administered to a patient simultaneously, so that effective amounts or concentrations of each of the two or more compounds are present in the patient for a given period of time. While compounds according to the present disclosure can be co-administered to a patient at the same time, the term also encompasses administration of two or more agents at the same time or at different times, so long as effective concentrations of all co-administered compounds or compositions are present in the patient for a given period of time. In certain preferred embodiments of the present disclosure, one or more of the present compounds described above are co-administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents. In particular embodiments of the present disclosure, co-administration of compounds results in synergistic treatment, including anti-cancer treatment.

[0074] This disclosure provides two Sensuality The present disclosure describes compounds and methods for their use that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Sensuality

[0003] The present invention provides proteolytic or proteolytic targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of tau protein. An advantage of the compounds provided herein is their potential for broad pharmacological activity, consistent with the degradation / inhibition of tau protein.

[0075] Thus, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase targeting moiety (ULM) conjugated to a tau protein target binding moiety (PTM), This leads to ubiquitination of tau protein, which is then degraded (and and / or inhibition). The present disclosure also provides libraries of compositions and uses thereof.

[0076] The present description is directed to ligands, e.g., small molecule ligands (i.e., 2000 daltons, 1,000 daltons, and a compound comprising a ubiquitin ligase (having a molecular weight of less than 500 daltons, 500 daltons, or 200 daltons), which compound is capable of binding to a ubiquitin ligase, such as VHL or cereblon. The protein also includes a moiety that can bind to a target protein in a manner that places the target protein in proximity to a ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. In addition to the above, small molecule means that the molecule is non-peptidyl, i.e., in many cases contains fewer than 4, 3, or 2 amino acids, for example. According to the present specification, a PTM, ULM, or PROTAC molecule may be a small molecule.

[0077] In one embodiment, the present disclosure provides compositions useful for regulating protein activity. The compositions comprise a polypeptide (preferably directed against VHL or cereblon) according to a defined chemical structure. and a ubiquitin pathway protein binding moiety, and a tau protein targeting moiety, preferably linked together via a linker, wherein the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein and the targeting moiety recognizes a tau target protein, wherein the ubiquitin pathway protein binding moiety is linked to the tau targeting moiety.

[0078] In another embodiment, the disclosure provides a library of compounds, the library comprising a plurality of compounds, wherein each compound has a ubiquitin pathway protein binding moiety (preferably VHL or cereblon) and a tau protein binding moiety, wherein ULM is attached to tau (preferably via a linker moiety), and wherein the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein, particularly an E3 ubiquitin ligase.

[0079] In another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein (e.g., tau) in a cell. The method includes a bilayer comprising a ubiquitin pathway protein binding moiety and a targeting moiety, preferably linked via a linker moiety as otherwise described herein. Sensuality and administering to the subject a compound that binds to the ubiquitin pathway, wherein the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein (e.g., VHL, cereblon) and the targeting moiety targets the subject. Recognition of a protein (e.g., tau) results in degradation of the target protein when it is brought into proximity with the ubiquitin ligase, resulting in a reduction / inhibition of the action of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition, which is regulated via the target protein by reducing the level of that protein in the patient's cells.

[0080] In yet another embodiment, the present disclosure is directed to a method of treating a patient in need for a disease state or condition regulated through a protein (e.g., tau), where degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial organism or a foreign agent, such as a virus, bacteria, fungus, protozoan, or other microorganism, or may be a disease caused by overexpression of a protein, i.e., accumulation or aggregation of tau protein, which results in the disease state and / or condition.

[0081] In one embodiment, the present disclosure provides compounds useful for regulating protein activity. The compositions include compounds that bind to E3 ubiquitin ligases, ubiquitin pathway protein binding moieties, and proteins. and a targeting moiety, preferably linked or attached together via a linker, where the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein and the targeting moiety recognizes a target protein (e.g., tau). Such compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, or prodrugs thereof, may be referred to herein as PROTAC compounds or PROTACs, having the following general chemical structure: ULM-L-PTM, wherein ULM is a small molecule E3 ubiquitin ligase-binding moiety that binds to E3 ubiquitin ligase; A PTM is a small molecule that contains a tau protein targeting moiety that degrades tau protein; and Beauty L is a bond or chemical linking moiety connecting the ULM and the PTM.

[0082] In certain embodiments, the E3 ubiquitin ligase binding moiety targets one of the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).

[0083] In one embodiment, the present disclosure provides tau protein binding moieties (PTMs). In the form, 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 or represented by formula XI:

[0084] [ka]

[0085] , in the formula: 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 L PTM is selected from a bond, alkyl, alkenyl, or alkynyl, and optionally one The ring (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) may be interrupted by one or more functional groups, such as —O—, —S—, —NR 1 PTM - (where R 1 PTM is selected from H or alkyl), —N═N—, —S(O)—, —SO—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO—, —NHC(O)NH—, —NHC(O)O—, or —OC(O)NH—, , the functional groups are optionally located at either end of the linker.

[0086] In certain embodiments, the aryl and heteroaryl rings of A, B, C, D, E, and F of the PTMs The aryl ring is optionally substituted with 1 to 3 substituents each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups are further optionally substituted.

[0087] In certain embodiments, the ring of at least one of A, B, C, F, or a combination thereof is selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring; In certain embodiments, the PTM has the chemical structure of Formula I, wherein: The A, B, and C rings are independently 5- or 6-membered fused aryl or heteroaryl rings. the law of nature; L PTM is selected from a bond or alkyl, and 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.

[0088] In certain additional embodiments, the PTM has the 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; and D is a 6-membered heteroaryl or 6-membered heterocycloalkyl ring; wherein each of A, B, C, and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano, and wherein a nitrogen atom in any of the A, B, C, and D rings is not directly bonded to a heteroatom or carbon atom to which another heteroatom is directly attached.

[0089] In other embodiments, the PTM has the chemical structure of Formula III or Formula IV, wherein A, B and and C are 5- or 6-membered fused aryl or heteroaryl rings; L PTM is selected from a bond or alkyl; D and E are 5- or 6-membered fused aryl or heteroaryl rings; and A, B, C, D, and E are alkyl, haloalkyl, halogen, , hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0090] In certain embodiments, the PTM is represented by the following chemical structure:

[0091] [ka]

[0092] [ka]

[0093] 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, and halogen; and R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen; , the PTM is linked to the ULM via L.

[0094] In any of the embodiments or aspects described herein, the PTM is covalently attached to one or more ULM (VLM or CLM) groups, or to a linker that is attached to one or more ULM (VLM or CLM) groups as described herein.

[0095] In certain embodiments, the PTM is represented by the following chemical structure:

[0096] [ka]

[0097] [ka]

[0098] During the ceremony: R 1 , R 2 and R 3 is independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and R 7 , R 8 , R 9 and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano, and PTM is connected via L to ULM. (VLM or CLM).

[0099] In certain additional embodiments, the PTM is represented by the following chemical structure:

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] In certain embodiments, the linker attachment point to the PTM is as indicated by the dotted line:

[0104] [ka]

[0105] Example VLM: In one embodiment, the ULM is VHL.

[0106] In certain embodiments of the compounds described herein, the ULM is a VLM, as defined below: ULM-a The compound includes a chemical structure selected from the group consisting of:

[0107] [ka]

[0108] During the ceremony: The dashed lines indicate attachment of at least one PTM, another ULM or VLM or CLM (i.e., a ULM' or VLM' or CLM'), or a chemical linker moiety; or VLM' or CLM' attached to the other end of the linker; X 1 , X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO2 groups Selected from; RY3 , R Y4 are each independently H, straight or branched chain C 1~6 alkyl, optionally with one or more halo, C 1~6 substituted by alkoxyl; R P are 1, 2 or 3 groups, each independently H, halo, —OH, C 1-3 Selected from the group of alkyl Selected; W 3 is optionally substituted -TN(R 1a R 1b ), optionally substituted -TN(R 1a R 1b )X 3 , -T-aryl , optionally substituted -T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle; X 3 is C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b are each independently optionally substituted with H, one or more halo or -OH groups; A straight or branched C1-C6 alkyl group, 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; where T is X 1 Covalently bonded to W 4is an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or optionally substituted -NR 1 -T-heterocycle, where preferably -NR 1 is X 2 is covalently bonded to R 1 is H or CH3.

[0109] In any of the embodiments described herein, T is optionally substituted alkyl , -(CH2) n - groups, wherein each one of the methylene groups is selected from the group consisting of halogen, methyl, straight or branched C1-C6 alkyl groups optionally substituted with one or more halogens or -OH. optionally substituted with one or two substituents selected from the group consisting of alkyl groups, or optionally substituted amino acid side chains; and n is 0 to 6, and is often 0, 1, 2, or 3, and preferably 0 or 1.

[0110] In certain embodiments, W 4 teeth,

[0111] [ka]

[0112] where R 14a、 R 14b、 are each independently selected from the group H, haloalkyl, or optionally substituted alkyl; In any of the aspects or embodiments described herein, W 5 is selected from the group of phenyl or 5-10 membered heteroaryl; R 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; In additional embodiments, W for use in the present disclosure 4 Substituents further include the W groups present in certain compounds disclosed herein. 4 These W substituents are specifically included (but are not limited to the particular disclosed compounds). 4 Each of the substituents may be any number of W 3 They may be used in conjunction with substituents, which are also disclosed herein.

[0113] In certain additional embodiments, ULM-a has 1 to 3 R in the pyrrolidine moiety. P Assigned by the basis Each R P are independently H, halo, -OH, C 1-3 It is alkyl.

[0114] In any of the embodiments described herein, W 3 , W 4 may be independently covalently attached to a linker to which one or more PTM groups are attached. and wherein the dashed line indicates at least one PTM, another ULM (ULM′), or at least one The binding sites of the chemical linker moieties that connect the PTM or ULM' or both to ULM are shown. vinegar.

[0115] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0116] [ka]

[0117] During the ceremony: W 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0118] [ka]

[0119] selected from the group consisting of: R9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R 9. R 10 and the carbon atoms to which they are attached are optionally Forming a substituted cycloalkyl; R 11 is an optionally substituted heterocyclic, an optionally substituted alkoxy, an optionally substituted helical, aryl, optionally substituted aryl;

[0120] [ka]

[0121] selected from the group consisting of: R 12 is selected from the group of H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted selected from the group of optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R 14a、 R 14b are each independently H, haloalkyl, or optionally substituted alkyl selected from the group consisting of: W 5 is selected from the group of phenyl or 5-10 membered heteroaryl; 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. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl (each independently optionally substituted); R 16 is independently selected from the group of H, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R 18 are independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, is selected from the group consisting of haloalkyl, haloalkoxy, or a linker; and p is 0, 1, 2, 3, or 4, and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

[0122] In certain embodiments, R 15 teeth,

[0123] [ka]

[0124] where R 17 is H, halo, optionally substituted C 3~6Cycloalkyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkenyl, and C 1~6 Haloalkyl and Xa is S or O.

[0125] In certain embodiments, R 17 is methyl, ethyl, isopropyl and cyclopropyl are selected.

[0126] In certain additional embodiments, R 15 is selected from the group consisting of:

[0127] [ka]

[0128] In certain embodiments, R 11 is selected from the group consisting of:

[0129] [ka]

[0130] In certain embodiments, ULM has a chemical structure selected from the following group:

[0131] [ka]

[0132] During the ceremony: R1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R 14ais H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R 15 H, halogen, CN, OH, NO 2、 optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl; and X is C, CH, or C=O. R3 is a bond or an optionally substituted 5- or 6-membered heteroaryl; and wherein the dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM (ULM-a). show.

[0133] In certain embodiments, a ULM comprises a group according to the following chemical structure:

[0134] [ka]

[0135] During the ceremony: R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 is H; R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclo butyl, cyclopentyl, or cyclohexyl; R 11 teeth,

[0136] [ka]

[0137] or optionally substituted heteroaryl; p is 0, 1, 2, 3, or 4; Each R 18 are independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkoxy, alkyl, haloalkyl, haloalkoxy or a linker; R 12 is H, C=O; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R 15 H, halogens, Cl, CN, OH, NO 2、 optionally substituted heteroaryl, optionally substituted aryl selected from the group consisting of:

[0138] [ka]

[0139] selected from the group consisting of: wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

[0140] In certain embodiments, ULM is selected from the following structures:

[0141] [ka]

[0142] In the formula, n is 0 or 1. In certain embodiments, ULM is selected from the following structures:

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] Here, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d2 The phenyl ring of ULM-d9 is optionally substituted with fluorine, lower alkyl, and alkoxy groups, where the dashed lines indicate the sites of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM-a.

[0148] In one embodiment, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, And the phenyl ring of ULM-d1 to ULM-d9 can be functionalized as an ester to make it part of a prodrug.

[0149] In certain embodiments, ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and the hydroxyl group on the pyrrolidine ring of ULM-d1 to ULM-d9 each contains an ester-linked prodrug moiety.

[0150] In any of the aspects or embodiments described herein, ULM and present ULM', if any, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof The entities are each independently a group conforming to the following chemical structure:

[0151] [ka]

[0152] During the ceremony: ULM-g R 1’ is an optionally substituted C1-C6 alkyl group, optionally substituted -(CH2) n OH, any Substituted with -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6) alkyl group, epoxide moiety Optionally substituted (CH2) containing WCOCW n -WCOCW-(C0-C6) alkyl group, wherein Each W is independently H or a C1-C3 alkyl group, optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)—(C1-C6 alkyl), optionally substituted —(CH2) n NHC(O)-R1, optionally substituted -(CH2) n C(O)-NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), optionally substituted —(CHO) nCOOH, optionally substituted -(OCH2) n O—(C1-C6 alkyl), optionally substituted —(CHO) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O)-R1, optionally substituted -(CHO) n C(O)-NR1R2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2) n O—(C1-C6 alkyl), optionally substituted —(CH2CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) n NHC(O)-R1, optionally substituted -(CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 of ULM-g are each independently H or a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). It is a base; ULM-g R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocyclic group, or -(CH2) m is an NR1R2 group; X and X' of ULM-g are each independently C=O, C=S, -S(O), or S(O)2 (preferably X and X' and X' are both C=O); ULM-g R 2’ is an optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w alkyl group, optionally substituted -(CH2) n-(C=O) u (NR1) v (SO2) w NR 1N R 2N group, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, any Substituted with -(CH2) n -(C=O) v NR1(SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) w-heterocycle, optionally substituted -X R2’ -Alkyl group; optionally substituted -X R2’ -aryl group; optionally substituted -X R2’ - heteroaryl group; optionally substituted -X R2’ -heterocyclic group; optionally substituted; ULM-g R 3’ is an optionally substituted alkyl 、 optionally substituted -(CH2) n -(O) u (NR1) v (SO2) w -alkyl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted Ru-(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted Ru-(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -alkyl, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted Ru-O-(CH2) n -(C=O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted —O—(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -O-(CH2)n -(C=O) u (NR1) v (SO2) w heteroaryl, or optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heterocycle;-(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, any optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted -(CH) n -(V) n’ -(CH2) n -(V) n’ -Complex ring group , optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -alkyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl group, optionally substituted -(CH) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclic group, optionally substituted -X R3’ - alkyl group; optionally substituted -X R3’ - an aryl group; optionally substituted -X R3’- heteroaryl group; optionally substituted -X R3’ - a heterocyclic group; optionally substituted; ULM-g R 1N and R 2N are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups or up to three halogen groups, or optionally substituted -(CH2) n -a Reel, -(CH2) n -heteroaryl, or -(CH2) n - a heterocyclic group; V of ULM-g is O, S, or NR1; R1 of ULM-g is the same as above; ULM-g R 1 and R 1’ are each independently H or a C1-C3 alkyl group; ULM-g X R2’ and X R3’ are each independently optionally substituted with - ( CH2) n -,- ( CH2) n -CH(X v )=CH(X v )-(cis or trans), - ( CH2) n -CH≡CH-, -(CHCHO) n - or C3-C6 cycloalkenyl is an alkyl group, wherein X v is H, halo, or an optionally substituted C1-C3 alkyl group; Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' in ULM-g is independently 0 or 1; Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w in ULM-g is independently 0 or 1; and ULM-g R 1’ , R 2’ , R 3’ wherein any one or more of X and X' are optionally modified to be covalently linked to the PTM group via a linker group if the PTM is not a ULM', and R of each of the ULM and ULM' if the PTM is a ULM'. 1’ , R 2’ , R 3’ , any one of X and X' The above are optionally modified and covalently linked to each other either directly or via a linker group.

[0153] In any of the aspects or embodiments described herein, ULM and present In some cases, ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvent thereof A solvate or polymorph is, independently, a group conforming to the following chemical structure:

[0154] [ka]

[0155] During the ceremony: ULM-h R 1’ , R 2’ and R 3’ are the same as above, and X is a C=O, C=S, or -S(O) group. or an S(O) group, more preferably a C=O group, and ULM-h R 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or to each of R of the ULM and ULM' if the PTM is a ULM'. 1’ , R 2’ , R 3’ One or more of the following: are optionally modified and are covalently linked to each other directly or via a linker group.

[0156] In any of the aspects or embodiments described herein, ULM and present In some cases, ULM', or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvent thereof The solvates or polymorphs each independently conform to the following chemical structure:

[0157] [ka]

[0158] wherein: R of ULM-I 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or to each of R of the ULM and ULM' if the PTM is a ULM'. 1’ , R 2’ , R 3’ Any one of One or more are optionally modified and covalently linked to each other directly or via a linker group.

[0159] In a further preferred embodiment of the present invention, R of ULM-g to ULM-i 1’ is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl group or a carboxylic acid group, thereby rendering the compound a prodrug form of the active compound. 1’ Examples of groups include -(CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), or optionally substituted —(CH2) n C(O)-O-(C1-C6 alkyl) In the formula, n is 0 or 1. 1’ is a carboxylic acid group, a hydroxyl group, or is or contains a hydroxyl group, carboxylic acid group or amine group, each of which may be optionally substituted, and the hydroxyl group, carboxylic acid group or amine may be further chemically modified to provide a covalent bond to a linker group that is attached to a PTM group (including a ULM' group); X and X′ of ULM-g and ULM-h, when present, are preferably C═O, C═S, —S(O) groups or is an S(O)2 group, more preferably a C=O group; ULM-g~ULM-i R 2’ is preferably an optionally substituted —NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or optionally substituted -NR 1 -T-heterocycle, wherein R 1 is H or CH, preferably H, and T is optionally substituted -(CH) n -Based wherein each one of the methylene groups is preferably selected from one or two substituents selected from halogen, an amino acid side chain as otherwise described herein, or a C1-C3 alkyl group. and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -It was and all of these groups are optionally substituted.

[0160] ULM-g~ULM-i R 2’ Preferred aryl groups for the The phenyl or naphthyl group can be attached to a PTM group (including a ULM′ group) by a linker group, a halogen (preferably F or Cl), an amino group, or a methyl group. and / or F, Cl, OH, 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 (which itself is optionally linked to a PTM group (including a ULM' group) via a linker group), and / or F, Cl, OH, COOH, 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). at least one of the following: optionally substituted naphthyl group, optionally substituted heteroaryl, preferably optionally substituted isoxazole including methyl substituted isoxazole, optionally substituted oxazole including methyl substituted oxazole, optionally substituted thiazole including methyl substituted thiazole, optionally substituted isothiazole including methyl substituted isothiazole, optionally substituted pyrrole including methyl substituted pyrrole, optionally substituted imidazole including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximi optionally substituted diazole groups including methyldiazole groups; optionally substituted triazole groups including methyl-substituted triazole groups; optionally substituted pyridine groups including halo- (preferably F) or methyl-substituted pyridine groups or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen); optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), optionally substituted quinoline, optionally linked via an optionally substituted group according to the chemical structure.

[0161] [ka]

[0162] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, such as oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably having a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, or morpholine (each of which groups, when substituted, is preferably Preferably, the group is substituted with methyl or halo (F, Br, Cl), each of which groups is linked to a linker group. a PTM group (including a ULM′ group) via a cleavage site.

[0163] In certain preferred embodiments, ULM-g through ULM-i are:

[0164] [ka]

[0165] and In the formula, R of ULM-g to ULM-i PRO is the same as above.

[0166] ULM-g~ULM-i of R 2’ Preferred heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3-, or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or a group according to the following chemical structure:

[0167] [ka]

[0168] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R of ULM-g to ULM-i a is H or C1-C6 an acetylene group, which is an alkyl group (preferably C1-C3 alkyl); ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C-C alkyl (preferably H or C-C alkyl), or —C(O)(C-C alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); , each of which groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0169] ULM-g~ULM-i of R 2’ Preferred heterocyclic groups for include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which may be optionally substituted or may be a group conforming to the following chemical structure:

[0170] [ka]

[0171] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1). and each of these groups can be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0172] Preferred R of ULM-g to ULM-i 2' The substituents include those described in the specific compounds disclosed herein ( R found in2' Substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). 2' Each of the substituents may be any number of R 3’ They may be used in conjunction with substituents, which are also disclosed herein.

[0173] ULM-g~ULM-i R 3’ is preferably an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted -T-heterocycle, an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle, where R 1 is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted Reru-(CH2) n - group, wherein each one of the methylene groups is preferably selected from a halogen, a C1-C3 alkyl group, or the side chain of an amino acid as otherwise described herein. It may be optionally substituted with one or two substituents, preferably optionally substituted methyl; and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - may be a base Each of these groups is optionally substituted.

[0174] ULM-g~ULM-i of R 3' Preferred aryl groups for the and a phenyl or naphthyl group, preferably a phenyl group, in which case the phenyl or naphthyl group may be linked to a linker group and / or a halogen (preferably F or Cl). ), amines, mono- or dialkylamines (preferably dimethylamine), amide groups (preferably -(CH2) m -NR1C(O)R2, where m, R1 and R2 are as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN or is S(O)2R S Group (R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or or heterocyclic group, or (CH2) m NR1R2 groups), each of which is an aryl group on a phenyl ring and optionally bonded to a PTM group (including a ULM' group) via an aryl (preferably phenyl), heteroaryl, or heterocycle. Preferred phenyl groups of the substituents are optionally substituted phenyl groups (i.e., the phenyl group of the substituent is itself preferably substituted with at least one of F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or a linker group). These groups are attached to PTM groups (including ULM' groups), where substitution occurs at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), naphthyl groups which may be optionally substituted including those described above, optionally substituted heteroaryls (preferably optionally substituted isoxazoles including methyl substituted isoxazoles, optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted pyrroles including methyl substituted pyrroles, methylimidazoles, optionally substituted imidazoles including benzylimidazoles or methoxybenzylimidazoles, oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl substituted triazole groups, halo (preferably F) or methyl substituted and optionally substituted heterocycles (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane). Each aryl, heteroaryl, or heterocycle group may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0175] ULM-g~ULM-i R 3' Preferred heteroaryl groups for are optionally substituted aryl groups. Quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted (CH m -O-C1-C6 alkyl group, or optionally substituted (CH2) m 1,2,3-Triazo substituted with -C(O)-O-C1-C6 alkyl group pyridine (2, 3, or 4-pyridine), optionally substituted pyridine, or a group according to the following chemical structure:

[0176] [ka]

[0177] During the ceremony: ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C-C alkyl (preferably H or C-C alkyl), or —C(O)(C-C alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and ULM-g~ULM-i Y C is N or CR YC where RYC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably one or two hydroxy groups), hydroxyl groups or up to three halo groups (e.g., CF3), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group, which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl). Each of said heteroaryl groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0178] ULM-g~ULM-i of R 3’ Preferred heterocyclic groups for include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, or thiane, each of which may be optionally substituted or may be a group conforming to the following chemical structure:

[0179] [ka]

[0180] During the ceremony: ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, such as oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably having a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group, and each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of said heterocyclic groups can be optionally attached to a PTM group (including a ULM' group) via a linker group.

[0181] Preferred R of ULM-g to ULM-i 3' The substituents include those described in the specific compounds disclosed herein ( R found in 3' Substituents are also specifically mentioned (but are not limited to the particular compounds disclosed). 3’ Each of the substituents may be any number of R 2’ Substituents may also be used in conjunction with the is disclosed in the book.

[0182] In certain other preferred embodiments, R of ULM-g to ULM-i 2’ is an optionally substituted -NR1-X R2’ -Alkyl group, -NR1-X R2’ -aryl group; optionally substituted -NR1- X R2’ -HET, optionally placed Converted to -NR1-XR2’ -aryl-HET or optionally substituted -NR1- X R2’ -HET-aryl and During the ceremony: R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H); ULM-g~ULM-i X R2’ is optionally replaced by - ( CH2) n -,- ( CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group; and ULM-g~ULM-i X v is H, halo, or optionally one or two hydroxyl groups or a C1-C3 alkyl group substituted with up to three halogen groups; The alkyl of ULM-g to ULM-i is optionally substituted C1-C 10 Alkyl (preferably C1-C6 alkyl) (in certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); Aryl of ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each, if substituted, preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according to the following structure:

[0183] [ka]

[0184] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, such as oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably having a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0185] Each of the foregoing groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0186] In another specific preferred embodiment of the present invention, R of ULM-g to ULM-i 3’ is an optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -R S3’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -R S3’ group, optionally substituted -X R3’ -alkyl group, optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group, or Optionally replaced -X R3’-HET-aryl group, During the ceremony: R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), an optionally substituted aryl group or a HET group; R 1’ is H or a C1-C3 alkyl group (preferably H); V is O, S or NR 1’ and; X R3’ is -(CH2) n -, -(CH2CH2O) n -,- ( CH2) n -CH(X v )=CH(X v )- (cis or trans), - ( CH2) n -CH≡CH-, or a C3-C6 cycloalkyl group, all of which are optionally substituted; X v is H, halo, or optionally one or two hydroxyl groups or up to three halo groups a C1-C3 alkyl group substituted with an halogen group; Alkyl is an optionally substituted C-C 10 an alkyl (preferably C1-C6 alkyl) group ( In certain preferred embodiments, the alkyl group is terminated with a halo group, often Cl or Br); Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); and HET is an optionally substituted oxazole, isoxazole, thiazole, or isothiazole. , imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pi Lysine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each preferably a C1-C3 alkyl group when substituted), preferably substituted with methyl, or halo groups, preferably F or Cl), or is a group that conforms to the structure:

[0187] [ka]

[0188] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, such as oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably having a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' in ULM-g through ULM-i is 0 or 1; and Each n' in ULM-g to ULM-i is 0 or 1; wherein each of the above compounds, preferably an alkyl group, an aryl group or a Het group, is optionally , is attached to a PTM group (including a ULM' group) via a linker group.

[0189] In another embodiment, R of ULM-g to ULM-i 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET or -(CH2CH2O) n -HET, During the ceremony: The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, in which case the substituents are preferably —(CH) n OH, itself CN, Halo (the most (large with three halo groups), OH, -(CH2) n O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) C1-C6 alkyl optionally further substituted with alkyl)amine, wherein the alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or The aryl group of ULM-g to ULM-i is —(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n-(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6) alkyl, amine, substituted with mono- or di-(C1-C6 alkyl), where the alkyl group of the amine is substituted with one or two hydroxyl groups, or up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG groups, where V is O, S, or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), R PEG is H or an optionally substituted C1-C6 alkyl group (including one optionally substituted with a carboxyl group), or The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each is preferably C1-C3 aryl). alkyl groups, preferably methyl, or halo groups, preferably F or Cl), or or optionally substituted with a heterocycle, including heteroaryl, selected from the group consisting of groups conforming to the structure:

[0190] [ka]

[0191] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YCis H, OH, 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(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted Aryl (phenyl or naphthyl), heteroaryl or heterocyclic groups, such as oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably having a C1-C3 alkyl group, preferably methyl groups, or halo groups, preferably substituted with F or Cl), benzofuran, indole selected from the group consisting of dhole, indolizine, and azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isobutanol, or thiazole. thiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the following structure:

[0192] [ka]

[0193] ULM-g~ULM-i S c is CHR SS , N.R. URE or O; ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups), an optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably an acetylene group, preferably C1-C3 alkyl; ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably containing one or two hydroxyl groups or up to three halo groups). optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); (substituted with a halo group of the formula: ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C1-C6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo group), or an optionally substituted acetylenic group -C≡CR a wherein , R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); ; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; Each m' in ULM-g through ULM-i is independently 0 or 1; and each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); wherein preferably each of said compounds of said aryl group or HET group optionally comprises a linker is bonded to a PTM group (including a ULM' group) via a - group.

[0194] In yet additional embodiments, preferred compounds include those according to the following chemical structure, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof:

[0195] [ka]

[0196] During the ceremony: ULM-i R 1’ is OH or a group that is metabolized to OH in the patient or subject; ULM-i R 2’ is -NH-CH-aryl-HET- (preferably a phenyl directly attached to a methyl substituted thiazole); ULM-i R 3’ is -CHR CR3’ -NH-C(O)-R 3P1 group or -CHR CR3’ -R 3P2 It is a base; ULM-i R CR3’ is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl Chill; ULM-i R 3P1 is a C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably a methyl-substituted —(CH2) n OCH3 group, where n is 1 or 2 (preferably 2). ), or

[0197] [ka]

[0198] (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (attached to the carbonyl at the 2- or 3-position); ULM-i R 3P2 teeth,

[0199] [ka]

[0200] and; The aryl of ULM-i is phenyl; HET of ULM-i is an optionally substituted thiazole or isothiazole; and ULM-i R HET is H or a halo group (preferably H); In this case, the compounds are each optionally attached to a PTM group (including a ULM' group) via a linker group.

[0201] In certain embodiments, a ubiquitin E3 ligase binding moiety (ULM) is Sensuality sexual compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein the ULM is a group according to the following chemical structure:

[0202] [ka]

[0203] During the ceremony: each R5 and R6 of ULM-j is independently OH, SH, or optionally substituted alkyl; or R5, R6 and the carbon atom to which they are attached form a carbonyl; R7 of ULM-j is H or optionally substituted alkyl; E of ULM-j is a bond, C=O, or C=S; G of ULM-j is a bond, optionally substituted alkyl, —COOH, or C═J; J of ULM-j is O or N-R8; R8 of ULM-j is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or

[0204] [ka]

[0205] and; R9 and R of ULM-j 10 are independently H, optionally substituted alkyl, optionally substituted cyclo is an optionally substituted hydroxyalkyl, an optionally substituted thioalkyl, a disulfide-linked ULM, an optionally substituted heteroaryl or haloalkyl; ,or R 9. R 10 and the carbon atom to which they are attached is optionally substituted cycloalkyl. Forming a le; ULM-j R 11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

[0206] [ka]

[0207] and R of ULM-j 12 is H or optionally substituted alkyl; ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate; Each R of ULM-j 14 are independently H, haloalkyl, optionally substituted cycloalkyl, is a substituted alkyl or an optionally substituted heterocycloalkyl; ULM-j R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R of ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; Each R of ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 the groups may be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH; Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; and The o in ULM-j is 0, 1, 2, 3, or 4.

[0208] In certain embodiments, G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and o is 0.

[0209] In certain embodiments, G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and R 15 is an optionally substituted heteroaryl and o is 0. In other examples, E is C=O and M is

[0210] [ka]

[0211] is. In certain embodiments, E of ULM-j is C=O and R 11 is an optionally substituted heterocyclic or

[0212] [ka]

[0213] and M is

[0214] [ka]

[0215] is. In certain embodiments, E of ULM-j is C=O and M is

[0216] [ka]

[0217] and R 11 teeth

[0218] [ka]

[0219] or

[0220] [ka]

[0221] and each R 18 are independently halo, optionally substituted alkoxy, cyano, optionally substituted and p is 0, 1, 2, 3, or 4.

[0222] In certain embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0223] [ka]

[0224] During the ceremony: The G of ULM-k is C=J, where J is O; R7 of ULM-k is H; each R of ULM-k is H 14 is H; ULM-k's o is 0; ULM-k R 15 teeth

[0225] [ka]

[0226] and ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl , optionally substituted alkenyl, and haloalkyl.

[0227] In another example, the R 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0228] In other embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0229] [ka]

[0230] During the ceremony: The G of ULM-k is C=J, where J is O; R7 of ULM-k is H; Each R of ULM-k 14 is H; o of ULM-k is 0; and ULM-k R 15 is selected from the group consisting of:

[0231] [ka]

[0232] In other embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0233] [ka]

[0234] During the ceremony: E of ULM-k is C=O; The M in ULM-k is

[0235] [ka]

[0236] and ULM-k R 11 is selected from the group consisting of:

[0237] [ka]

[0238] In yet another embodiment, a compound of the following chemical structure:

[0239] [ka]

[0240] During the ceremony: E of ULM-k is C=O; ULM-k R 11 teeth

[0241] [ka]

[0242] and The M in ULM-k is

[0243] [ka]

[0244] and; ULM-k, q is 1 or 2; ULM-k R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally aryl substituted with, or

[0245] [ka]

[0246] and; ULM-k R 21 is H or optionally substituted alkyl; and ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or halo. It is a hydroxyalkyl.

[0247] In any embodiment described herein, R of ULM-j or ULM-k 11 is from below Selected from the group consisting of:

[0248] [ka]

[0249] [ka]

[0250] In certain embodiments, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0251] [ka]

[0252] [ka]

[0253] In certain embodiments, ULM (or ULM′, when present) is a group according to the following chemical structure:

[0254] [ka]

[0255] During the ceremony: X of ULM-l is O or S; Y of ULM-l is H, methyl or ethyl; ULM-l R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0256] [ka]

[0257] and; R9 of ULM-l is H; ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl; ULM-l R 11 is an optionally substituted heteroaromatic, an optionally substituted heterocyclic, an optionally substituted aryl, or

[0258] [ka]

[0259] and; ULM-l R 12 is H or optionally substituted alkyl; and ULM-l R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate.

[0260] In some embodiments, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0261] [ka]

[0262] During the ceremony: Y in ULM-m is H, methyol, or ethyl R9 of ULM-m is H; R 10is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocycle.

[0263] In another preferred embodiment of the invention, ULM, and, if present, ULM′, are each independently In other words, it is a group according to the following chemical structure:

[0264] [ka]

[0265] During the ceremony: ULM-n R 17 is methyl, ethyl, or cyclopropyl; and ULM-n R9, R 10 , and R 11 is as defined above. In other examples, R9 is H; and ULM-n R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0266] In any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Further, in any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be attached to a PTM directly via a bond or by a chemical linker.

[0267] In certain embodiments of the invention, the ULM moiety is selected from the group consisting of:

[0268]

change

[0269]

change

[0270]

change

[0271]

change

[0272]

change

[0273]

change

[0274]

change

[0275]

change

[0276]

change

[0277]

change

[0278]

change

[0279]

change

[0280]

change

[0281]

change

[0282]

change

[0283]

change

[0284]

change

[0285]

change

[0286]

change

[0287]

change

[0288]

change

[0289] [ka]

[0290] [ka]

[0291] In this case, the VLM may be attached to the PTM via a linker as described herein, optionally via any suitable functional group, such as an amine, ester, ether, alkyl, or alkoxy, at any suitable location, including, for example, the phenyl of an aryl, heteroaryl, phenyl, or indole group.

[0292] Example CLM: In any aspect or embodiment described herein, the description provides compounds useful for binding and / or inhibiting cereblon (e.g., the ULM is a CLM, the PTM is a CLM, or both the ULM and PTM are CLM).

[0293] In some embodiments, the ULM is thalidomide, lenalidomide, pomalidomide, or and CLM, which is an analog, an isostere thereof, or a derivative thereof.

[0294] Neo-imide compounds In certain embodiments, the CLM is selected from the group consisting of the following chemical structures:

[0295] [ka]

[0296] During the ceremony: W is selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl; each X is independently selected from the group consisting of O, S, and H2; Y is CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl , N-heterocyclyl, O and S; Z is selected from the group consisting of O, S, and H2; G and G' are independently selected from H, alkyl (linear, branched chain optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and substituted benzyl; Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the group H, alkyl, cycloalkyl, Cl, and F; R is -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -hetaryl, -alkyl (optionally substituted straight or branched chain), -cyclohexyl, ... including, but not limited to, chloroalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, or -OCF3; R' and R" are independently a bond, H, N,N-oxide, alkyl (straight or branched chain), cycloalkyl, or alkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, or heterocyclyl and selected from the group consisting of:

[0297] [ka]

[0298] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains a functional group or atom, wherein n is an integer from 1 to 4, and If n is 1, R n is modified to be covalently attached to a linker group (L), and If n is 2, 3, or 4, one R n is modified to be covalently attached to a linker group (L), and any other R n is optionally covalently linked to a PTM, a CLM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof. It will be modified to

[0299] Exemplary CLM In any of the compounds described herein, the CLM may have a chemical structure selected from the group consisting of: Construction includes:

[0300] [ka]

[0301] During the ceremony: W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl; X is independently selected from the group O, S, and H2; Y independently represents CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cyclo selected from the group alkyl, N-heterocyclyl, O and S; Z is independently selected from the group of O, and S or H2, provided that both X and Z cannot be H2; G and G' are independently selected from H, alkyl (linear, branched chain optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and is selected from the group of substituted benzyl; Q1 to Q4 represent carbon atoms C substituted with groups independently selected from R', N, or N-oxide. ; A is independently selected from the group H, alkyl, cycloalkyl, Cl, and F; R includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -hetaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR 'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, or -OCF3 R' and R" are independently a bond, H, N,N-oxide, alkyl (straight or branched chain), cycloalkyl, or alkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, or heterocyclyl and selected from the group consisting of: n is an integer from 1 to 4;

[0302] [ka]

[0303] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independent functional groups or atoms, and optionally one of which is modified to be an ABM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof. Covalently bonded.

[0304] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the following group:

[0305] [ka]

[0306] During the ceremony: W is independently selected from the group CH2, C=O, NH and N-alkyl; R is independently selected from H, methyl, and alkyl;

[0307] [ka]

[0308] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independently selected functional groups or atoms, one of which is optionally modified to covalently bond to a PTM, a chemical linker group (L), a CLM (or CLM'), or a combination thereof.

[0309] In some embodiments, the CLM is represented by the following structure, with the dashed line indicating the linker attachment point:

[0310] [ka]

[0311] More specifically, non-limiting examples of CLMs include those shown below, as well as those molecules These include "hybrid" molecules resulting from the combination of one or more of the different properties exhibited in It can be obtained.

[0312] [ka]

[0313] [ka]

[0314] [ka]

[0315] [ka]

[0316] [ka]

[0317] [ka]

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321] [ka]

[0322] In any of the compounds described herein, the CLM may have a chemical structure selected from the group consisting of: Construction includes:

[0323] [ka]

[0324] [ka]

[0325] During the ceremony: W in formulas (h) to (ab) is independently selected from CH, CHR, C=O, SO, NH, and N-alkyl; Q1, Q2, Q3, Q4, and Q5 in formulas (h) to (ab) are independently selected from R', N, and N-oxide. represents a carbon C substituted with a group selected from the group R in formula (h) to formula (ab) 1 is selected from H, CN, C1-C3 alkyl; R in formula (h) to formula (ab) 2 is selected from the group consisting of H, CN, C1-C3 alkyl, CHF2, CF3, and CHO; R in formula (h) to formula (ab) 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R in formula (h) to formula (ab) 4 is selected from H, alkyl, and substituted alkyl; R in formula (h) to formula (ab) 5 is H or lower alkyl; X in formulas (h) to (ab) is C, CH, or N; R' in formulas (h) to (ab) is H, halogen, alkyl, substituted alkyl, alkoxy, substituted selected from alkoxy; R in formulas (h) to (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower The alkyl group is preferably lower alkyl, lower alkoxy, or halogenated lower alkyl. Equations (h) to (ab)

[0326] [ka]

[0327] teeth , a single bond or a double bond; and The CLM is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0328] In any aspect or embodiment described herein, CLM or CLM′ may be represented by the formula (h ) to the R group of formula (ab) (e.g., R, R 1 , R 2 , R 3 , R 4 or R'), W, X, or Q groups (e.g. , Q1, Q2, Q3, Q4, or Q5) to a PTM, chemical linker group (L), ULM, CLM, CLM', or combination thereof.

[0329] In any of the embodiments described herein, CLM or CLM′ is a group represented by the formula (h )~W, X, R, R in formula (ab) 1 , R 2 , R 3 , R 4 , R 5 , R', Q1, Q2, Q3, Q4, and Q5, are covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM', or a combination thereof. do.

[0330] In any of the embodiments described herein, W, X, R of formula (h) to formula (ab) 1 , R 2 , R 3 , R 4R', Q1, Q2, Q3, Q4, and Q5 may independently be covalently attached to a linker. and / or a linker bonded to one or more PTM, ULM, ULM', CLM or CLM' groups. The hydroxyl group may be covalently attached to the anchor.

[0331] More specifically, non-limiting examples of CLMs include the following compounds: These include "hybrid" molecules or compounds resulting from the combination of one or more properties of Can be:

[0332] [ka]

[0333] [ka]

[0334] During the ceremony: W in formula (ac) to formula (an) is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl. Selected; R in formula (ac) to formula (an) 1 is selected from the group consisting of H, CN, and C1-C3 alkyl; R in formula (ac) to formula (an) 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R in formula (ac) to formula (an) is H;

[0335] [ka]

[0336] is a single or double bond; and Rn in formulae (ac) to (an) includes a functional group or atom.

[0337] In any of the embodiments described herein, W, R in formula (ac) to formula (an) 1 , R 2 , Q1, Q2, Q3, Q4, and Rn may independently be covalently linked to a linker, and / or or covalently attached to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups. They may be combined.

[0338] In any of the embodiments described herein, R of Formula (ac) to Formula (an) 1 , R 2 , Q1 Q2, Q3, Q4, and Rn may independently be covalently bonded to a linker; and / or is covalently attached to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups. This may also be done.

[0339] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn of formula (ac) through formula (an) may independently be covalently bonded to a linker and / or one or more may be covalently attached to a linker that is attached to a PTM, ULM, ULM', CLM or CLM' group above. stomach.

[0340] In any aspect or embodiment described herein, R of Formula (ac) to Formula (an) n is modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0341] In any aspect or embodiment described herein, the CLM is selected from: R:

[0342] [ka]

[0343] where R' is a halogen and R 1 is as described above for formulas (h) to (ab) or formulas (ac) to (an).

[0344] In certain instances, the CLM may be an imide that binds to cereblon E3 ligase. These imide and linker attachment points may be, but are not limited to, the following structures:

[0345] [ka]

[0346] wherein R' is a halogen. Exemplary linkers: In any of the aspects or embodiments comprising the structure of a ULM-L-PTM, the linker (L) comprises a chemical structural unit represented by the following formula: -(A) q -, During the ceremony: A is a group linked to a ULM moiety or a PTM moiety; and q is an integer equal to or greater than 1, In the formula, A is a bond, 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 , 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), NRL3 C(=CNO2)NR L4 , 0 to 6 R L1 Groups and / or R L2 Optionally substituted with a group C 3-11 Cycloalkyl, 0 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 6 R L1 Groups and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 Groups and / or R L2 and heteroaryl optionally substituted with a group. In the formula, R L1 or R L2 are each independently optionally bonded to each other, 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, or C 1-8 Alkyl, OC 1-8 Alkyl , SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 cycloalkyl , N.H.C. 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl) SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0347] In any aspect or embodiment described herein, the linker (L) may be: Chemical structure including:

[0348] [ka]

[0349] During the ceremony: W L1 and W L2 are each independently, RQ 4 with 0-4 heteroatoms, optionally substituted with 8-membered ring, and each R Q are independently H, halo, OH, CN, CF, C-C alkyl (optionally substituted straight or branched chain), C-C alkoxy (optionally substituted straight or branched chain); or two R's Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, C1-C6 alkyl (optionally substituted straight chain, branched chain), and optionally one or more C atoms are O, or C1-C6 alkoxy (optionally substituted straight chain, branched chain), , branched chain); and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0350] In any aspect or embodiment described herein, the linker (L) may be: Chemical structure including:

[0351] [ka]

[0352] During the ceremony: W L1 and W L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1~6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally containing R Q Each R is replaced by Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2~6 Alkenyl, C 2~6 Alkynyl, C1-C6 alkyl (optionally substituted straight chain, Branched chain), C1-C6 alkoxy (optionally substituted straight or branched chain), OC 1~3 Alkyl(mono) (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN or two R Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms is substituted with O, C1-C6 alkoxy (optionally substituted straight chain, branched chain); Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 R Q Each R is replaced by Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 substituted with alkoxyl) or two R Q groups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight or branched chain, optionally with one or more halo, C 1-6 substituted with alkoxyl) or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0 to 10; and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0353] In some embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -N(R)-(CH2) m -O(CH2) n-O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[0354] [ka]

[0355] wherein m, n, o, p, q, and r are each independently 0, 1, 2, 3, 4, 5, or 6; provided that if the number is zero and there are no N-O or O-O bonds, then R is selected from the group H, methyl, or ethyl, and X is selected from the group H or F;

[0356] [ka]

[0357] [ka]

[0358] [ka]

[0359] [ka]

[0360] [ka]

[0361] [ka]

[0362] In some additional embodiments, the linker (L) is selected from the group consisting of:

[0363] [ka]

[0364] [ka]

[0365] [ka]

[0366] In some preferred embodiments, the linker (L) is selected from the group consisting of:

[0367] [ka]

[0368] [ka]

[0369] [ka]

[0370] [ka]

[0371] [ka]

[0372] [ka]

[0373] [ka]

[0374] [ka]

[0375] [ka]

[0376] [ka]

[0377] [ka]

[0378] [ka]

[0379] [ka]

[0380] wherein each n and m is independently 0, 1, 2, 3, 4, 5, or 6. In some embodiments, L is an optionally substituted polyethyleneoxy group containing 1 to 10 units.

[0381] In some additional embodiments, L is a polyethylene group optionally substituted with aryl or phenyl, comprising 1 to 10 ethylene glycol units.

[0382] In any embodiment, the compound comprises multiple ULMs, multiple PTMs, multiple linkers, or any combination thereof.

[0383] Exemplary Tau-PROTAC Compounds As noted above, in certain embodiments, the present disclosure provides a method for the production of at least one PTM as described herein. a linker, and at least one ULM (VLM or CLM) group. Sensuality The present invention provides a novel PROTAC compound.

[0384] In certain embodiments, the compound is selected from the group consisting of compounds 1-330 (eg, compounds selected from Tables 1 or 2), and salts and polymorphs thereof.

[0385] In certain embodiments, the compound is selected from Table 1 or Table 2 (ie, the compound is selected from Compounds 1-330), and salts and polymorphs thereof.

[0386] In any aspect or embodiment described herein, the compound is selected from the following formulae CI-CV:

[0387] [ka]

[0388] [ka]

[0389] 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 Selected; 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 , R122 and R 123 are each independently H, alkyl, halogen, or haloalkyl; Selected from; R 108 are independently selected from H, alkyl, halogen, haloalkyl, cyano, or methoxy. 1 to 2 substituents selected from the group consisting of 1 to 2 R 115 is selected from H, alkyl and haloalkyl; R 118 and R 119 are independently selected from H, alkyl, halogen, or haloalkyl or R 118 and R 119 together with the carbon atoms to which they are attached represent a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, such as, for example, cyclopropane or oxetane; R 124 and R 125 are independently selected from H, alkyl, halogen, or haloalkyl or R 124 and R 125 together with the carbon atoms to which they are attached represent a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, such as, for example, cyclopropane or oxetane; G is phenyl or a 5- or 6-membered heteroaryl ring; and Z is CH2 or C=O.

[0390] In any aspect or embodiment described herein, at least one of the following: 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 and; 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 or CH3; R 111 and R 112 are each independently H, F, or CH3; R 113 and R 114 are each independently H or CH3; R 115 is H or CH3; R 116 and R 117 are each independently H or CH3; R 118 and R 119 are each independently H, CH3, F, or R 118 and R 119 is that 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 or CH3; R 122 and R 123 are each independently H or CH3; R 124 and R 125 are each independently H, CH3, F, or R 124 and R 125 is that 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 or CH3; A is pyridine or pyrimidine; Z is CH2 or C=O; or A combination of them.

[0391] In any aspect or embodiment described herein, the compound is selected from the group consisting of: (2S,4R)-1-((S)-14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1); 4-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2); 4-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3); 4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4); (2S,4R)-1-((S)-2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)acetamido)-3,3- (2S,4R)-1-((S)-17-(5-(5H-pyrido[4,3-b]indole-7-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (5); (2S,4R)-1-((S)-17-(5-(5H-pyrido[4,3-b]indole-7-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (5); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azaheptanecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (6); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- Carboxamide (7); (2S,4R)-1-((S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl) (I)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azapentadecane)-4-hydroxy (2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (9); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (10); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (11); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (12); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (13); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecano yl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxylate Voxamide (14); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl) (I)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecane (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]phenyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (15); ...)); pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (16); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (16) (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydrogen 2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carbo (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (19); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (19) (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (20); (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydrogen hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylate Ruboxamide (22); (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidine-2- (2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidinyl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (23); ... (2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxo-2-(phenyl-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxo- 4-((2-(2-(2-(2-(4-(benzo[4,5]imidazo[1,2-a] Pyrimidin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (25); 4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-3,6,9,12-tetraoxate (2S,4R)-1-((S)-2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)phenyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26); (2S,4R)-1-((S)-2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)phenyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (27); (2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (29); (2S,4R)-1-((S)-2-tert-butyl-14-(2-(4 -(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)e (2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(diphenyl)-2-methyl-1,4-diphenyl ... Methylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3- (2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (31); (2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (32); (2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)methyl)ethyl)pyrrolidine-2-carboxamide (32); (2S,4R)-1-((S)-2-(2-(4-(dimethylamino)methyl)ethyl)pyrrolidine-2-carboxamide (32); (amino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl N-(4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxylate Boxamide (33); (2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (34); (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy) (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (35); (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)prop (S)-1-(4-(4-methyl-4-hydroxy-N-((4-hydroxy-3,3-dimethylbutanoyl)-4-hydroxy-N-( ...(S (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (37); (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (38); (ethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethyl (S)-1-(4-(4-methylthiazol-5-yl)phenyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethoxy (2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(diphenyl)-2-methyl-2-methyl-1 ... Methylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3- Azaoctadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) 4-(15-(2-(4-(dimethylamino)phenyl)-1,4-dichlorophenyl)-2-pyrrolidine-2-carboxamide (39); (2,6-dioxopyridine-6-yloxy)-3,6,9,12-tetraoxapentadecylamino)-2-( ... 4-((2-(2-(2-(2-(4-(benzo[4,5]i) midazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (41); 4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (42); (2S,4R)-1-((2S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-4-oxo-6,9,12-trioxa 3-Azapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pi loridine-2-carboxamide (43); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (44); 4-(15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2S,4R)-1-((2S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-3,6,9,12-tetraoxapentadecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (45); (2S,4R)-1-((2S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-17-hydroxy N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (46); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-2-hydroxypropoxy)ethoxy)-4-hydroxy-N ... 2-(2,6-dioxopiperidin-3-yl)-4-(14-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecyl)- ... 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-1-oxoisoindoline-1,3-dione (48); 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-1-oxoisoindoline-1,3-dione Indolin-2-yl)piperidine-2,6-dione (49); 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50); 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)o 5-((5-(4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)pi (perazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (52); 5-(4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-1,3-dione) (2,6-dioxopyrazin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopyrazin-2-yl) 5-((5-(4-(3-(5-(5H-pyrido[4,3-b] (indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (54); 5-(3-(6-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pi Lysin-3-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (55); 5-((5-(4-(2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6- 5-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)oxo 5-((5-(2-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazine-1- 5-((5-(4-(2-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-1,3-yl)ethoxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58); 5-((5-(4-(2-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-1,3-yl)ethoxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5-(4-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoromethyl)phenyl)- ... 3-(5-((5-(4-(3-(5-(5-methylethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione (61); 3-(5-((5-(4-(3-(5-(5-methyl 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (62); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl 5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (64); 5-((5-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperazin-3-yl)isoindoline-1,3-dione Lysin-3-yl)isoindoline-1,3-dione (65); 5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyridinyl) 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (67); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7-yl) 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-piperidin-3-yl)-2-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione (68); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-piperidin-3-yl)-2-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione (69); Lido[4,3-b]indol-7-yl)-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,6, 9,12-Tetraoxatetradecyl)oxy)isoindoline-1,3-dione (69); 2-(2,6-dioxatetradecyl)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (70); 2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetrahydrobenzoate 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetrahydroxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione (71); 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetrahydroxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione (2,6-dioxopiperidin-3-yl)-4,6,7-trifluoromethyl-2-(2,6-dioxotetradecyl)oxy Pyrindoline-1,3-dione (72); [5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indoline 2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione (74); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((5-(5-(5-methyl-5H- Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl) Piperidin-1-yl)isoindoline-1,3-dione (75); 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione -5-(3-(3-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)propoxy)azetidin-1-yl)isoindol Phosphorus-1,3-dione (76); 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl) Pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxy) 2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (77); 2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione (79); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione -5-((1-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azetidin-3-yl)oxy)isoindoline-1,3-di 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (81); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) 5-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (83); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 1r)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione (84); 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione (85); 4-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (86); 6-((14-((5-(5H-pyrido[4,3-b]indo 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (87); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)- 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-3-yl)oxy)isoindoline-1,3-dione (88); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-3-yl)oxy)isoindoline-1,3-dione (89); Lysin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoyl Indolin-1,3-dione (89); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)but-2-yn-1-yl)oxy)butoxy)butoxy)isoindoline-1,3-dione (90); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)octyl)piperazin-1-yl)isoindoline-1,3-dione (91); 5-((14-((3-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (92); 5-((6-((5-(2,2-difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)ethoxy)pentyl)oxy)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (93); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pi 2-(2,6-dioxopyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione (94); 5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)iso Indoline-1,3-dione (95); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutene 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H- Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (97); 2-(2,6-dioxo Piperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hexyl)oxy)i 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)silane (98); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)silane Chlorobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-di 2-(2,6-dioxopiperidin-3-yl)-5-(6-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione (100); 5-((1-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (101); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindo 5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (103); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (104); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy) Isoindoline-1,3-dione (105); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin-1-yl)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione (106); 2-(2,6- Dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)butoxy)butoxy)isoindoline-1,3-dione (107); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) Cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)iso Indoline-1,3-dione (108); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione (109); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione (110); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin- 5-((14-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxate (tradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (112); 5-((14-((4-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindoline-1,3-dione (114); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione (115); 2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butyl)-2-azaspiro[3.3]heptan-6-yl)oxy)isoindoline-1,3-dione (116); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl) (2-yn-1-yl)oxy)isoindoline-1,3-dione (117); 2-(2,6-dioxopipe Lysin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione (118); (2S,4R)-1-((S)-17-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-aza (heptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) (2S,4R)-1-((S)-2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)acetamido)-3,3-dimethyl (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) (2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (121); (2S,4R)-1-((S)-23-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (121) 4-hydroxy-N-((S)-1-(4-(4-methyl-2-pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azatricosanoyl)- ... Thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (122); 2-(2,6- Dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]i 3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-7-yl Peridine-1-yl)pentyl)oxy)isoindoline-1,3-dione (123); 2-(2,6-dioxo Piperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hex-5-yn-1-yl)oxy 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl) 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (125); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (125); Thiyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) Oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)i Soindoline-1,3-dione (126); 3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indoline) 3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127); 3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (128); 2-(2,6-dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexa 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (129); 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (129); 2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione (131); 2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione (131); 2-(2,6-Dioxopiperidin-3-yl)-5-((20-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15,18-hexaoxaicosyl)oxy)isoindole 2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-1,3-dione (133); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-1,3-dione (134); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione (135); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione (136); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione (137); 5-((14-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (138); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (139); 2-(2,6-Dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (140); 2-(2,6-Dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-. yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoi Indolin-1,3-dione (141); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione (142); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (143); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl -5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hexa-5-ynyloxy)isoindoline-1,3-dione (144); 2-(2,6-dioxo) isopiperidin-3-yl)-5-(6- (6-((1s,3s)-3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hexyloxy)isoindoline-1,3-dione (145); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hexa-5-yl 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (146); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hexyl)oxy)isoindoline-1,3-dione (147); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin- 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hexyl)oxy)isoindoline-1,3-dione] (149); 5-(6-(2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hexyl)oxy)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hexyl)oxy)isoindoline-1,3-dione (151); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione (152); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2,2,2-trifluoro-1-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione (154); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione (155); 2-(2,6-dioxopiperidin 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione (156); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy) Isoindoline-1,3-dione (157); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindolin 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione (159); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) Pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione (160); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione (161); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)butoxy)azetidin-1-yl)i Soindoline-1,3-dione (162); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-((1r, 3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)silyl Clobutoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione (163); 5-(6-(4-((1r,3r)-3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)piperidin-1-yl)-6-oxohexyloxy)-2-(2,6-dioxopiperidine 5-((5-((1-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidine (2,6-dioxopiperidin-3-yl)isoindoline Phosphorus-1,3-dione (165); 5-((5-((1-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indole-7-yl) (I)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pe 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-(3-((5-methyl-5H-pyrido[4,3-b] Indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propionyl 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azetidin-1-yl 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)o 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxo)cyclobutoxy)methyl)oxetan-3-yl)methoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (169); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxo Cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-di 5-((4,4-difluoro-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl) 5-((6-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (171); 5-((6-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclohexyl) (2,6-dioxopiperidine)hex-5-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-2-yl)hex-5-yn-1-yl)oxy 5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (172); 5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione (174); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione (175); 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (176); 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoin 2-(2,6-dioxopiperidin-3-yl)-5-(3-(((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)methyl)azetidin-1-yl)isoindoline-1,3-dione (178); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (179); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) pentyl)oxy)cyclobutoxy)pentyl)oxy)ethyl)azetidin-1-yl)isopropyl Indolin-1,3-dione (181); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol 5-((3-(5-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (183); 2-(2,6-dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione (184); (2S,4R)-N-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (185); (2S,4R)-N-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl) (2S,4R)-N-(2-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxo-1-yl)-2-methyl- Soyisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (187); 5-(2-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin- 5-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)prop-2-yl 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H- Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione (190); 2-(2,6-dioxo Piperidin-3-yl)-5-(3-((3-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)propoxy)methyl)azeta 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindoline-1,3-dione (192); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5- Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (193); 5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl) Pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy (2S,4R)-N-(2-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (195); (2S,4R)-N-(2-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (196); Do[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy (4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (196); 5-(6-((2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyrrolidine-2-carboxamide) Lysin-2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (197); 2-(2,6- Dioxopiperidin-3-yl)-5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (198); 3-((4-((2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)methyl 2-(2,6-dioxopiperidin-3-yl)-5-(3-((7-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)heptyl)oxy)azeti Zin-1-yl)isoindoline-1,3-dione (200); (2S,4R)—N-(2-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)piperidin Rolidin-2-carboxamide (201); 2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)azetidin-3-yl)methoxy)-N-methyl-N-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide (202); 2-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (203); 5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-difluoro 2-(2,6-dioxopiperidin-3-yl)-isoindoline-1,3-dione (204); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione (205); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione (Chlorobutoxy)ethoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindoline-1,3-dione (206); 5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin (2,6-dioxopiperidine-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidine 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (208); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5- Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) 2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione (210); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2- Azaspiro[3.3]heptan-2-yl)ethoxy)propoxy)azetidin-1-yl)isoindo Phosphorin-1,3-dione (211); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azetidin-1-yl)isoindoline-1,3-di 2-(2,6-dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl) Piperazin-1-yl)isoindoline-1,3-dione (214); 2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-(isopropyl(2-(3-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]i) androgen-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino) 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethoxy)piperidin-1-yl)isoindolin-1,3-dione (215); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethoxy)piperidin-1-yl)isoindolin-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-((2-(3-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy)isoindoline-1,3-dione (217); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(4-fluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (218); 3-(5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin (2-indolin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (220); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (221); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) pyrimidin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)pyrimidin 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (223); 3-(5-(3-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (224); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propionate 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-4,6-difluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (226); 3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutoxy 3-(5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutene oxy)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)-1-oxoisoindo 2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole 3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutyl)-1-oxoisoindolin-2-yl)pyridin-2-yl 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (231); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrazin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (232); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridyl Iodo[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidinyl 3-(5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indo) 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-yl)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (234); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-yl)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (235); -yl)oxy)ethoxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (235); 5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (236); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl) prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (237); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5- Methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile (238); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (239); 3-(5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (240); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2-oxo-1-yl)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoin 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (242); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (244); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione 2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (245); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione Indoline-1,3-dione (246); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine Lysine-2,6-dione (247); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutene 3-(5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-1-oxoisoindoline-1,3-dione (248); ... Indolin-2-yl)piperidine-2,6-dione (249); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2- yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)isoi Endrine-1,3-dione (250); 3-(5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b] indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (251); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin-1-yl)ethoxy)ethoxy) Ethoxy)ethoxy)isoindoline-1,3-dione (252); N-(2-((1-(2-(2,6-dioxopipene) Lysin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)ethyl)-N-methyl-4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butanamide (253); 2-(2,6-dioxopiperidin-3-yl) yl)-5-((1-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridyl 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethyl)azetidin-3-yl)oxy)isoindoline-1,3-dione (254); ... 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenoxy)azetidin-1-yl)isoindoline-1,3-dione (256); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(((1s,3s)-1-hydroxy 3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-di 2-(2,6-dioxopiperidin-3-yl)-5-(2-(9-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy)isoindoline-1,3-dione (257); 2-(2,6-dioxopiperidin-3-yl)-5-((4-(9-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)but-2-yn-1-yl)oxy)isoindoline-1,3-dione (259); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (260); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione (261); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione (262); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-((3-hydroxyphenyl) hydroxy-1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione (263); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((5'-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3'H-spiro[cyclobutane-1,2'-furo[2,3-b]pyridin]-3-yl)oxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione (264); 5-((14-((5-(6,8-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidine-3- 2-(2,6-dioxopiperidin-3-yl)-5-((14-((1-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione (266); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)cyclobutyl)ethoxy)azetidin-1-yl)isoindoline-1,3-dione (267); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((1S,2R)-2-((4-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)methyl)cyclopropyl) 2-(azetidin-1-yl)isoindoline-1,3-dione (268); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((1R,2R)-2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropyl)methoxy)butoxy)azetidin-1-yl)isoindoline-1,3-dione (269); 2 -(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(((1R,2R)-2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropan-1-yl 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl 5-(3-(3-(2,2-difluoro-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7-yl)methyl)cyclobutoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione (271); ... 5-(3-(2,2-diphenyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (272); Fluoro-3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin 2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (273); 2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (273); din-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7- 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propoxy)isoindoline-1,3-dione (274); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propoxy)isoindoline-1,3-dione 5-(2-((1,1-difluoro-3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (276); 3-(5-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (277); 3-(5-(((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) 3-(5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (278); 3-(5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b] Indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)buta-3- (2,6-dioxopiperidin-3-yl)isoin Indolin-1,3-dione (280); 5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (281); 3-(5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (282); 2-(2,6-Dioxopiperidin-3-yl)-5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione (283); 3-(5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione 5-(2-(2,2-difluoro-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-2-(2,6-dioxoisoindolin-2-yl)piperidine-2,6-dione (284); 5-(2-(2,2-difluoro-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-2-(2,6-dioxoisoindolin-2-yl)piperidine-2,6-dione (285); 2-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5H-pyrido[4,3-b]indol-7-yl) 3-(5-((3-(5-((1r,3r)-3-((3-methyl-5-(5H-pyrido[4,3-b] Indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propan-2 -yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (287); 3-(5-((3-(5-((1r,3r)-3-((5-(4-chloro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (287); 3-(5-((3-(5-((1r,3r)-3-((5-(4-fluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (289); 3-(5-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-di 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl bicyclo[1.1.1]pentan-1-yl)prop-2-yn-1-yl)oxy)ethoxy)isoin Indolin-1,3-dione (291); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutyl)prop-2-yn-1-yl)oxy)ethoxy)isopropyl Indolin-1,3-dione (292); 3-(5-(4-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indolin) 6-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (293); 6-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2,6-dione 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)biphenyl; Cyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione (295); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-1,3-dione) indol-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isoni Cotinonitrile (296); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl) indol-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isoni Cotinonitrile (297); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (298); 3-(5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop Pa-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6- Dione (299); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridine-2- yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (301); 6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclo butoxy)picolinonitrile (302); 6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile (303); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile (304) Cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoin Indolin-1,3-dione (304); 3-(5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (305); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (306); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (307); 2-(2,6-Dioxopiperidin-3-yl)-5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)isoindoline-1,3-dione (308); 3-(5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine Dine-2,6-dione (309); 3-(5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl) Cyclopropoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (310); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H- Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)isoindoline-1,3-dione (311); 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (312); 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop Pa-1-yn-1-yl)-2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indole-7-yl) 3-(5-((3-(4-methyl-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile (313); 3-(5-((3-(4-methyl-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yl 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (315); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl) Pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine Lysine-2,6-dione (316); 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl) indolin-5-yl)oxy)prop-1-yn-1-yl)-4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)nicotinonitrile (317); 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo soyisoindolin-5-yl)oxy)prop-1-yn-1-yl)-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pi Peridine-1-yl)benzonitrile (319); 3-(5-((3-(3-methyl-5-(4-((1r,3r)-3-((5-(5- Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) Piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (320); 3-(5-((3 -(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) (trifluoromethyl)phenyl)propan-1-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)propan-1-yl 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)pyridin-2,6-dione (321); 3-(5-((3-(4-(4-((1r,3r)-3-((5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2,6-dione) Lysin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pi Lysin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (323); 2-(2,6-dioxopiperidin-3-yl)-5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)but-3-yn-2-yl)oxy)isoindoline-1,3-dione (324); 3-(5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl 5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin (Peridine-1-yl)phenyl)but-3-yn-2-yl)oxy)-1-oxoisoindoline-2-yl 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (326); 3-(5-((1,1-difluoro-3-(4-(4-((1r,3r)-3-((5-(5- Methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) Piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoin 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (328); 6-(3-((2-(2,6-dioxopiperidine-3- yl)-1-oxoisoindolin-5-yl)oxy)-3-methylbut-1-yn-1-yl)-4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy) Cyclobutoxy)piperidin-1-yl)nicotinonitrile (329); 2-(3-(2-((2-(2,6-dioxo) 5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)-3-methylbut-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)-3-methylbut-1-yn-1-yl) Lysin-2-yl)oxy)cyclobutoxy)isonicotinonitrile (330).

[0392] The present specification includes compositions that include pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds of the present disclosure, where applicable.

[0393] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, where appropriate, one or more salt forms of the compounds described herein, which salt forms increase the solubility of the compound in the gastric juices of a patient's digestive tract, facilitating the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0394] The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds useful in the present disclosure are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, perphosphate, acetate, lactate, citrate, percitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose, among many others. The acid forms esters, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)].

[0395] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other base salts. Examples of pharmaceutically acceptable base salts of organic amines include:

[0396] Composition: In another aspect, the present disclosure provides compositions comprising a compound described herein, including salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0397] The amount of compound in the pharmaceutical composition of the present disclosure that can be combined with carrier materials to produce a single dosage form will vary depending on the host and disease being treated, and the particular mode of administration. Generally, an amount of active ingredient between 0.1 mg / kg body weight and 1000 mg / kg body weight per day is used depending on the efficacy of the agent. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. Compounds that exhibit toxic side effects are preferred. While compounds that exhibit toxic side effects can be used, care must be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to non-affected cells and limit side effects. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For any compound used in the disclosed methods, a therapeutically effective dose can be initially estimated from cell culture assays. Doses can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a 50% inhibition of symptoms) determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[0398] The compositions of the present disclosure can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can 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 proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixtures, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, wax, polyethylene- Examples include polyoxypropylene block polymers, polyethylene glycol, and wool fat. can be done.

[0399] In any of the aspects or embodiments described herein, the PTM, ULM, or both have an affinity (IC) for their respective target proteins of less than about 500 μM, 450 μM, 400 μM, 350 μM, 300 μM, 250 μM, 200 μM, 150 μM, 100 μM, 50 μM, 10 μM, 0.10 μM, 0.01 μM, 0.001 μM, 0.1 nM, 0.01 nM, 0.001 nM. 50 ) IC 50 Determination of can be performed using methods known to those of skill in the art in light of the present disclosure.

[0400] In any of the aspects or embodiments, the compounds described herein effect ubiquitination of a target protein at a level or amount sufficient to exert an effect on or induce degradation of the target protein.

[0401] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication, but which does not cause serious toxic effects in the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein range from about 10 ng / kg to 300 mg / kg, preferably from 0.1 to 100 mg / kg per day, more usually from 0.5 to about 25 mg per kg of recipient / patient body weight per day. Typical topical dosages can range from 0.01 to 5% wt / wt in a suitable carrier.

[0402] The compound is conveniently administered in any suitable unit dosage form, including but not limited to, containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of is often convenient.

[0403] The active ingredient is administered to a patient in need thereof at a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. It is preferable to administer the active ingredient in a manner that achieves a desired concentration. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline solution or aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for achieving an effective plasma concentration of the active agent.

[0404] The concentration of the active compound in the drug composition will depend on the absorption, distribution, inactivation, 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. Furthermore, it should be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once, or may be divided into multiple smaller doses to be administered at varying time intervals.

[0405] When administered intravenously, preferred carriers are saline or phosphate buffered saline (PBS )

[0406] In one embodiment, active compound is prepared with a carrier that protects compound from rapid excretion from the body, for example, controlled release formulations, including implants and microencapsulated delivery systems.For example, biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.The preparation method of such formulations will be clear to those skilled in the art.

[0407] Liposomal suspensions may also be pharmaceutically acceptable carriers. These are described, for example, in U.S. Pat. It can be prepared according to the method known to those skilled in the art, such as that described in No. 4,522,811 (incorporated herein in its entirety by reference).For example, liposome preparations can be prepared by dissolving suitable lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol, etc.) in an inorganic solvent, and then evaporating, leaving a thin film of dried lipid on the surface of the container.Then, an aqueous solution of active compound is added to the container.Then, the container is rotated by hand to remove lipid material from the side of the container, disperse lipid mass, and form a liposome suspension.

[0408] Mode of administration In any of the aspects or embodiments described herein, the therapeutic compositions comprising the compounds described herein may be in any suitable dosage form adapted to be delivered by any suitable route. The compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, for example, transdermally in liquid, cream, gel, or solid form, rectally, nasally, buccally, vaginally, or via an implanted reservoir, or in aerosol form.

[0409] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0410] The compounds described herein may be administered orally, parenterally, or topically, in a single dose or in divided doses. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID), and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, sublingual, and suppository administration, among other routes of administration. Enteric-coated oral tablets may 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 agent selected and the severity of the patient's disease.

[0411] Compounds can be administered as sprays, mist or aerosols for intranasal administration, intratracheal administration or pulmonary administration.The compounds described herein can be administered in immediate release, intermediate release, sustained release or controlled release form.Sustained release or controlled release form is preferably administered orally, but can also be administered via suppository, transdermal or other topical forms.Intramuscular injection of liposomes can be used to control or maintain the release of compound at injection site.

[0412] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be employed, 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 oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helvetica or similar alcohols.

[0413] The pharmaceutical compositions described herein may be in the form of, but not limited to, capsules, tablets, aqueous suspensions or water. Any orally acceptable dosage form, including a solution, may be orally administered. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are necessary for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added. Oral compositions will generally contain an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be combined with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials are included as part of the composition.

[0414] Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid, Primogel, or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty acid. Furthermore, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as sugar coatings, shellac, or enteric agents.

[0415] 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 / or certain preservatives, dyes and colorings, and flavors.

[0416] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore will melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0417] The pharmaceutical compositions of the present disclosure may be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected with a rectal suppository formulation (see above) or a suitable enema. A topically acceptable transdermal patch may also be used. For topical application, the pharmaceutical composition may be formulated with a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred embodiments of the present disclosure, the compound may be coated onto a stent that is surgically implanted in a patient, thereby preventing or reducing the likelihood of the stent becoming occluded in the patient.

[0418] Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0419] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0420] The pharmaceutical compositions of this disclosure may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques known in the pharmaceutical formulation art and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0421] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, 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 the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0422] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0423] Patients or subjects in need of treatment with the compounds described herein can be treated by administering to the patient (subject) an effective amount of the compound, including a pharmaceutically acceptable salt, solvate, or polymorph thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known agents.

[0424] Coadministration Symptom conditions that can be treated using the compounds or compositions herein include, but are not limited to, cancer (e.g., prostate cancer) and Kennedy's disease. In certain embodiments, the therapeutic or pharmaceutical composition comprises an effective amount of an additional biological or bioactive agent, e.g., a co-administered agent effective in treating cancer.

[0425] The term "co-administration" or "combination therapy" is intended to mean that at least two compounds or compositions are administered to a patient simultaneously, so that effective amounts or concentrations of each of the two or more compounds are present in the patient for a given period of time. While compounds according to the present disclosure can be co-administered to a patient at the same time, the term also encompasses administration of two or more agents at the same time or at different times, so long as effective concentrations of all co-administered compounds or compositions are present in the patient for a given period of time. In certain preferred embodiments of the present disclosure, one or more of the present compounds described above are co-administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents. In particularly preferred embodiments of the present disclosure, co-administration of compounds results in synergistic treatment, including anti-cancer treatment.

[0426] In another aspect, the present disclosure provides a method for treating a cancer, comprising administering to a patient a therapeutically effective amount of two or more of the PROTAC compounds described herein, and and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises an effective or synergistic amount of another bioactive agent that is not a PROTAC compound.

[0427] At least one of the two methods according to the present disclosure Sensuality Pharmaceutical compositions comprising an effective amount of the compound, and combinations of effective amounts of one or more of the compounds described elsewhere herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent a further aspect of the disclosure.

[0428] The term "bioactive agent" is used to describe an agent, other than the PROTAC compounds described herein, that is used in combination with the present compounds as an agent having biological activity to assist in achieving the intended therapeutic, inhibitory, and / or preventative / prophylactic effect for which the present compounds are used. Preferred bioactive agents for use herein include agents that assist in achieving the intended therapeutic effect, such as P-gp inhibitors, or agents with pharmacological activity similar to the intended pharmacological activity for which the present compounds are used or administered, such as anti-neurodegenerative agents.

[0429] The term "P-gp" is used to describe the "permeability glycoprotein" or P-glycoprotein (ABCB1), discovered in 1976 in rodent cells. The presence of "targeted" P-gp poses a potential challenge to achieving targeted exposure to therapeutic agents. P-gp is expressed in barrier tissues to protective sites (e.g., the blood-brain barrier) and in secretory / absorptive tissues (e.g., the gastrointestinal tract) (Cordon-Cardo et al., 1989, 1990). This protein acts as a cellular defense mechanism, actively extruding (effluxing) many drugs from the intracellular environment, thereby affecting their overall pharmacokinetic profile and reducing their penetration through barrier tissues. In particular, P-gp efflux can reduce drug penetration across gastrointestinal membranes, leading to reduced systemic exposure of the drug. P-gp efflux also reduces drug penetration across the blood-brain barrier. P-gp inhibitors may indirectly contribute to efficacy by increasing PROTAC exposure, particularly CNS exposure.

[0430] The term "additional anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that may be used in combination with the PROTAC compounds herein to treat a neurodegenerative disease.

[0431] In certain embodiments, a PROTAC is used in conjunction with a P-gp inhibitor. In certain additional embodiments, the P-gp inhibitor is selected from the group consisting of amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, lithotripsy, thiazolinone ... The antihistamines may be selected from the group consisting of, but not limited to, Ritonavir, Tariquidar, Elacridar and Verapamil.

[0432] treatment 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 PROTAC compound described herein, or a composition comprising an effective amount of such a compound, wherein the compound or composition comprising the compound is effective in modulating protein ubiquitination and protein degradation in the subject. In certain embodiments, the protein is tau protein.

[0433] In certain embodiments, the present specification provides a method of regulating the protein activity of tau protein by denaturing tau aggregates in a patient in need thereof, the method comprising administering to the patient an amount of a compound described herein.

[0434] In yet additional embodiments, the present disclosure provides a method of treating a disease state or condition in a patient, wherein dysregulated protein activity (e.g., tau aggregation and accumulation) is the cause of the disease state or condition, the method comprising administering to the patient an effective amount of a compound described herein to regulate the protein activity in the patient. In certain embodiments, the protein is tau.

[0435] As used herein, the terms "treat," "treating," and "treatment" refer to any action that benefits a patient, including the treatment of any disease state or condition for which the compounds may be administered that is modulated via the protein to which the compounds bind. Disease states or conditions, including neurological and neurodegenerative diseases, that may be treated using compounds according to the present disclosure are described herein above.

[0436] In another aspect, the disclosure provides a method of modulating tau 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 compound described herein, or a composition comprising an effective amount of a compound described herein, wherein the compound, or composition comprising the compound, is effective to modulate tau protein ubiquitination and proteolysis in the subject.

[0437] In another aspect, the disclosure provides a method of treating or ameliorating a symptom of a disease associated with tau accumulation or aggregation in a subject, e.g., a cell, tissue, mammal, or human patient, the method comprising administering to a subject in need thereof an effective amount of a compound 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 a symptom of a disease associated with tau aggregation in the subject.

[0438] In certain embodiments, the disease or disorder is a defect of the septum pellucidum, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Adie pupil, Adie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, AIDS-neurological complications, Alexander disease, Alpers syndrome, alternating hemiplegia of childhood, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, aphasia ataxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, dyskinesia, telangiectasia, ataxia and cerebellar degeneration / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Troth syndrome, Binswanger's disease, eyelid Convulsions, Bloch-Sulzberger syndrome, brachial plexus birth trauma, traumatic brachial plexus palsy, pure autonomic dysfunction, brain and spinal cord tumors, cerebral aneurysms, brain trauma, Brown-Séquard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernoma, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, head injury, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism Disease, cerebral hypoxia, cerebral palsy, cerebro-oculo-facial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic hypotension, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, agenesis of the corpus callosum, coma and persistent vegetative state, complex regional pain syndrome, congenital bilateral facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascular malformation, corticobasal degeneration, cranial arteries inflammation, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disease, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, opsoclonus-myoclonus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, brachial plexus neuropathy, dementia, multi-infarct dementia, semantic dementia , subcortical dementia, dementia with Lewy bodies, myoclonic cerebellar synergy disorder, dentatorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's disease, diabetes Neuropathy, diffuse sclerosis, dysautonomia, dysgraphia, dyslexia, dysphagia, dyspraxia, myoclonic dyssynergia, progressive cerebellar dyssynergia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis lethargica, encephalopathy, trigeminal angiomatosis, epilepsy, upper and lower paresis, Erb's palsy, Fabry's disease, Fahr's disease, syncope, familial dysautonomia, familial hematoma Tuberculosis, familial basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden- Spatz disease, head injury, headache, persistent hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, polyneuropathy-type hereditary ataxia, herpes zoster, otic varicella, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotension - infancy Hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, childhood hypotonia, childhood neuroaxonal dystrophy, childhood phytanic acid storage disease, childhood Refsum's disease, childhood convulsions, inflammatory myopathy, foramen occipitalis prolapse, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Joubert syndrome, Kearns-Sayre syndrome, Kennedy's disease, opsoclonus-myoclonus syndrome (Kinsbourne syndrome), Kleine-Lewin syndrome, Klippel-Feil syndrome, Klippel-Feil syndrome, Per-Trenaunay-Weber syndrome (KTS), Klüver-Bucy syndrome, Col syndrome Sackhoff amnesia syndrome, Krabbe disease, Kugelberg-Welander disease, Kuhl-, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment, lateral medullary syndrome , learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Levine-Critchley syndrome, dementia with Lewy bodies, lipid storage diseases, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lupus erythematosus - neurological type, sequelae, Lyme disease - neurological type, complications, Machado-Joseph disease, encephalopathy, mania, megaloencephaly, Melkerson-Rosenthal syndrome, meningitis, meningitis and encephalitis, Menkes disease, dysesthesias femoral neuralgia, metachromatic type, leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, minor stroke, mitochondrial myopathy, Moebius syndrome, Hirayama disease, motor neuron disease, moyamoya disease, mucolipidoses, mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis Multiple system atrophy, Multiple system atrophy with orthostatic hypotension, Muscular dystrophy, Myasthenia - congenital, Myasthenia gravis, Demyelinating diffuse sclerosis, Myoclonic encephalopathy of childhood, Myoclonus, Myopathy, Myopathy - congenital, Myopathy - thyrotoxicity, 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 manifestations of Pompe disease, Neurological sequelae of lupus erythematosus, Neuromyelitis optica, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorder, Neuropathy - hereditary, Neurosarcoidosis, Neurotoxicity, Cavernous nevus Cavernosus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, split spinal cord, Ohtahara syndrome, olivopontocerebellar atrophy, ocular myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome Syndrome, Overuse Syndrome, Chronic Pain, Pain, Pantothenate Kinase-Related Neurodegeneration, Paraneoplastic Syndrome, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Migraine, Facial Hemiatrophy, Pelizaeus-Merzbacher Disease, Pena-Shocker Syndrome Type II, Perineural Cyst, Periodic Paralysis, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorder, Phytanic Acid Storage Disease, Pick's Disease, Stiff Neck, Piriformis Syndrome, Pituitary Tumor, Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postpolio Syndrome, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, Orthostatic Tachycardia Syndrome, Primary Dentatum Atrophy, Primary Lateral Sclerosis, Primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive gait ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (obsolete name), Ramsay Hunt syndrome II (obsolete name), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Refsum's disease, Refsum's disease-childhood type, repetitive movement disorder, repetitive strain injury, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Relay-Day syndrome, sacral nerve root cyst, chorea, salivary gland Disease, Sandhoff disease, Schilder's disease, schizencephaly, Seitelberger's disease, seizure disorder, semantic dementia, septo-optic dysplasia, shaken baby syndrome, shingles, Scheid-Rager syndrome, Sjogren's syndrome, sleep apnea syndrome, African sleeping sickness, Sotos disease, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, cutaneous Substances that may be presenting include: Substances that may be presenting, such as ... are presenting, such as: Substances that are presenting, such as: Substances that are presenting, such as: Substances that are presenting, such as: Substances that are presenting, such as: Substances that are presenting, such as: Substances that are presenting, such as: (Vasculitis including Temporal Arteritis), von Echonomo disease, von Hippe disease Von Recklinghausen's disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash syndrome, Whipple's disease, Williams syndrome, Wilson's disease, X-linked spinal-bulbar muscular atrophy, or Tufts syndrome Neurological disorders include Werberger syndrome.

[0439] In certain embodiments, 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, postherpetic neuralgia, spinal cord tumors, and stroke.

[0440] In certain embodiments, the disease or disorder is Alzheimer's disease. In another aspect, the disclosure provides a method of treating or ameliorating symptoms of a disease associated with tau accumulation or aggregation in a subject, e.g., a cell, tissue, mammal, or human patient, the method comprising administering to a subject in need thereof an effective amount of a compound described herein or a composition comprising an effective amount of the compound and an effective or synergistic amount of another bioactive agent, wherein the composition comprising the compound is effective to treat or ameliorate symptoms of a disease associated with tau accumulation or aggregation by degrading / inhibiting tau in the subject.

[0441] In certain embodiments, the disease being treated is a neurological disorder. In a preferred embodiment, the subject is a human.

[0442] In certain additional embodiments, the additional bioactive agent is an anti-neurodegenerative agent. In another aspect, the present disclosure provides a method for treating a pathology by degrading a protein or polypeptide, wherein the pathology or condition is regulated via the protein or polypeptide, the method comprising administering to the patient or subject an effective amount of at least one compound described above, optionally in combination with an additional bioactive agent. By doing so, many neurological conditions or states can be treated.

[0443] 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.

[0444] kit In another aspect, the present disclosure provides kits containing the compounds or compositions described herein. The kits may be advertised, distributed, or sold as a unit for practicing the methods of the present disclosure. Furthermore, the kits of the present disclosure may preferably include instructions for proper use. Such kits can be conveniently used, for example, in a clinical setting, to treat patients with neurological disorders.

[0445] Example The PROTAC compounds of the present disclosure are effective in degrading tau. Exemplary compounds are presented in Tables 1 and 2, and in vitro data for some selected compounds showing degradation of tau protein are presented in Tables 2 and 3. In vivo experiments showing degradation of tau protein are shown in the figures.

[0446] 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 routes shown in the schemes of this disclosure are described as one method that can be used to obtain the desired compounds. Other methods can be used by those skilled in the synthetic arts. The ULM and PTM depicted in the schemes represent only one of many ULMs and PTMs in this application.

[0447] LC-MS method for purity analysis (quality control) LCMS method : Instrumentation: Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer The analysis was performed at 45 °C on a Poroshell 120 EC C18 column (50 mm x 3.0 mm internal diameter). 2 .7μm packing This is done using the diameter of the hole. The solvents employed were: A = 0.1% v / v formic acid in water. B = 0.1% v / v formic acid in acetonitrile. The gradient used is:

[0448] [Table 1]

[0449] UV detection is by averaging signals from wavelengths between 210 nm and 350 nm, and mass spectra are recorded on a mass spectrometer using electrospray ionization in positive mode.

[0450] Abbreviation: ACN: acetonitrile Boc2O: di-tert-butyl dicarbonate D CM: 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: ammonium tetrabutyl chloride TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: Trimethylsilyl t R :Holding time TsCl: p-toluenesulfonyl chloride 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 Salt (ULM-1)

[0451] [ka]

[0452] Step 1: Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile A stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA (250 mL) was placed 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 under atmospheric pressure. The mixture was heated to 50°C and stirred at this temperature for 5 hours, at which point LC-MS indicated the reaction was complete. The mixture was cooled to room temperature, diluted with 1 L of water, and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and then The mixture was 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 colorless solid.

[0453] Step 2: Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol) tetrahydrofuran LiAlH4 (20 g, 526.32 mmol) was added to a stirred solution of 1000 mL of toluene under a nitrogen atmosphere at 0°C for 10 min. The resulting mixture was then stirred at 60° C. for 3 h, at which point LC-MS indicated the reaction was complete. The mixture was cooled to 0° C. and then added with water (20 mL added slowly). The mixture was quenched by adding aqueous NaOH (15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined and Wash with ethanol (100 mL), dry over anhydrous sodium sulfate, and then concentrate under reduced pressure to give a crude The residue was purified by flash silica gel column chromatography (eluent: dichloromethane / methanol (v:v=10:1)) to give the title compound as a yellow oil. (Yield: 56%).

[0454] 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 overnight at room temperature. The reaction mixture was diluted with water (20 mL) and ethyl acetate was added. The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane / methanol (v:v=20:1)) to give the title compound (yield: 56%) as a yellow solid.

[0455] Step 4: (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl Preparation of ethyl]pyrrolidine-2-carboxamide To a 1 L round-bottom flask containing a dioxane solution of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate (45 g, 107.78 mmol), a dioxane solution of hydrogen chloride (4N, 300 mL) was added. The resulting solution was stirred at room temperature for 2 hours, and the solid was collected by filtration to give the title product (yield: 98%) as a yellow solid.

[0456] Step 5: 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-oxobutane-2- Preparation of tert-butyl [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) was 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-thiazolinone]-2-yl]amino}-3,3-dimethylbutanoic acid (15.7 g, 68.0 mmol). azol-5-yl)-phenyl]methyl} pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol) was added.

[0457] The resulting solution was stirred at room temperature for 16 hours, and LC-MS showed that the desired product had formed. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The extracts 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.

[0458] Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1) 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] To a stirred solution of tert-butyl carbamate (12 g, 22.61 mmol) in dioxane (20 mL) was added chloride. A solution of hydrogen in dioxane (4N, 80 mL) was added at room temperature, and the resulting solution was stirred at room temperature for 2 hours. 4, at which point LC-MS indicated the reaction was complete. The precipitated solid was collected by filtration to give the title compound. The product (yield: 48%) was obtained as a yellow solid.

[0459] d: 48%) as a yellow solid. 1 HNMR (400 MHz, 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.

[0460] 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)

[0461] [ka]

[0462] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate To a solution of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) and NaHCO3 (1.24 g, 14.8 mmol) in a mixture of HO (10 mL) and ethyl acetate (10 mL) was added (Boc)2O (5.20 g, 23.8 mmol) at 5 °C. The reaction was continued for 2 h. TLC showed that the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 mL) and 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%).

[0463] 1 HNMR (400 MHz, DMSO-d6): δ 1.28 (d, J = 7.2 Hz, 3H), 1.36 (s, 9H), 4.55-4.60 (m, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.39 (br, 1H), 7.49 (d, J = 8.4 Hz, 2H).

[0464] Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (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) A mixture of HCl (2.61 g, 26.6 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred at 90 °C under N for 18 h. After cooling to ambient temperature, the reaction mixture was filtered. The filtrate was diluted with HO (50 mL). ) was added and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. was collected by filtration and dried in an oven at 50°C to give 1-(4-(4-methylthiazol-5-yl)- (S)-tert-butyl ((S)phenyl)ethylcarbamate (3.48 g, 82.3%) was obtained as a gray solid. Ta.

[0465] 1 HNMR (400 MHz, DMSO-d6): δ 1.33 (d, J = 7.2 Hz, 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 = 8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1] + : 319.5 This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloride in methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol), and the mixture was stirred at ambient temperature for 3 hours. The mixture was 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)ethane. The amine hydrochloride salt (1.3 g, 85%) was obtained as a light green solid.

[0466] 1 HNMR (400 MHz, DMSO-d6): δ .56 (d, J = 6.8 Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H), 7.57 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4 Hz), 8.75 (s, 3H), 9.17 (s, 1H); LC-MS [M+1] + : 219.2 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 dissolved in (S)-2-(tert-butoxycarbonyl)amino-3,3-dimethyl Butanoic acid (1.25g, 5.4mol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate To a solution of the acid salt (0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) in DMF (10 mL) was added under nitrogen at 0° C. The mixture was stirred at ambient temperature for 18 hours. TLC showed the reaction was complete. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layers were washed with 5% citric acid (10 mL x 2), saturated NaHCO3 solution (10 mL x 2), brine (10 mL x 2). The organic solution was filtered and concentrated to give (2S,4R)-methyl 1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine. The azine-2-carboxylate was obtained 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 dissolved in THF (20 mL) and HO (10 mL). The resulting mixture was stirred at ambient 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 H2O (6 mL x 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% for two steps).

[0467] 1 HNMR (400 MHz, DMSO-d6): δ 6.50 (d,J = .6 Hz, 1H), 5.19 (br s, 1H), 4.32 (br s, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.16 (d, J = .2 Hz, 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).

[0468] Step 4: (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 Preparation of salt (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 allowed to warm to ambient temperature and continued to stir 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 dissolved in methanol (10 mL) and activated carbon (150 mg) was added. The resulting mixture was heated to 80°C and stirred for 1 hour. The mixture was cooled to ambient temperature and stirred for 18 hours. The mixture was stirred for 1 hour. 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 (1.41 g, 74.2%) as a white solid.

[0469] 1 H NMR (400 MHz, CDCl3): δ 1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J = 7.2 Hz, 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 = 11.2 Hz, 3.2 Hz, 1H), 4.11 (d, J = 11.6 Hz, 1H), 4.22 (d, J = 9.2 Hz, 1H), 4.51 (br, 1H), 4.79 (t, J = 8.0 Hz, 1H), 5.04-5.11 (m, 1H), 5.22 (d, J = 8.8 Hz, 1H), 7.36-7.42 (m, 4H), 7.61 (d, J = 7.6 Hz 1H), 8.68 (s, 1H).

[0470] This solid (1.04 g, 1.9 mmol) was dissolved in 4N hydrogen chloride in methanol (3.0 mL), The mixture was stirred at ambient temperature for 3 hours. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove all volatiles, giving a light yellow solid. The solid was added to TBME (5 mL). The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered to collect the solid. The mixture was dried in an oven at 50° C. to give the title compound (0.92 g, 100%).

[0471] 1 H NMR (400 MHz, DMSO-d6): δ .03 (s, 9H), 1.38 (d, J = 7.2 Hz, 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), 4.31 (br, 1H), 4.56 (t, J = 8.4 Hz, 1H), 4.89-4.95 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 8.20 (br, 3H), 8.67 (d, J = 7.6 Hz, 1H), 9.22 (s, 1H); 13 C NMR (400 MHz, DMSO-d6): δ 170.7, 167.1, 153.0, 146.5, 145.7, 132.5, 129.4, 129.3, 126.9, 69.4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8, 26.6, 23.0, 15.7; LC-MS [M+1] + :445.6 Intermediate 3: (2S,4R)-4-Hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)benzyl (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (ULM-3)

[0472] [ka]

[0473] 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 anhydrous NMP (125 mL) was stirred at 110 °C under a nitrogen atmosphere for 6 h. TLC showed the reaction was complete. The mixture was first cooled to room temperature and then partitioned between EtOAc and water. The combined product was filtered, and the filtrate was washed with water, brine, dried over anhydrous Na2SO4, and concentrated. The residue was dissolved in toluene (100 mL) and re-evaporated to give the crude product. The product was treated with cold MeOH (80 mL) and the resulting precipitate was collected by filtration, washed with MeOH (20 mL) and dried under vacuum to give the title compound (10.5 g, 64%) as a light yellow solid.

[0474] LC / MS: 217.2 [M+1] + . 1 HNMR (400 MHz, 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=8.0 Hz,1H), 9.07(s, 1H), 11.34 (s, 1H).

[0475] Step 2: Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol Free of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (2.9 g, 13.41 mmol) To a solution of water and THF (150 mL), LiAlH4 (1.5 g, 40.23 mmol) was added in small portions at 0°C. The mixture was stirred at 50°C under nitrogen atmosphere for 3 hours. TLC showed the reaction was complete. The mixture was cooled in an ice-water bath and then diluted with Na2SO4 . Carefully add 10H2O (5 g) and keep at this temperature for 1 The mixture was stirred for 1 hour. The mixture was filtered and the filter cake was washed four times with 10% MeOH in DCM. The filtrates were combined and concentrated to give 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (2.0 g, 68%) as a crude light yellow solid, which was further purified in the next step. It was used without any problems.

[0476] 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).

[0477] Step 3: Preparation of (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid L-valine (4.37 g, 37.3 mmol) was dissolved in 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 hot, and the filtrate was allowed to cool slowly 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%).

[0478] 1 HNMR (400 MHz, DMSO-d6): δ .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).

[0479] 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 of 4-hydroxy-L-proline methyl ester hydrochloride (1.0 g, 5.52 mmol), (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid (1.16 g, 4.97 mmol), and DIPEA (2.58 g, 20 mmol) in anhydrous DMF (15 mL) 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 layer was washed with water, brine, and dried over anhydrous Na2SO4. The residue was dissolved in 30% to 50% EtOAc in hexane. Purification by silica gel chromatography using as a separator gave the title compound as a light yellow solid (1.21 g, 67.6%).

[0480] LCMS:361.3[M+1] + . Step 5: (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl) Preparation of (butanoyl)pyrrolidine-2-carboxylic acid 4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate (2S,4R)-methyl (1.2 g, 3.33 mmol), LiOH. HO (559 mg, 13.32 mmol) A mixture of THF (20 mL) and HO (10 mL) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction mixture was acidified with 1N HCl to pH 1-2 and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the title compound as a light yellow solid (1.05 g, 91% yield).

[0481] 1 HNMR (400MHz, CDCl3): δ0.91 (d, J=6.4Hz, 3H), 1.05 (d, J=6.8Hz, 3 H), 2.30 (dd, J=8.4,2.8 Hz, 2H), 2.44-2.50 (m, 1H), 3.75 (dd, J=11.2, 3.2 Hz, 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), 4.83 (d, J=11.2Hz, 1H), 7.42-7.45 (m, 2H), 7.51-7.56 (m, 1H), 7.78 (d, J=7.6 Hz, 1H).

[0482] Step 6: (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzoate (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2- Preparation of carboxamides To a solution of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid (1.0 g, 2.89 mmol), 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (954 g, 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 hour. TLC showed the reaction was complete. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. The residue was dissolved in DCM and HCl. The crude product was purified by silica gel column chromatography using 2% to 5% MeOH to give the title compound as a light yellow solid (650 mg, 43% yield).

[0483] 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, 3.6 Hz ,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, 2.0 Hz,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).

[0484] 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)

[0485] [ka]

[0486] Preparation of ULM-2 using (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride This compound was synthesized using the same method as described in. 1 HNMR (400 MHz, CD3OD): δ 1.14 (s, 9H), 1.55 (d, J = 6.8 Hz, 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 = 8.0 Hz, 2H), 7.67 (d, J = .0 Hz, 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] 1-[(2S)-1-[(2S,4R)-4-hydroxy-2-(4-methyl-1-oxobutan-2-yl)-1,3-dimethyl-1-oxobutan-2-yl]carbamate (ULM-5-A) and tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-(4-methyl-1-oxobutan-2-yl)-2-yl]pyrrolidin-1-yl]carbamate (ULM-5-A) -{[(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)

[0487] [ka]

[0488] Step 1: Synthesis of 2-(4-bromophenyl)oxirane 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) A mixture of acetonitrile (20 mL) was heated to 55°C for 4 hours. The resulting solution was diluted with water and diethyl ether. The organic layer was washed with water, dilute hydrochloric acid, and brine, and dried over sodium sulfate. The organic solvent was removed under reduced pressure to give crude 2-(4-bromophenyl)oxirane (2.20 g, 81.8% yield), which was used in the next reaction without further purification.

[0489] 1 H NMR (400 MHz, CDCl3) δ 2.74 (1H, q, J = 2.8 Hz), 3.14 (1H, dd, J= 4.0 Hz, 5.2 Hz), 3.82 (1H, dd, J = 2.4 Hz, 4.0 Hz), 7.15 (2H, d, J= 8.4 Hz), 7.47 (2H, d, J = .8 Hz).

[0490] 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), sodium azide (3.28 g, 50.5 mmol) was added, and the resulting mixture was stirred at 60°C for 4 hours. After the reaction was completed, the mixture was extracted with EtOAc, washed with brine, and The crude product was used directly in the next step.

[0491] 1 H NMR (400 MHz, CDCl3) δ 1.94 (1H, s), 3.63-3.66 (2H, m), 4.57 (1H, dd, J = 5.2 Hz, 7.6 Hz), 7.15 (2H, d, J= 8.4 Hz), 7.46 (2H, d, J = .4 Hz).

[0492] Step 3: Synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride 2-Azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) in tetrahydrofuran To a solution of 20.0 mL of ethanol and 5.00 mL of water, triphenylphosphine (4.35 g, 16.6 mmol) was added. The reaction mixture was stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was dissolved in HCl / dioxane (4 M, 10.0 mL) and stirred at room temperature for 1 hour. After concentration, the solid was dissolved in dichloromethane. The extract was washed with water to give 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.5 g, yield 72.1%) as a white solid.

[0493] 1 H NMR (400 MHz, CDCl3) δ 3.70 (2H, s), 4.28 (1H, s), 5.55 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz), 8.61 (3H, s); LC / MS 216.2 [M+H] + .

[0494] 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), imidazole (1.95 g, 2.87 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.63 g, 10.8 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous layer was extracted with dichloromethane (30 mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude compound. The crude compound was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5%). :1) to give 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy) ethoxylate. Tanamine (1.50 g, 63.6%) was obtained as a white solid.

[0495] LC / MS: 330.1 [M+H] + ; 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 heated at room temperature. The mixture was stirred overnight and then quenched with water. The aqueous layer was extracted with ethyl acetate (50 mL x 3) and washed with brine. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude compound. The crude compound was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give 1-(4-bromophenyl)-2-(tert- (butyldimethylsilyloxy)ethyl tert-butyl carbamate (1.80 g, 92.0%) pale yellow Obtained as a colored oil.

[0496] 1 H NMR (400 MHz, CDCl3) δ 0.01 (6H, d, J = 9.6 Hz), 0.86 (9H, s), 1.42 (9H, s), 3.65-3.70 (2H, m), 4.60-4.63 (1H, m), 7.34 (2H, d, J = .0 Hz), 7.39 (1H, d, J =8.8 Hz), 7.56 (2H, d, J = 8.4 Hz).

[0497] Step 6: 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamate Synthesis of tert-butyl phosphate tert-Butyl 1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (4.0 g, 9 A mixture of 1.85 g (18.6 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 hours, then The mixture was diluted with water at rt. The aqueous layer was extracted with ethyl acetate (50 mL x 3) and washed with brine. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give the crude compound, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give 2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)-ethyl caprylamide gel. Tert-butyl carbamate was obtained as a pale yellow solid (1.30 g, 41.8%).

[0498] 1 H NMR (400 MHz, CDCl3) δ 1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J=6.0 Hz), 4.55-4.58 (1H, m), 4.84 (1H, t, J =6.0 Hz), 7.30 (1H, d, J=8.0 Hz), 7.38-7.45 (4H, m), 8.99 (1H, s); LC / MS 335.2 [M+H] + ; Rt = 1.859 minutes Step 7: Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride 2-Hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate tert- Butyl (300 mg, 0 0.536 mmol) was dissolved in hydrochloric acid / dioxane (5 mL, 4 M). The reaction mixture was stirred at room temperature for 3 hours, and 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.

[0499] 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} Synthesis of [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) 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, 50.19mmol), 1-hydroxybenzotriazole (HOBT) (695mg, 5.19mmol), (2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidone A solution of lysine-2-carboxylic acid (1273 mg, 3.70 mmol) and triethylamine (747 mg, 7.40 mmol) in N,N-dimethylformamide (50 mL) was stirred under argon overnight at room temperature, and then water (80 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 mL x 5). The combined organic layer was 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 (S)-1-((2S,4R)-4-hydroxy-2-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)-2-yl)-2-methyl-1-propan-1-yl)-2-hydroxy-1-(4-methylthiazol-5-yl)-2-methyl-1-propan-1 ... (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 tert-butyl (700 mg) was obtained as a yellow oil, and (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 tert-butyl (500 mg) was obtained as a pale yellow oil.

[0500] ULM-5-A: 1 H NMR (400 MHz, 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= 8.0 Hz), 4.78 (1H, t, J = 5.6 Hz), 4.81-4.88 (1H, m), 5.12-5.16 (1H, m), 6.46 (1H, d, J = .2 Hz), 7.36-7.46 (4H, m), 8.41 (1H, d, J = .0 Hz), 8.99 (1H, s); LC / MS 561.2 [M+H] + ; Rt = 1.897 minutes ULM-5-B: 1 H NMR (400 MHz, 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= .6 Hz), 4.76-4.81 (1H, m), 4.87 (1H, t, J = .6 Hz), 5.146 (1H, d, J= 2.8 Hz), 6.47 (1H, d, J = 8.8 Hz), 7.37 (2H, d, J = .0 Hz), 7.51 (2H, d, J = 8.0 Hz), 8.37 (1H, d, J = 7.6 Hz), 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)

[0501] [ka]

[0502] 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). Alkylation with 2-iodopropane is described in the literature. The desired ULM-6 was obtained from the intermediate It was prepared using the same synthetic method as described in the preparation of compound ULM-3.

[0503] 1 H NMR (400 MHz, CDCl3) : δ 9.33 (s, 0.5H), 9.20 (s, 0.5H), 8.07(t, J = 6.4 Hz, 0.5H), 7.83(t, J = .0 Hz, 0.5H), 6.99(dd, J = 2.4, 8.0 Hz, 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 = 6.4 Hz, 1.5), 4.16-4.25(m, 2H), 3.72-3.76(m, 0.5H), 3.61(d, J= 9.2 Hz, 1.0H), 3.51-3.55(m, 1.5H), 2.30-2.46(m, 2.5H), 2.26(s, 1.5H), 2.24(s, 1.5H), 1.95-2.05(m, 1H), 1.01(d, J = 6.8 Hz, 1.5H), 0.82-0.87(m, 4.5H); LC-MS 436.1 [M+1] + ; Rt =3.57 minutes.

[0504] PTM synthesis: Preferred PTM embodiments of the present disclosure are prepared according to the synthetic routes shown in Schemes 1-3 below. These routes can be modified and adapted for the synthesis of specific PTM embodiments using general methods known to those skilled in the art.

[0505] [ka]

[0506] [ka]

[0507] [ka]

[0508] Exemplary PROTAC Synthesis: Intermediate 1

[0509] [ka]

[0510] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)-2-(2-hydroxyethoxy)ethoxy) ethoxy)isoindoline-1,3-dione

[0511] [ka]

[0512] 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500mg To a solution of 4-methyl-2-benzophenone (1.82 mmol) in DMF (10 mL) was added K2CO3 (756 mg, 5.47 mmol) and 4-methyl-2-benzophenone (1.82 mmol). 2-(2-(2-hydroxyethoxy)ethoxy)ethyl sulfonate (832 mg, 2.73 mmol) was added at 25°C. The resulting solution was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction was quenched with H2O (10 mL) and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layer was washed with anhydrous After drying over sodium sulfate and concentration, the residue was purified on a silica gel column to give the desired product (95 mg, 13% yield).

[0513] Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- 5-yl)oxy)ethoxy)ethoxy)acetaldehyde

[0514] [ka]

[0515] 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy To a solution of (Isoindoline-1,3-dione) (95 mg, 0.23 mmol) in CH3CN (5 mL) was added IBX (130 mg, 0.46 mmol) at 25°C. The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was The mixture was filtered through Celite and the filtrate was concentrated to give crude intermediate 1, 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde (90 mg), which was used without further purification.

[0516] Intermediate 2

[0517] [ka]

[0518] 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 for 16 hours at 90°C. After cooling to room temperature, the reaction was quenched with water (100 mL) and the mixture was extracted with ErOAc (300 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 100 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 light yellow solid.

[0519] Synthesis scheme of exemplary compound 51 Step 1: 3-(4-bromophenyl)-4-nitropyridine

[0520] [ka]

[0521] 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) To a stirred solution of water (100 ml), tetrakis(triphenylphosphine)palladium (14.8 g, 12.8 mmol) was added under a nitrogen atmosphere at room temperature. child The mixture was degassed with nitrogen three times. The resulting mixture was stirred at 50°C overnight. TLC showed that the reaction was complete. The solid was removed by filtration. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine (400 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified on a silica gel pad (eluted with 10-33% ethyl acetate in hexane) to give 3-(4-bromophenyl)-4-nitropyridine (89 g, 65% yield) as a yellow solid.

[0522] Step 2: 7-Bromo-5H-pyrido[4,3-b]indole

[0523] [ka]

[0524] A mixture of 3-(4-bromophenyl)-4-nitropyridine (20.0 g, 71.7 mmol) and triethyl phosphate (400 mL) under a nitrogen atmosphere was stirred at 110 °C 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 (methanol) to give 7-bromo-5H-pyrido[4,3-b]indole (11.0 g, 62% yield) as a brown solid.

[0525] Step 3: 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

[0526] [ka]

[0527] 7-Bromo-5H-pyrido[4,3-b]indole (400 mg, 1.63 mmol), (6-fluoropyridin-3-yl)boronic acid (344 mg, 2.44 mmol), PdCl2(dppf) (120 mg, 0.163 mmol), tBu3PHBF4 (95 mg, 0.326 mmol), and Cs2CO3 (1.1 g, 3.26 mmol) in a mixture of dioxane / water (20 mL, 20:1). The mixture was heated to 90°C under N2 for 4 hours. The solid was filtered and the filtrate was evaporated. Purify by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1). As a result, 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (250 mg, yield 59%) was obtained.

[0528] Step 4: 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

[0529] [ka]

[0530] Dissolve 3,6,9,12-tetraoxatetradecane-1,14-diol (270 mg, 1.13 mmol) in THF (10 mL To the solution of 7-(6-), NaH (45 mg, 60%, 1.13 mmol) was added at 0°C. After stirring at 20°C for 1 hour, Dissolve 150 mg (0.57 mmol) of fluoropyridin-3-yl-5H-pyrido[4,3-b]indole in DMF (2.0 mL) The resulting solution was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction mixture The mixture was diluted with EA (30 mL) and washed with brine. The organic layer was evaporated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel (DCM / MeOH = 4 / 1). This gave the desired product (200 mg, 72.89% yield) as a colorless oil.

[0531] Step 5: 7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin tert-Butyl 5H-pyrido[4,3-b]indole-5-carboxylate

[0532] [ka]

[0533] 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetrahydrofuran To a solution of tetraoxatetradecan-1-ol (150 mg, 0.31 mmol) in DCM (10 mL) was added NEt (94.5 mg, 0.93 mmol) and BocO (102.0 mg, 0.47 mmol). The resulting solution was stirred at ambient temperature for 12 h. The solvent was removed in vacuo. The residue was diluted with EA (30 mL), and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired product (120 mg, 66% yield), which was used in the next step without further purification.

[0534] Step 6: tert-butyl 7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

[0535] [ka]

[0536] 7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl To a solution of tert-butyl 5H-pyrido[4,3-b]indole-5-carboxylate (120 mg, 0.31 mmol) and NEt3 (93.9 mg, 0.93 mmol) in DCM (10 mL) was added MsCl (38.9 mg, 0.34 mmol) at 0 °C. After stirring at 30 °C for 1 h, the solvent was removed. The residue was diluted with EA (30 mL) and washed with brine. The organic layer was concentrated to give the intermediate mesylate salt.

[0537] To a stirred solution of the mesylate (100 mg, 0.15 mmol) in anhydrous DMF (10 mL) was added 2-(2,6-dioxopipene) Lysin-3-yl)-5-hydroxyisoindoline-1,3-dione (45.6 mg, 0To the resulting mixture was added K2CO3 (31.4 mg, 0.23 mmol). The resulting mixture was stirred at 68 °C for 4 h. The mixture was diluted with EtOAc (40 mL), washed twice with brine, and dried over anhydrous sodium sulfate. The organic layer was reduced The residue was purified by prep-TLC (DCM / MeOH=20 / 1) to give the desired product. was obtained as a yellow solid (15 mg, 23.6% yield).

[0538] Step 7: 5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0539] [ka]

[0540] To a solution of tert-butyl 7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate (30 mg, 0.036 mmol) in DCM (2 mL) was added TFA (5 mL). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (10 mg, 38% yield). I got it. 1H NMR (400 MHz, CDCl3): δ 12.34 - 12.48 (m, 1H), 9.19 - 9.29 (m, 1H), 8.80 (s, 1H), 8.29 - 8.42 (m, 1H),...

Claims

1. 1. A bifunctional compound having the following chemical structure: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof: ULM-L-PTM, During the ceremony: The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase. and the PTM is a tau protein targeting moiety; and wherein L is a bond or chemical linking moiety connecting a ULM and a PTM.

2. 2. The compound of claim 1, wherein the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase selected from the group consisting of von Hippel-Lindau (VLM) and cereblon (CLM).

3. The PTM is represented by at least one of the following formulas I-XI: 【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; L ＰＴＭ is selected from a bond, alkyl, alkenyl, or alkynyl, and optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) or one or more functional groups, such as —O—, —S—, —NR 1 PTM -, -N=N-, -S(O)-, -SO 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, wherein said functional groups are optionally located at either terminus of the linker. Positioned; and R 1 PTM 3. The compound of claim 1 or 2, wherein is selected from H or alkyl.

4. At least one of A, B, C, and F, or a combination thereof, is optionally substituted. or a 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, wherein said alkyl and alkenyl groups are further optionally substituted; or 4. The compound according to claim 3, wherein the compound is at least one of:

5. The PTM is of Formula I, and: Rings A, B, and C are independently 5- or 6-membered fused aryl or heteroaryl rings. can be; L ＰＴＭ is selected from a bond or alkyl; and D is selected from a 6-membered aryl, heteroaryl, or heterocycloalkyl; 4. The compound of claim 3, wherein A, B, C, and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

6. The PTM is of Formula I, and: A and C are phenyl or a 6-membered heteroaryl ring; B is a 5-membered heteroaryl ring; L ＰＴＭ is a bond; and D is a 6-membered heteroaryl or 6-membered heterocycloalkyl ring; 4. The compound of claim 3, wherein each of A, B, C, and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, and wherein a nitrogen atom of any of the A, B, C, and D rings is not directly bonded to a heteroatom or carbon atom to which another heteroatom is directly attached.

7. the PTM is of Formula III or Formula IV, and: A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings; L ＰＴＭ is selected from a bond or alkyl; and D and E are 5- or 6-membered fused aryl or heteroaryl rings; In the formula, A, B, C, D and E are alkyl, haloalkyl, halogen, hydroxyl, a 4. The compound of claim 3, optionally substituted with alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

8. The PTM is represented by a chemical structure selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 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, and halogen; and R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen; The compound according to any one of claims 1 to 3.

9. The PTM is represented by a chemical structure selected from the group consisting of: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 During the ceremony: R 1 , R 2 and R 3 is independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and 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.

10. 3. The method according to claim 1, wherein the PTM is represented by a chemical structure selected from the group consisting of: is a compound according to any one of claims 9: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】

11. The ULM is a von Hippel-Lindau (VHL) ligase binding moiety (VLM) represented by the following structure: 【Transformation 5】 During the ceremony: X 1 , X 2 are each independently a bond, O, or NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO 2 group of Selected from: R Y3 , R Y4 are each independently H, straight or branched chain C 1～6 alkyl, optionally with one or more halo, C 1～6 substituted by alkoxyl; R P are 1, 2 or 3 groups, each independently H, halo, —OH, C 1-3 From the alkyl group Selected; W 3 is optionally substituted -TN(R 1a R 1b ), optionally substituted -TN(R 1a R 1b )X 3 , -T-Aly optionally substituted -T-heteroaryl, optionally substituted -T-heterocycle, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocycle; X 3 is C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b are each independently a straight or branched chain C optionally substituted with H, one or more halo or -OH groups. 1 -C 6 Alkyl group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO 2 , 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 )SO 2 selected from the group consisting of: T is optionally substituted alkyl, -(CH 2 ) n - groups, wherein the methylene group each one optionally substituted with halogen, methyl, one or more halogens or -OH groups; Straight or branched chain C 1 -C 6 alkyl groups or optionally substituted amino acid side chains optionally substituted with one or two substituents selected from the group: n is 0 to 6; W 4 teeth, 【Transformation 6】 R 14a、 R 14b are each independently H, haloalkyl, or optionally substituted alkyl. selected from the group consisting of: W 5 is selected from the group of phenyl or 5-10 membered heteroaryl; and R 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl aryl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

12. The ULM is a von Hippel-Lindau (VHL) ligase binding moiety (VLM) represented by the following structure: 【Transformation 7】 During the ceremony: W 3 is optionally substituted aryl, optionally substituted heteroaryl, or 【Transformation 8】 selected from the group R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cyclo alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 and the carbon atoms to which they are attached are any forming a cycloalkyl substituted with R 11 is an optionally substituted heterocyclic, an optionally substituted alkoxy, an optionally substituted heteroaryl, optionally substituted aryl; 【Chemistry 9】 selected from the group R 12 is selected from the group of H or optionally substituted alkyl; R 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 14a、 R 14b are each independently H, haloalkyl, or optionally substituted alkyl. selected from the group consisting of: W 5 is selected from the group of phenyl or 5-10 membered heteroaryl; R 15 H, halogen, CN, OH, NO 2 , N.R. 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO 2 NR 14a R 14b , N.R. 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl aryl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, each independently optionally substituted; R 16 is independently selected from the group of H, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R 18 are independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkoxy, is selected from the group of alkyl, haloalkyl, haloalkoxy or linker; and The compound of any one of claims 1-11, wherein p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

13. The ULM has a chemical structure selected from the group consisting of: 【Chemistry 10】 During the ceremony: R 1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R 15 H, halogen, CN, OH, NO 2、 optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl; X is C, CH 2 or C=O; and R 3 is a bond or an optionally substituted 5- or 6-membered heteroaryl; wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

14. The ULM comprises a group according to the following chemical structure: 【Chemistry 11】 During the ceremony: R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R 9 is H; R 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclo cyclobutyl, cyclopentyl, or cyclohexyl; R11 is 【Chemistry 12】 or optionally substituted heteroaryl; p is 0, 1, 2, 3, or 4; Each R 18 are independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkoxy, alkyl, haloalkyl, haloalkoxy or a linker; R 12 is H, C=O; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; and R 15 H, halogens, Cl, CN, OH, NO 2、 optionally substituted heteroaryl, optionally substituted substituted aryl; 【Chemistry 13】 wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM.

15. the ULM comprises a group selected from the chemical structures consisting of: 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 where ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 the compound of any one of claims 1-14, wherein the phenyl rings of ULM-d9 through ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, where the dashed lines indicate the sites of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM-a.

16. The ULM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isoforms thereof 11. The compound of any one of claims 1 to 10, which is a cereblon E3 ligase binding moiety (CLM) selected from the group consisting of star, and derivatives thereof.

17. The CLM has a chemical structure represented by: 【Chemistry 15】 During the ceremony: W is CH 2 , CHR, C=O, SO 2 , NH, and N-alkyl; Each X is O, S, and H 2 are independently selected from the group consisting of: Y is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl selected from the group consisting of aryl, N-heterocyclyl, O and S; Z is O, S and H 2 selected from the group consisting of: G and G' are independently H, alkyl (linear, branched, optionally substituted with R'), OH, R 'OCOOR, R'OCONRR", CH optionally substituted with R' 2 -heterocyclyl, and benzyl optionally substituted with R'; Q 1 , Q 2 , Q 3 , and Q 4 represents a carbon C substituted with a group independently selected from R′, N, or N-oxide; A is independently selected from the group H, alkyl, cycloalkyl, Cl, and F; Rは、-CONR’R”、-OR’、-NR’R”、-SR’、-SO 2 R’、-SO 2 NR’R”、-CR’R”-、-CR 'NR'R"-, -aryl, -hetaryl, -alkyl (optionally substituted straight or branched chain), -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF 3 , -CN, -NR'SO 2 NR'R", -NR'CONR'R",-CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO 2 )NR'R”, -SO 2 NR'COR”, -NO 2 , -CO 2 R', -C(C=N-OR')R", -CR'=CR'R", -CCR' , -S(C=O)(C=N-R')R", -SF 5 , or -OCF 3 Including; R' and R" are independently a bond, H, N,N-oxide, alkyl (straight or branched chain), cyclohexane, alkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, or heterocyclyl each of which is optionally substituted; 【Chemistry 16】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains a functional group or atom, wherein n is an integer from 1 to 4, and If n is 1, R n is modified to be covalently attached to a linker group (L), and If n is 2, 3, or 4, one R n is modified to be covalently attached to a linker group (L), and any other R n is optionally covalently linked to a PTM, a CLM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

17. The compound of any one of claims 1 to 10 or 16, modified to be

18. The CLM has a chemical structure represented by: 【Chemistry 17】 During the ceremony: W is independently selected from the group consisting of CH2, C=O, NH and N-alkyl; R is independently selected from H, methyl, and alkyl; [Chemistry 18] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independently selected functional groups or atoms, optionally one of which is modified to be covalently attached to a PTM, a chemical linker group (L), a CLM (or CLM'), or a combination thereof.

19. The CLM has a chemical structure represented by: 【Chemistry 19】 19. The method of claim 1, wherein the dashed line indicates a linker attachment point. Compound.

20. The linker (L) comprises a chemical structural unit represented by the following formula: -(A) q -、 During the ceremony: A is a group linked to a ULM moiety or a PTM moiety; and q is an integer equal to or greater than 1, In the formula, A is a bond, CR L1 R L2 ,O,S,SO,SO 2 , N.R. L3 , SO 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR 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(=CNO 2 )NR L4 , 0 to 6 R L1 Groups and / or R L2 Arbitrarily placed in the base Converted C 3-11 cycloalkyl, 0 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 6 R L1 Groups and / or R L2 Aryl optionally substituted with a group , 0 to 6 R L1 Groups and / or R L2 heteroaryl optionally substituted with a group, wherein R L1 or R L2 are each independently optionally bonded to each other, 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, or C 1-8 Alkyl, OC 1-8 Archi Le, 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 Cycloalkane Le, NHC 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl) 2 , N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , SO 2 NHC 1-8 Alkyl, SO 2 N(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 ,NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH 2 20. The compound according to any one of claims 1 to 19, wherein

21. The linker (L) is -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2- -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-; 【Chemistry 20】 In the formula, m, n, o, p, q, and r are each independently 0, 1, 2, 3, 4, 5, or 6.

20. The compound of claim 1, wherein R is selected from the group H, methyl or ethyl, and X is selected from the group H or F, provided that when the number is zero and there are no N-O or O-O bonds, R is selected from the group H, methyl or ethyl, and X is selected from the group H or F. 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】

22. 21. The method according to claim 1, wherein the linker (L) is selected from the group consisting of: The compound: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】

23. The linker (L) is selected from the group consisting of: 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 [Chemistry 23-4] 【Chemistry 23-5】 【Chemistry 23-6】 【Chemistry 23-7】 【Chemistry 23-8】 【Chemistry 23-9】 【Chemistry 23-10】 【Chemistry 23-11】 【Chemistry 23-12】 【Chemistry 23-13】 [Chemistry 23-14] 21. The compound of any one of claims 1 to 20, wherein each n and m is independently 0, 1, 2, 3, 4, 5, or 6.

24. wherein L comprises the following chemical structure: 【Chemistry 24】 During the ceremony: W L1 and W L2 are each independently a 4-8 membered ring with 0-4 heteroatoms optionally substituted with RQ, and each RQ is independently H, halo, OH, CN, CF3, C1-C6 alkyl (optionally substituted), C1-C6 alkoxy (optionally substituted straight or branched chain) or C1-C6 alkoxy (optionally substituted straight or branched chain) or two RQ groups together with the atom to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, C1-C6 alkyl (optionally substituted straight or branched chain), and optionally one or more C atoms are O, or C1-C6 alkoxy (optionally substituted straight or branched chain), substituted with (non-chain, branched chain); and 21. Any one of claims 1 to 20, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety. The compound described in

25. L comprises the following chemical structure: 【Chemistry 25】 During the ceremony: W L1 and W L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1～6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic; Each is optional. Q Each R is replaced by Q are independently H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1 -C 6 Alkyl (optionally substituted straight or branched chain), C 1 -C 6 Alkoxy (optionally substituted straight or branched chain), OC 1～3 Alkyl (optionally substituted with one or more -F), OH, NH 2 , N.R. Ｙ1 R Y2 , CN or two R Q the groups, together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO 2 , C 1 -C 6 alkyl (straight or branched, optionally substituted) and optionally one or more C atoms are O, C 1 -C 6 substituted with alkoxy (straight or branched chain, optionally substituted); Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 R Q Each R is replaced by Q are independently H, C 1～6 Alkyl (straight or branched chain, optionally with one or more halo, C 1～6 substituted with alkoxyl) or two R Q groups together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight or branched chain, optionally one More halo, C 1-6 substituted with alkoxyl) or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0 to 10; and 21. Any one of claims 1 to 20, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety. The compound described in

26. 21. The compound of any one of claims 1 to 20, wherein L is a polyethyleneoxy group optionally substituted with aryl or phenyl, comprising 1 to 10 ethylene glycol units.

27. 27. The bifunctional compound of any one of claims 1 to 26, wherein the compound is selected from the group consisting of compounds 1 to 330 (Tables 1 and 2).

28. The compound has a chemical structure selected from the following formulae CI-CV: 【Chemistry 26-1】 【Chemistry 26-2】 During the ceremony: R 101 is 1 to 2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano; R 102 is H, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl Selected from; 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 each independently represents H, alkyl, halogen, or haloalkyl Selected from: R 108 is independently H, alkyl, halogen, haloalkyl, cyano, or methoxy. are 1 to 2 selected substituents; R 115 is selected from H, alkyl and haloalkyl; R 118 and R 119 are independently selected from H, alkyl, halogen, or haloalkyl; or R 118 and R 119 together with the carbon atoms to which they are attached represent a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, such as, for example, cyclopropane or oxetane; R 124 and R 125 are independently selected from H, alkyl, halogen, or haloalkyl; or R 124 and R 125 together with the carbon atoms to which they are attached represent a 3- to 6-membered cycloalkyl or heterocycloalkyl ring, such as, for example, cyclopropane or oxetane; G is phenyl or a 5- or 6-membered heteroaryl ring; and Z is CH 2 or C=O.

29. A method for treating a bifunctional compound comprising administering to a subject a pharmaceutical composition comprising the bifunctional compound of any one of claims 1 to 28 and a pharmaceutically acceptable carrier. A composition comprising:

30. The composition according to any one of claims 1 to 29, wherein the composition further comprises at least one additional bioactive agent.

30. The composition of claim 29, further comprising another bifunctional compound according to paragraph 1, or a combination thereof.

31. 31. The composition of claim 30, wherein the additional bioactive agent is an anti-neurodegenerative agent.

32. 31. The composition of claim 30, wherein the additional bioactive agent is a P-gp inhibitor.

33. The P-gp inhibitor is amiodarone, azithromycin , Captopril, Clarithromycin, Cyclosporin Cyclosporine, Piperine, Quercetin, Quinidine, Quinine, Reserpine, Ritonavir, 33. The composition of claim 32, which is Tariquidar, Elacridar, or Verapamil.

34. 29. A method for treating a tau-related disease or disorder in a subject, comprising administering to a subject a pharmaceutically acceptable carrier and at least one compound according to any one of claims 1 to 28.

10. A method of treating or ameliorating at least one symptom of said disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound comprising:

35. 35. The composition of claim 34, wherein the disease or disorder is associated with tau accumulation and aggregation.

36. 36. The composition of claim 34 or 35, wherein the disease or disorder is a neurodegenerative disease associated with tau accumulation and aggregation.

37. The disease or disorder may be acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Adie pupil, Adie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, AIDS-neurological complications, Alexander disease, Alpers syndrome, alternating hemiplegia of childhood, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, or arachnoiditis. , Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, ataxia, telangiectasia, ataxia and cerebellar degeneration / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Troth syndrome, Binswanger's disease, blepharospasm, Bloch's syndrome Zuberger's syndrome, brachial plexus birth trauma, traumatic brachial plexus palsy, pure autonomic dysfunction, brain and spinal cord tumors, cerebral aneurysms, cerebral trauma, Brown-Séquard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernoma, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, head injury, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoplasia Oxygen, Cerebral Palsy, Cerebro-Eye-Facial-Skeletal Syndrome, Charcot-Marie-Tooth Disease, Chiari Malformation, Chorea, Acanthocytic Chorea, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Hypotension, Chronic Pain, Cockayne Syndrome Type II, Coffin-Lowry Syndrome, COFS, Agenesis of the Corpus Callosum, Coma and Persistent Vegetative State, Complex Regional Pain Syndrome, Congenital Bilateral Facial Palsy, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular Cavernous, Malformation, Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis, Creutzfeldt's Disease -Jakob disease, cumulative trauma disease, Cushing's syndrome, giant cytomegalic inclusion disease, cytomegalovirus infection, opsoclonus-myoclonus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, brachial plexus neuropathy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, myoclonic cerebellar synergistic disorder, dentatorubral atrophy, dermatomyositis, developmental dyspraxia, Devic's disease, diabetic neuropathy, diffuse sclerosis, Autonomic dysfunction, dysgraphia, dyslexia, dysphagia, dyspraxia, myoclonic dyssynergia, progressive cerebellar dyssynergia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis lethargica, encephalopathy, trigeminal angiomatosis, epilepsy, upper and lower paralysis, Erb's palsy, Fabry's disease, Fahr's disease, syncope, familial autonomic dysfunction, familial hemangiomas, familial basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher's syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, Gerstmann-Straussler syndrome Scheinker's disease, giant cell arteritis, giant cell inclusion body disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome, Hallervorden-Spatz disease, head injury, headache, persistent hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, hereditary ataxia of the polyneuropathy type, herpes zoster, herpes zoster oticus, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus, normal pressure hydrocephalus, hydrospinal fluid Myelopathy, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotonia - infancy, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, childhood hypotonia, childhood neuroaxonal dystrophy, childhood phytanic acid storage disease, childhood Refsum's disease, childhood convulsions, inflammatory myopathy, foramen occipitalis, intestinal lipodystrophy, intracranial cysts, increased intracranial pressure, Isaac's syndrome, Joubert's syndrome, Kearns-Sayre syndrome, Kennedy's disease, opsoclonus-myoclonus syndrome (Kinsbourne syndrome), Kleine-Lehmann's syndrome Vinh syndrome, Klippel-Feil syndrome, Klippel-Trenaunay-Weber syndrome (KTS), Klüver-Bucy syndrome, Korsakoff amnesia syndrome, Krabbe disease, Coutts disease Gelberg-Welander disease, Kuru, Lambert-Eaton myasthenic syndrome, Landauer-Leuven syndrome Huhner's syndrome, Lateral femoral cutaneous nerve entrapment, Lateral cord syndrome, Learning disability, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Cerebral leukodystrophy, Levine-Critchley syndrome, Dementia with Lewy bodies, Lipid storage disease, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease, Lupus erythematosus - neurological type, Sequelae, Lyme disease - neurological type, Complications, Machado-Joseph disease, Encephalopathy, Mania, Megalencephaly, Melkerson-Rosenthal syndrome, Meningitis, Meningitis and encephalitis, Menkes disease, Dysesthesias femoral neuralgia, Metachromatic type, Cerebral leukodystrophy, Microcephaly, Migraine, Miller Fisher syndrome, Minor stroke, Mitochondrial myopathy, Moebius syndrome, Hirayama disease, Motor neuron disease, Moyamoya disease, Mucolipidoses, Mucopolysaccharidosis, Multifocal movement disorder Neuropathy, Multi-infarct dementia, Multiple sclerosis, Multiple system atrophy, Multiple system atrophy with orthostatic hypotension, Muscular dystrophy, Myasthenia - congenital, Myasthenia gravis, Demyelinating diffuse sclerosis, Myoclonic encephalopathy of childhood, Myoclonus, Myopathy, Myopathy - congenital, Myopathy - thyrotoxicosis, Myotonia, Myotonia congenita, Narcolepsy, Neuroacanthocytosis, Cerebral iron accumulation Neurodegeneration, Neurofibromatosis, Neuroleptic malignant syndrome, Neurological complications of AIDS, Neurological complications of Lyme disease, Neurological effects of cytomegalovirus infection, Neurological manifestations of Pompe disease, Neurological sequelae of lupus erythematosus, Neuromyelitis optica, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorder, Neuropathy - hereditary, Neurosarcoidosis, Neurotoxicity, Nevus cavernosus, Niemann-Pick disease, Normal pressure hydrocephalus, Occipital neuralgia, Obesity, Split cord, Ohtahara syndrome, Olivopontocerebellar atrophy, Ocular myoclonus, Orthostatic hypotension, O'Sullivan-McLeod syndrome Syndrome), Overuse Syndrome, Chronic Pain, Pain, Pantothenate Kinase-Related Neurodegeneration, Paraneoplastic Syndrome, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Migraine, Facial Hemiatrophy, Pelizaeus-Merzbacher Disease, Pena-Shocker Syndrome Type II, Perineural Cyst, Periodic Paralysis, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorder, Phytanic Acid Storage Disease, Pick's Disease, Stiff Neck, Piriformis Syndrome, Pituitary Tumor, Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postpolio Syndrome, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, Orthostatic Tachycardia Syndrome, Primary Dentate Atrophy Atrophy), primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive gait ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (previous (previous name), Ramsay Hunt syndrome II (old name), Rasmussen's encephalitis, reflex sympathetic dystrophy syndrome, Refsum's disease, Refsum's disease - childhood type, repetitive movement disorder, repetitive strain injury, restless legs syndrome, retroviral-associated myelopathy, Rett's syndrome, Reye's syndrome, Relay-Day syndrome, sacral radicular cyst, chorea, salivary gland disease, Sandhoff's disease, Schilder's disease, cleft palate Encephalopathy, Seitelberger's disease, seizure disorders, semantic dementia, septo-optic dysplasia, shaken baby syndrome, shingles, Shyde-Rager syndrome, Sjogren's syndrome, sleep apnea syndrome, African sleeping sickness, Sotos disease, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor Tumors, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT Headache Swallowing Disorders, Sydenham chorea, syncope, syphilitic spinal sclerosis Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cyst, Tay-Sachs Disease, Temporal Arteritis, Tethered Cord Syndrome, Thomsen's Myotonia, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Trigeminal Neuralgia, Todd's Palsy, Tourette's Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathy, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis Including Temporal Arteritis 37. The composition of any one of claims 35-36, wherein the disease is selected from the group consisting of: von Echonomo disease, von Hippel-Lindau disease (VHL), von Recklinghausen disease, Wallenberg syndrome, Werdnig-Hoffmann disease, Wernicke-Korsakoff syndrome, West syndrome, whiplash injury, Whipple disease, Williams syndrome, Wilson disease, X-linked spinal-bulbar muscular atrophy, and Zellberger syndrome.

38. 35. The composition of any one of claims 33-34, wherein the disease or disorder is a neurological disorder involving 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 malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors, and stroke.

39. The composition of any one of claims 35 to 36, wherein the disease or disorder is Alzheimer's disease.

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