Tau protein targeting PROTAC and related usage methods

Abstract

This disclosure relates to bifunctional compounds that can be used as regulators of tau protein. Specifically, this disclosure relates to bifunctional compounds having a VHL or cereblon ligand at one end that binds to E3 ubiquitin ligases and a tau protein-binding moiety at the other end, thereby placing the tau protein near the ubiquitin ligase to achieve tau degradation (and inhibition). This disclosure exhibits a broad range of pharmacological activities associated with tau protein degradation / inhibition. The compounds and compositions of this disclosure can be used to treat or prevent diseases or conditions arising from the aggregation or accumulation of tau protein.

Description

[0001] Cross-references to related applications

[0002] This disclosure claims priority to U.S. Provisional Application No. 62 / 415,830, filed November 1, 2016, which is incorporated herein by reference in its entirety.

[0003] Incorporate by reference

[0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016; and U.S. Patent Application Serial No. 62 / 406,888, filed October 11, 2016; and U.S. Patent Application Serial No. 14 / 686,640, filed April 14, 2015, disclosed as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application Publication No. 2016 / 0058872, filed April 14, 2015. U.S. Patent Application Serial No. 14 / 792,414, filed July 6, 2014; and U.S. Patent Application Serial No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and U.S. Patent Application Serial No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639, are incorporated herein by reference in their entirety. Furthermore, all references cited herein are incorporated herein by reference in their entirety. background 1. Technical Field

[0006] This specification relates to bifunctional compounds that can be used to modify intracellular ubiquitination and subsequent degradation of target peptides and proteins, particularly Tau protein. The compounds of this disclosure place the target protein / peptide near a ubiquitin ligase to achieve ubiquitination and degradation (and inhibition) of Tau protein. 2. Background Technology

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

[0009] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, the substrate recognition subunit of the E3 ligase complex VCB, which is also composed of extended proteins B and C, Cul2, and Rbx1. The major substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-inducing cytokine erythropoietin in response to hypoxia levels. The first small-molecule ligand of von Hippel-Lindau (VHL) targeting the substrate recognition subunit of the E3 ligase was generated, and its crystal structure was obtained, confirming that this compound mimics the binding pattern of the transcription factor HIF-1α (the major substrate of VHL).

[0010] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plant to human, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullin regulator 1 (ROC1). This complex ubiquitinates many other proteins. Through a mechanism not yet fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates many developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which acts as a DNA damage-binding protein.

[0011] Tau protein is an abundant protein in the central nervous system, primarily found in neurons, although it is expressed at lower levels in other cells of the central nervous system. In healthy neurons, Tau binds to microtubules and regulates microtubule stability, which is crucial for axonal growth and neuronal plasticity. When pathologically altered, Tau molecules become unstable in microtubules and readily form insoluble aggregates. Once Tau protein forms insoluble aggregates in cells, cellular dysfunction occurs, axonal transport is impaired, and neuronal loss follows. The accumulation of abnormal Tau aggregates in neurons is a key pathological feature of many neurodegenerative diseases, including Alzheimer's disease. Under certain pathological conditions, Tau aggregation leads to double helical filaments (PHF), straight filaments (SF), and / or neurofibrillary tangles (NFT). The accumulation of PHF and NFT in neurons is directly associated with microtubule dysfunction and neuronal degeneration. Neurons containing tau PHF, SF, and / or NFT activate different cellular mechanisms to attempt to remove abnormal protein aggregates from the cell.

[0012] Recent research suggests that, instead of large, insoluble filaments, soluble Tau oligomers may play a more crucial role in the onset and progression of disease before the development of PHF or NFT-induced neurotoxicity. Different types of Tau oligomers can act as seeds for natural Tau aggregation, thereby promoting neurotoxic Tau accumulation. Accumulated evidence suggests that Tau aggregates can spread from one cell to another in a prion-like manner.

[0013] Tau alterations and dysfunction, along with widespread neuronal loss, have long been associated with several neurodegenerative diseases (now collectively known as tau lesions).

[0014] The term "tauopathy" or "tauopathies" in this article refers to a class of neurodegenerative diseases associated with the pathological accumulation of Tau protein in neurofibrils or glial fibrillary tangles in the human brain. Examples of tau lesions include, but are not limited to, Alzheimer's disease (AD), Down syndrome, frontotemporal dementia (FTLD), cotricobasal degeneration (CBD), and progressive supranuclear palsy (PSP).

[0015] Due to its pathological significance in a variety of neurodegenerative diseases, tau is an important therapeutic target. Preventing tau accumulation has become a potential strategy for treating tau-related neurodegenerative diseases. To date, significant efforts have been made to identify the molecular mechanisms of tau accumulation and to find therapeutic agents to halt the progression of neurodegeneration.

[0016] Tau aggregation inhibitors with promising preclinical data have proven ineffective in recent clinical trials for the treatment of various tau lesions. Therefore, there is a need in the art for effective treatment of diseases and conditions associated with tau aggregation in neurodegenerative disorders such as tau lesions. Summary of the Invention

[0017] This disclosure describes bifunctional compounds, including compositions comprising them, that act to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation, and methods of using them. In particular, this disclosure provides bifunctional or proteolytically targeted chimeric (PROTAC) compounds that can be used as regulators of targeted ubiquitination and Tau protein aggregate degradation. Additionally, this specification provides methods for treating or improving disease conditions such as tau lesions due to the accumulation or aggregation of Tau protein, using effective amounts of the compounds described herein. These diseases or conditions include, but are not limited to, neurological conditions or neurodegenerative conditions.

[0018] Therefore, in one aspect, this disclosure provides compounds that act to recruit endogenous proteins (e.g., Tau) to E3 ubiquitin ligases for ubiquitination and degradation.

[0019] In any embodiment, the compound has the following general structure.

[0020] PTM-L-ULM

[0021] In some embodiments, the compound has the following general structure (A).

[0022] PTM-L-VLM (A)

[0023] In some embodiments, the compound has the following general structure (B).

[0024] PTM-L-CLM (B)

[0025] In this context, PTM represents the protein-targeting moiety, ULM represents the E3 ubiquitin ligase-targeting moiety, including but not limited to VLM (VHL ligase-binding moiety) and CLM (cereblon ligase-binding moiety), and L represents the linker, such as a bond or chemical linker moiety. As will be understood by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and position of each functional moiety can be varied as needed.

[0026] In some embodiments, the PTM in structure (A) is a ligand that binds to Tau and VHL E3 ubiquitin ligase.

[0027] In some embodiments, the PTM in structure (B) is a ligand that binds to Tau and CLM E3 ubiquitin ligase.

[0028] In some embodiments, the compounds described herein comprise multiple ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof. In another aspect, this specification provides therapeutic compositions comprising an effective amount of a compound as described herein or a salt thereof, and a pharmaceutically acceptable carrier. The therapeutic compositions modulate protein degradation in a patient or subject (e.g., an animal, such as a human) and can be used to treat or improve disease states or conditions regulated by the degraded protein. In some embodiments, the therapeutic compositions described herein can be used to achieve the degradation of a target protein for the treatment or improvement of diseases, such as neuronal diseases. In yet another aspect, this disclosure provides methods for ubiquitinizing / degrading target proteins in cells. In some embodiments, the method includes administering a bifunctional compound comprising a ULM and a PTM, as described herein, which can be linked via a linker portion, as described elsewhere herein, wherein the ULM is coupled to the PTM and wherein the ULM recognizes ubiquitin pathway proteins, such as ubiquitin ligases, such as E3 ubiquitin ligases, more preferably VLMs and CLMs, and the PTM recognizes a target protein (TBM) such that when the target protein (e.g., Tau) is placed in the vicinity of the ubiquitin ligase, degradation of the target protein occurs, thus leading to degradation of the target protein, inhibition of its effects, and control of protein levels. In another aspect, the target protein is Tau. This disclosure provides treatment for disease states or conditions controlled by protein levels, i.e., by reducing the level of such protein (e.g., Tau protein) in patient cells via degradation.

[0029] Specifically, PTM is a molecule that binds to Tau protein (TBM), and ULM is a molecule that binds to VHL E3 ubiquitin ligase and / or CLM E3 ubiquitin ligase, having the following general structure:

[0030] TBM-L-VLM / CLM

[0031] The PTM (protein targeting portion) of the PROTAC in this disclosure is represented by general formulas I, II, III, IV, V, VI, VII, VIII, XI, X, and XI:

[0032]

[0033] in:

[0034] A, B, C, D, E, and F are each independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl rings, wherein the contact between the rings indicates ring fusion; and

[0035] L PTMSelected from bonds, alkyl, alkenyl or ynyl groups, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups, said functional groups may include -O-, -S-, -NR. 1 PTM -(where R) 1 PTM Selected from H or alkyl), -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH-, wherein the functional group may optionally be located at either end of the connector (i.e., directly adjacent to rings A, B, C, D, E or F).

[0036] The aryl and heteroaryl rings described above may optionally be substituted by 1 to 3 substituents, each of which is independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, amide, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups may be further substituted.

[0037] In any aspect or embodiment described herein, at least one of A, B, C, F, or a combination thereof is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[0038] In some embodiments of this disclosure, PTM is represented by formula I and / or II, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L PTM The group is selected from alkyl or alkyl groups, and D is selected from 6-membered aryl, heteroaryl, or heterocyclic alkyl groups, wherein A, B, C, and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano groups.

[0039] In other embodiments, PTM is represented by formula III and / or IV, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L PTM Selected from alkyl or alkyl groups, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano groups.

[0040] In some other embodiments of this disclosure, PTM is represented by Formula I, wherein A is a phenyl or 6-membered heteroaryl ring, B is a 5-membered heteroaryl ring, C is a phenyl or 6-membered heteroaryl ring, and L... PTMIt is a bond, and D is a 6-membered heteroaryl or 6-membered heterocyclic alkyl ring, wherein each of A, B, C, and D is optionally independently substituted with an alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano group, wherein the condition is that the nitrogen atom of any of the rings A, B, C, and D is not directly bonded to a heteroatom or carbon atom of the LPTM, and the other heteroatom is bonded to the L PTM Direct attachment.

[0041] It should be understood that the general structure is exemplary, and the various parts can be arranged in space in any desired order, number, or configuration.

[0042] In further embodiments, this specification provides bifunctional compounds having structures selected from compounds 1-330 (e.g., compounds selected from Tables 1 and 2), their salts, polymorphs, and prodrugs.

[0043] In further embodiments, this specification provides bifunctional compounds having structures selected from Table 1 or Table 2 (e.g., chemical structures selected from compounds 1-330), their salts, polymorphs, and prodrugs.

[0044] In another aspect, this specification provides compositions comprising compounds as described herein and pharmaceutically acceptable carriers. In some embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of the compounds as described herein and pharmaceutically acceptable carriers. In some embodiments, the therapeutic or pharmaceutical composition comprises additional bioactive agents, such as agents effective for treating neuronal diseases.

[0045] In any aspect or embodiment described herein, a therapeutic composition comprising the compounds described herein may be any suitable dosage form, such as a solid or liquid, and is configured for delivery via any suitable route, such as oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.

[0046] In another aspect, this specification provides a method for modulating Tau protein, its ubiquitination and subsequent degradation in a subject (e.g., cells, tissues, mammals or human patients), the method comprising administering to the subject an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising thereof effectively modulates Tau ubiquitination and degradation in the subject.

[0047] In another aspect, this specification provides a method for treating or improving symptoms of a disease associated with TAU activity in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to a subject in need an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising thereof effectively treats or improves symptoms of a disease associated with TAU activity in the subject. In some embodiments, the disease to be treated is a neurological or neurodegenerative disease, such as Alzheimer's, Parkinson's, dementia, etc.

[0048] In a preferred embodiment, the subject is a human being.

[0049] In another aspect, this specification provides a method for using compounds according to this disclosure to identify the effects of target protein degradation in biological systems.

[0050] Unless otherwise stated, it is contemplated that any embodiment described herein can be combined with any other one or more embodiments, even if the embodiments are described under different aspects of this disclosure. Thus, the foregoing general field of application is given by way of example only and is not intended to limit the scope of this disclosure and the appended claims. Based on these claims, the specification, and examples, those skilled in the art will appreciate additional objects and advantages associated with the compositions, methods, and approaches of this disclosure. For example, various aspects and embodiments of this disclosure can be utilized in numerous combinations, all of which are expressly contemplated by this specification. These additional advantages, objects, and embodiments are expressly included within the scope of this disclosure. This document serves to elucidate the background of this disclosure, and in certain circumstances, publications and other materials providing additional details on practice are incorporated herein by reference. Attached Figure Description

[0051] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with the specification, serve to explain the principles of the present disclosure. The drawings are for illustrative purposes only and should not be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments of the present disclosure, wherein:

[0052] Figure 1 The total tau level in the hippocampal homogenate is shown. Data are presented as scatter plots. Statistically significant differences between the test item (TI) treatment group and the mediator control group were indicated by asterisks **p<0.01, *p<0.05, based on univariate ANOVA followed by Dunneett multiple comparison tests. Detailed Implementation

[0053] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Modifications and variations can be made to the embodiments described herein without departing from the spirit or scope of this disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly and integrally incorporated by reference.

[0054] This specification relates to a surprising and unexpected discovery that once an E3 ubiquitin ligase protein and a target protein are brought into contact via a chimeric construct (e.g., PROTAC) as described herein, the E3 ubiquitin ligase protein can ubiquitinate the target protein, said chimeric construct binding an E3 ubiquitin ligase protein (e.g., VHL and cereblon) and a target protein such as TAU. Accordingly, this specification provides compounds, compositions comprising them, and related methods of use for the ubiquitination and degradation of selected target proteins.

[0055] The following terms are used to describe the contents of this disclosure. Where a term is not specifically defined herein, it is given the field-accepted meaning used by those skilled in the art in the context of its use in describing the contents of this disclosure.

[0056] When providing value ranges, it should be understood that each intermediate value, up to one-tenth of the lower limit unit, is covered within this disclosure unless the context explicitly specifies otherwise (e.g., in the case of a group containing multiple carbon atoms, in which case the number of each carbon atom falling within the range is provided), between the upper and lower limits of the range, and any other values ​​or intermediate values ​​within the range. The upper and lower limits of these smaller ranges, which may be independently included, are also covered within this disclosure, subject to any specific exclusions within the range. When the range includes one or both limitations, the range excluding either of those limitations is also included in this disclosure.

[0057] The articles “a” and “an” as used herein and in the appended claims refer to one or more (i.e., at least one) grammatical objects of the article, unless the context clearly indicates otherwise. For example, “element” means one or more elements.

[0058] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so combined, i.e., elements that exist in combination in some cases and separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising,” a reference to “A and / or B” may, in one embodiment, refer only to A (optionally including elements other than B); in another embodiment, refer only to B (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements); and so on.

[0059] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, i.e., including at least one, but also including more than one of many elements or a list of elements, as well as optional, additionally unlisted items. Only when the opposite terms are explicitly indicated, such as “only one” or “exactly one”, or, when used in the claims, “consisting of” refers to exactly one of many elements or a list of elements. In general, when preceded by exclusive terms such as “any,” “one of,” “only one,” or “exactly one,” as used herein, the term “or” should only be interpreted as indicating an exclusive alternative (i.e., “one or the other but not both”).

[0060] In the claims and the foregoing description, all transitional phrases, such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “forming,” etc., shall be understood as open-ended, that is, meaning including but not limited to. Only the transitional phrases “consisting of” and “substantially consisting of” shall be closed or semi-closed transitional phrases, respectively, as described in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0061] As used herein in the specification and claims, when referring to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements, whether related to or unrelated to those specifically identified elements, in addition to those specifically identified within the list of elements referred to by the phrase "at least one". Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") in one embodiment may refer to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, it refers to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, it refers to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); etc.

[0062] It should also be understood that in some methods described herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are described, unless the context otherwise indicates.

[0063] Unless otherwise stated, as used herein, the term "compound" means any specific compound disclosed herein and includes its tautomers, regioisomers, geometric isomers, and applicable stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and, in the context, applicable pharmaceutically acceptable salts and their derivatives (including prodrug forms). Within its 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), and specific enantiomers or enantiomer-rich mixtures of the disclosed compounds. In the context, the term also refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the active site. It should be noted that numerous substituents and their associated variables are described in particular in the description of the compounds herein. Those skilled in the art will understand that the molecules described herein are stable compounds as generally described below.

[0064] When display key In this context, both double bonds and single bonds are represented in the context of the compound shown.

[0065] The terms "patient" or "subject" are used throughout the specification to describe an animal, preferably a human or domesticated animal, to which treatment, including preventative treatment, is provided with the compositions according to this disclosure. For treatment of infections, conditions, or disease states specific to a particular animal (e.g., a human patient), the term "patient" refers to that particular animal, including domesticated animals such as dogs or cats, or farm animals such as horses, cattle, sheep, etc. Generally, in this disclosure, unless otherwise stated or implied by the context in which the term is used, the term "patient" refers to a human patient.

[0066] The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term "effective" includes all other effective amounts or effective concentrations described or used in this patent application.

[0067] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, causes ubiquitin to attach to a lysine residue on a target protein and subsequently targets a specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugate, are responsible for the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases involve polyubiquitination, where a second ubiquitin attaches to a first ubiquitin; a third ubiquitin attaches to a second ubiquitin, and so on. Polyubiquitination tags proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysine residues in ubiquitin can be targeted by E3 to prepare the chain. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, which is recognized by the proteasome.

[0068] The term "protein target moiety" or PTM is used to describe small molecules that bind to a target protein or other target protein or peptide and place / are present in the vicinity of a ubiquitin ligase, allowing degradation of the protein or peptide by the ubiquitin ligase to occur. Non-limiting examples of small molecule target protein binding moieties include compounds targeting Tau protein.

[0069] The term "target protein" is used to describe a protein or polypeptide that is a target for binding to compounds according to this disclosure and for degradation by ubiquitin ligases described below. Such small-molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules capable of targeting the target protein. These binding moieties are linked to ULM groups via a linker group L.

[0070] Tau protein targets can be used in screening for compounds that bind to proteins, and by incorporating this moiety into compounds according to this disclosure, the activity level of the protein can be altered for therapeutic purposes.

[0071] The term "disease state or condition" is used to describe any disease state or condition in which a protein dysregulation occurs (i.e., an elevated amount of a protein expressed in a patient), and in which the degradation of Tau protein in the patient can provide beneficial treatment or symptom relief for the patient in need. In some cases, the disease state or condition can be cured.

[0072] Disease states or conditions that can be treated with the compounds according to this disclosure include neuronal diseases such as neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injury, epilepsy, seizures, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors, and stroke.

[0073] As used herein, the term "neurological disorder" or "neurological disorders" means any condition, disease, and / or syndrome that is caused by or originates from neurological, psychiatric, psychological, and / or cerebrovascular symptomatology or origin. As used herein, the term "neurological disorder" or "neurological disorders" also means a disease, condition, or state of the brain and nervous system, or a mental illness or state. Neurological conditions include, but are not limited to, septum pellucidum agenesis, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Addison's pupils, Addison's syndrome, adrenoleukodystrophy, corpus callosum dysplasia, agnosia, Eckhardt syndrome, AIDS-related neurological complications, Alexander disease, Alpert disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, hemangioma, hypoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Argive-Gilles malformation, arteriovenous malformation, and Aspergillus schizophrenia. Berger's syndrome, ataxia, telangiectasia, ataxia and cerebellar / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Bartholomew's syndrome, Barten's disease, Becker's myotonia, Behcet's disease, Bell's palsy, benign primary blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhardt-Rogson syndrome, Binswanger's disease, blepharospasm, Bruxelles-Sud syndrome, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal tumors, cerebral aneurysms. Brain injury, Brunswick-Sécal syndrome, bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome with burning pain, cavernous malformation, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central cord syndrome, central pain syndrome, cranial diseases, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, brain-ocular-facial-bone syndrome, Sharma-Tutus disease, Chiari malformation, chorea, chorea-acanthocytosis, chronic inflammatory demyelinating polyneuropathy ( CIDP), chronic orthostatic intolerance, type II chronic pain, Cocaine syndrome, Kohl's syndrome, COFS, cavitary brain, coma and persistent vegetative state, complex regional pain syndrome, congenital facial paralysis, congenital myasthenia gravis, congenital myopathy, congenital cavernous vascular malformation, cortical-basal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus infection, chorea syndrome, Dan Wolverine syndrome, Dawson's disease, De Moses syndrome, deep brain stimulation for Parkinson's disease.Dejerine-Klumpke paralysis, dementia, dementia with multiple cerebral infarctions, dementia with semantic function, dementia with subcortical function, Lewy body dementia, dentate nucleus-cerebellar ataxia, dentate nucleus-red nucleus atrophy, dermatomyositis, developmental motor disorders, Devectic syndrome, diabetic neuropathy, diffuse sclerosis, familial autonomic dysfunction, writing difficulties, dyslexia, dysphagia, motor disorders, cerebellar ataxia, myoclonus, progressive cerebellar ataxia, dystonia, early infantile epilepsy, encephalopathy, empty sella syndrome, encephalitis of lethargy, encephalocele, encephalopathy, trigeminal neuralgia, epilepsy, Erb-Duchenne and Dejerine-Klumpke paralysis, Oberle's paralysis, Fabry disease. Fay's syndrome, syncope, familial autonomic dysfunction, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, soft-bellied infant syndrome, Friedreich ataxia, frontotemporal dementia, Gaucher disease, Göstadmann syndrome, Gschich's disease, giant cell arteritis, giant cell inclusion body disease, globular cell leukodystrophy, glossopharyngeal neuralgia, Gaucher-Bartholin's syndrome, Has-Schwarz's disease, head injury, headache, persistent migraine, hemifacial spasm, hemiplegia, Alteras' disease, hereditary neuropathy, hereditary spastic paraplegia, hereditary ataxic polyneuritis, herpes zoster, otitis herpes zoster, Hirayama syndrome, Hodgkin's-Ellison syndrome Syndrome, holoprosencephaly, HTLV-1 related myelopathy, Huntington's disease, hydrocephalus, hydrocephalus-normal pressure, hydramnios, ADHD, Cushing's syndrome, hypersomnia, hypertonia, hypotonia-infantile, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinence pigmentosa, infantile hypotonia, infantile axonal dystrophy, infantile phytate storage disease, infantile Reifum disease, infantile spasms, inflammatory myopathy, cleft occipital bone with exposed brain, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, Isaac syndrome, Jubert syndrome, Kiehl's syndrome, Kennedy's disease, Kingsbrinner syndrome, Kiehl's syndrome, Kiehl's syndrome, Kiehl's syndrome, Kiehl's syndrome, Kiehl's syndrome (Kiehl's syndrome) TS), Korsakov amnesia, Klebsiella disease, Kuhl-Weil disease, Kuru disease, Langerhans-Ellison myasthenia gravis, Landau-Kleffner syndrome, lateral femoral nerve, cutaneous nerve entrapment, lateral medullary syndrome, learning disabilities, Lewy body disease, Ring-Gorbachev syndrome, Lyme disease, Lewy body dementia, Levine-Critchley syndrome, Lewy body dementia, lipid storage disease, gyri, locked-in syndrome, Glenk disease, lupus—neurology, sequelae, Lyme disease—neurological complications, Mayo C. Y. disease, megalencephaly, mania, megalencephaly, Milo-Ross syndrome, meningitis, meningitis and encephalitis, Menkes disease, paresthesia, metachromatic dysplasia,Leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mini-stroke, mitochondrial myopathy, Murbius syndrome, unilateral limb atrophy, motor neuron disease, Moyamoya disease, mucolipid storage disease, mucopolysaccharidosis, multifocal motor neuropathy, multiple infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, myasthenia gravis (congenital), myasthenia gravis, demyelinating diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myopathy (congenital), myopathy (thyroid toxin-induced), myotonia, congenital myotonia, narcolepsy, neuroacanthosis, neurodegeneration with cerebral siderotic syndrome, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological complications of cytomegalovirus infection. Neurological consequences, neurological manifestations of pampis disease, neurological sequelae of lupus, neuromyelitis optica, neurogenic myotonia, neuronal waxy deposits, lipofuscinosis, neuronal migration disorder, neuropathy—hereditary, neurosarcoma, neurotoxicity, cavernous nevus, Niemann-Pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, occult spinal canal closure sequence, Ōtahara syndrome, olivopontocerebellar atrophy, strabismus-clonic myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, Paine, pantothenic acid kinase-related neurodegeneration, paraneoplastic syndrome, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal migraine, Parry-Romberg, Peyreke's disease, Pena Shokeir II syndrome, fasciculus cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytate storage disease, Pick's disease, nerve pinching, piriformis syndrome, pituitary adenoma, polymyositis, pampiniformis, pore brain, postherpetic neuralgia, post-infectious encephalomyelitis, post-poliomyelitis syndrome, orthostatic hypotension, orthostatic hypotension, tachycardia syndrome, orthostatic tachycardia syndrome, primary Dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive Progressive sclerotic gray matter dystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsey Hunt syndrome I (formerly known as), Ramsey Hunt syndrome II (formerly known as), Rasmussen encephalitis, reflex sympathetic dystrophy syndrome, Reversum disease, Reversum disease in infancy, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Reid-Dell syndrome, sacral nerve root cyst, St. Vitus dance, salivary gland disease, Sandhof's disease, Sheldt's disease, schizophrenia, Setterberg's disease, epilepsy, semantic dementia, optic-septal dysplasia.Shaken baby syndrome, Shingles-Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, narcolepsy, Sotos syndrome, spastic state, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Slobodan syndrome, stiff-person syndrome, striatal substantia nigra degeneration, stroke, Slobodan-Weiss syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, Suntham's headache and dysphagia, Siddenham's chorea, syncope, syphilitic myelitis, syringomyelia, syringomyelia, systemic lupus erythematosus, tabes dorsalis varicose veins, Tarlov's cyst, Tey-Sachs disease, temporal arteritis, tethered cord syndrome Combined syndromes, Thomsen's myotonia, thoracic outlet syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's paralysis, Tourette syndrome, transient ischemic attack, infectious cavernous encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paralysis of the lower limbs, tuberous sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, Ekonomo's disease, Hey-Linden's disease (VHL), von Reckling-Hosezen's disease, Warenberg syndrome, Welch-Hosezen's disease, Welch-Colburn syndrome, West syndrome, whiplash, Whipple's disease, Williams syndrome, Wilson's disease, X-linked spinal-bulbar muscular atrophy or Zellweger syndrome.

[0074] The term "bioactive agent" is used to describe agents other than the compounds according to this disclosure, which, in combination with the compounds of this disclosure, are used as bioactive agents to help achieve the intended therapeutic, inhibitory, and / or preventive / protective effects of the compounds herein.

[0075] Where applicable, the term "pharmaceutically acceptable salt" is used throughout the specification to describe the salt form of one or more compounds described herein, which is used to increase the solubility of the compound in the gastric juices of a patient's gastrointestinal tract, thereby promoting the dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, and a host of other acids and bases well known in the pharmaceutical industry. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to this disclosure.

[0076] The term “pharmaceutical-acceptable derivative” is used throughout the product information to describe any pharmaceutically acceptable prodrug form (e.g., ester, amide, other prodrug group) that, when administered to a patient, directly or indirectly provides the active metabolite of the compound described herein.

[0077] The term "independently" is used in this article to indicate that variables applied independently change independently as the application differs.

[0078] The term "hydrocarbon group" should refer to compounds containing carbon and hydrogen and that can be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0079] The term "alkyl" in its context should refer to a straight-chain, branched, or cyclic fully saturated hydrocarbon group or alkyl group, preferably C1-C. 10 More preferably C1-C6, or alternatively C1-C3 alkyl, which may be optionally substituted. Examples of alkyl groups include, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl.

[0080] The term "lower alkyl" refers to an alkyl group having no more than six carbon atoms.

[0081] The term "unsubstituted" should mean substituted only by hydrogen atoms. The range of carbon atoms including C0 means that carbon is absent and the substitution is H. Therefore, the range of carbon atoms from C0 to C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, H substitutes for carbon. The term "substituted" or "optionally substituted" should independently (i.e., when more than one substituent is present, each substituent is independent of the others) mean one or more substituents at the carbon (or nitrogen) position anywhere on the molecule within the context (independently up to five substituents on a portion of the compound according to this disclosure, preferably up to three substituents, often one or two substituents, and may include substituents that themselves can be further substituted), and includes hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2, or 3 halogens, especially alkyl, especially methyl such as trifluoromethyl), alkyl (preferably C1-C...). 10，More preferably C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl) including alkylene esters (such that the attachment is on the alkylene group rather than at the ester functional group, which is preferably substituted by C1-C6 alkyl or aryl), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkylene amines, further including C1-C6 alkylene amines), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkylene amines, further including C1-C6 alkylene amines), and halogen (preferably C1-C6 alkylene amines). 6-alkylamines or C1-C6 dialkylamines, wherein the alkyl group may be substituted with one or two hydroxyl groups, or optionally substituted –N(C0-C6alkyl)C(O)(O-C1-C6alkyl) groups (which may optionally be further substituted with a polyethylene glycol chain, containing a single halogen, preferably a chlorinated alkyl group further bonded to the polyethylene glycol chain), hydrazine, amides preferably substituted with one or two C1-C6 alkyl groups (including formamides optionally substituted with one or two C1-C6 alkyl groups), alkanols (preferably C1-C6 alkyl or aryl), or alkanonic acids (preferably C1-C6 alkyl or aryl) as substituents. Substituents according to this disclosure may include, for example, –SiR1R2R3 groups, wherein R1 and R2 are each as described elsewhere herein, and R3 is H or C1-C6 alkyl, preferably C1-C3 alkyl (including isopropyl or tert-butyl) in this context. Each of the above groups can be directly attached to the substituted portion, or alternatively, the substituent can be connected via the optionally substituted –(CH2). m -Or alternatively, the substituted -(OCH2) can be selected. m -、-(OCH2CH2) m -or–(CH2CH2O) m - A group (which may be substituted by any one or more of the substituents described above) is attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety). As identified above, alkylene –(CH2) m -or–(CH2) n- Groups or other chains, such as ethylene glycol chains, can be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogens or C1-C6 (preferably C1-C3) 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 halogen groups (preferably F), or side chains of amino acids as described elsewhere herein, and optionally substituted amides (preferably formamides substituted as described above) or carbamate groups (often having one or two C0-C6 alkyl substituents, which may be further substituted). In some 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, or side chains of amino acids as described elsewhere herein. In this disclosure, a portion of the molecule may optionally be substituted with up to five substituents, preferably up to three substituents. Most often, in this disclosure, the substituted portion is substituted with one or two substituents.

[0082] The term "substituted" (each substituent independent of any other substituent) in its context should also mean C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, formamido, sulfone (including sulfonamides), ketones, carboxyl groups, C1-C6 esters (oxy-esters or carbonyl esters), C1-C6 ketones, carbamates -OC(O)-NR1R2 or –N(R1)-C(O)-O-R1, nitro, cyano, and amines (especially including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl-substituted amines, which may optionally be substituted with one or two hydroxyl groups). In this context, unless otherwise stated, each of these groups contains 1 to 6 carbon atoms. In some embodiments, preferred substituents include, for example, –NH-, -NHC(O)-, -O-, =O, -(CH2). m -(here, m and n are 1, 2, 3, 4, 5 or 6 in the context), -S-, -S(O)-, SO2- or –NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1、-(CH2) n C(O)-NR1R2、-(OCH2)n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1、-(CH2O) n C(O)-NR1R2、-S(O)2-R S -S(O)-R S (R S It is a C1-C6 alkyl group or –(CH2). m -NR1R2 group), NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. In the context, R1 and R2 are each H or C1-C6 alkyl (which may optionally be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). In the chemistry of the defined compound and the substituents used, the term "substituted" should also mean an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as described elsewhere herein. As disclosed elsewhere herein, alkylene groups may also be substituted, preferably having an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), a side chain of an amino acid group as described elsewhere herein, an amide group as described above, or a carbamate OC(O)-NR1R2 group, wherein R1 and R2 are as described elsewhere herein, although numerous other groups may also be used as substituents. Various optional substituted portions may be replaced by three or more substituents, preferably no more than three substituents, and more preferably one or two substituents. It should be noted that in compounds in which substitution is required at a specific position in the molecule (primarily due to valence) but the substitution is not indicated, the substituent is interpreted or understood to be H unless the context of the substitution suggests otherwise.

[0083] In this context, the term "aryl" or "aromatic" refers to a substituted (as described elsewhere herein) or unsubstituted monovalent aromatic group having a monocyclic (e.g., benzyl, phenyl, benzyl) or fused ring (e.g., naphthyl, anthracene, phenanthrene, etc.) group, and may be associated with compounds according to this disclosure at any available stable position on the ring or as otherwise indicated in the presented chemical structure. In this context, other examples of aryl groups may include "heteroaryl" groups in heterocyclic aromatic ring systems, particularly having one or more nitrogen, oxygen, or sulfur atoms in a ring (monocyclic) such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or a fused ring system such as indole, quinoline, indazine, azaindazine, benzofuran, etc., which may optionally be substituted as described above. Among the heteroaryl groups that can be mentioned, nitrogen-containing heteroaryl groups are particularly included, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazolium, indole, isoindole, indazine, azaindazine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinazine, phthalazine, naphthidine, quinoxaline, quinazoline, cinnamoline, pteridine, imidazopyridine, imidazotriazine, pyrazinodazine, acridine, phenanthridine, carbazole, carbazolinium. Pyridine, 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, cyclopentopyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazide, phenoxazine, isoxazole, furazine, phenoxazine, pyrazoloxazole, imidazothiazide, thienofuran, furanopyrrole, pyrrolopyridine, furanopyrimidine, thienoopyrimidine, and oxazole, all of which may be optionally substituted.

[0084] The term "heterocyclic" refers to a cyclic group containing at least one heteroatom, i.e., O, N, or S, and can be aromatic (heteroaryl) or non-aromatic. Therefore, depending on the context in which it is used, the heteroaryl portion is included under the definition of a heterocycle. Exemplary heteroaryls are as described above. As described herein, exemplary non-aromatic heterocyclic groups used in this disclosure include, in particular, pyrrolyl, pyrrolinyl, piperidinyl, piperazine, N-methylpiperazine, pyrazolyl, imidazoyl, morpholinyl, tetrahydropyranyl, azacyclic butyl, oxacyclic butyl, oxothiocyclic pentyl, pyridinone, 2-pyrrolidone, ethylurea, 1,3-dioxane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide.

[0085] The terms "co-administration" or "combination therapy" should mean the simultaneous administration of at least two compounds or compositions to a patient such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time point. Although the compounds according to this disclosure can be co-administered to a patient simultaneously, the term includes the simultaneous or different administration of two or more agents, provided that an effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In some preferred aspects of this disclosure, one or more of the compounds described above are co-administered in combination with at least one additional bioactive agent, particularly including anticancer agents. In certain aspects of this disclosure, the co-administration of the compounds results in synergistic therapy, including anticancer therapy.

[0086] This disclosure describes bifunctional compounds and methods of using them, which act to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, this disclosure provides bifunctional or proteolytic targeted chimeric (PROTAC) compounds that can be used as regulators of targeted ubiquitination of Tau protein. An advantage of the compounds provided herein is the availability of a broad range of pharmacological activities consistent with the degradation / inhibition of Tau protein.

[0087] In this manner, this disclosure provides compounds and compositions comprising an E3 ubiquitin ligase targeting moiety (“ULM”) coupled to a Tau protein target-binding moiety (“PTM”), which leads to ubiquitination of the Tau protein, resulting in the degradation (and / or inhibition) of the Tau protein. This disclosure also provides a library of compositions and their uses.

[0088] This specification provides compounds containing ligands, such as small molecule ligands (i.e., molecular weights below 2,000, 1,000, 500, or 200 Daltons), capable of binding ubiquitin ligases, such as VHL or cereblon. The compound also contains a portion capable of binding to a target protein in such a way that the target protein is placed near the ubiquitin ligase to achieve degradation (and / or inhibition) of the protein. In addition to the above, "small molecule" can also mean that the molecule is non-peptide-based, i.e., it is not generally considered a peptide, for example, containing fewer than 4, 3, or 2 amino acids. According to this specification, PTM, ULM, or PROTAC molecules can be small molecules.

[0089] In one embodiment, this specification provides a composition for modulating protein activity. The composition comprises a ubiquitin pathway protein-binding moiety (preferably for VHL or cereblon) and a Tau protein-targeting moiety, preferably linked together by a linker, according to a defined chemical structure, wherein the ubiquitin pathway protein-binding moiety recognizes a ubiquitin pathway protein, and the targeting moiety recognizes a Tau target protein, and wherein the ubiquitin pathway protein-binding moiety is coupled to the Tau targeting moiety.

[0090] In another embodiment, this disclosure provides a compound library. The library contains more than one compound, wherein each composition has a ubiquitin pathway protein-binding moiety (preferably VHL or cereblon) and a Tau protein-binding moiety, wherein a ULM is coupled (preferably via a linker moiety) to Tau, and wherein the ubiquitin pathway protein-binding moiety recognizes ubiquitin pathway proteins, particularly E3 ubiquitin ligases.

[0091] In another embodiment, this disclosure provides a method for ubiquitinizing / degrading a target protein (e.g., Tau) in cells. This method includes administering a bifunctional composition, as described elsewhere herein, comprising a ubiquitin pathway protein-binding portion and a targeting portion preferably linked by a linker portion, wherein the ubiquitin pathway protein-binding portion is coupled to the targeting portion, and wherein the chromophore ubiquitin pathway protein-binding portion recognizes ubiquitin pathway proteins (e.g., VHL, cereblon), and the targeting portion recognizes a target protein (e.g., Tau), such that when the target protein is placed in the vicinity of a ubiquitin ligase, degradation of the target protein occurs, thereby resulting in inhibition of the target protein degradation / effect and control of protein levels. The protein level control provided by this disclosure provides a treatment for a disease state or condition that is modulated by the target protein by reducing the level of this protein in the patient's cells.

[0092] In another embodiment, this disclosure relates to a method for treating a patient in need of a disease state or condition regulated by a protein (e.g., Tau), wherein the degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to the patient in need an effective amount of a compound according to this disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by microbial agents or other exogenous agents (e.g., viruses, bacteria, fungi, protozoa, or other microorganisms), or it may be a disease state caused by the overexpression of a protein, i.e., the accumulation or aggregation of the Tau protein, which leads to the disease state and / or condition.

[0093] In one aspect, this disclosure provides compounds for modulating protein activity. The composition comprises an E3 ubiquitin ligase, a ubiquitin pathway protein-binding moiety, and a protein-targeting moiety, preferably linked or coupled together by a linker, wherein the ubiquitin pathway protein-binding moiety recognizes ubiquitin pathway proteins, and the targeting moiety recognizes target proteins (e.g., Tau). Such compounds may be referred to herein as PROTAC compounds or PROTACs and have the following general chemical structure:

[0094] ULM―L―PTM,

[0095] Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug.

[0096] ULM is the small molecule E3 ubiquitin ligase binding site that binds to E3 ubiquitin ligase.

[0097] PTM is a small molecule containing the Tau protein targeting moiety that degrades Tau protein; and

[0098] L is the bond or chemical linker connecting ULM and PTM.

[0099] In some embodiments, the E3 ubiquitin ligase binding moiety targets members of the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse two-microsome homolog 2 (MLM), and IAP (ILM).

[0100] In one aspect, this specification provides a Tau protein binding moiety (PTM). In some embodiments, the PTM is represented by formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI:

[0101]

[0102] in:

[0103] 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 rings, wherein the contact between the rings indicates ring fusion; and

[0104] L PTM Selected from bonds, alkyl, alkenyl or ynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups selected from -O-, -S-, -NR. 1 PTM -(where R) 1 PTM The functional group 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- or -OC(O)NH-, wherein the functional group is optionally located at either end of the connector.

[0105] In some embodiments, the aryl and heteroaryl rings of A, B, C, D, E, and F of PTM are optionally substituted with 1 to 3 substituents, each of which is independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, amide, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups are further optionally substituted.

[0106] In some embodiments, at least one of A, B, C, F, or combinations thereof is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[0107] In some embodiments, PTM has the chemical structure of Formula I, wherein:

[0108] Rings A, B, and C are independently 5- or 6-membered fused aryl or heteroaryl rings;

[0109] L PTM Selected from bonds or alkyl groups, and

[0110] D is selected from 6-membered aryl, heteroaryl, or heterocyclic alkyl groups.

[0111] A, B, C, and D may be optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano groups.

[0112] In some other embodiments, PTM has the chemical structure of Formula I, wherein:

[0113] A and C are phenyl or 6-membered heteroaryl rings;

[0114] B is a 5-membered heteroaryl ring;

[0115] L PTM It is a key; and

[0116] D is a 6-membered heteroaryl or a 6-membered heterocyclic alkyl ring;

[0117] Each of A, B, C, and D may be optionally and independently substituted with an alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano group, and the nitrogen atom of any one of the rings A, B, C, and D is not directly attached to a heteroatom or carbon atom, while the other heteroatom is directly attached to the heteroatom or carbon atom.

[0118] In other embodiments, PTM has a chemical structure of formula III or IV, wherein A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, L PTM Selected from alkyl or alkyl groups, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano groups.

[0119] In some embodiments, PTM is represented by the following chemical structure:

[0120]

[0121]

[0122] in:

[0123] R 1 R 2 and R 3 Independently selected from H, methyl, ethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl;

[0124] R 4 and R 5 Independently selected from H, methyl, ethyl, and halogen; and

[0125] R 6 It is one or two substituents independently selected from H, methyl, ethyl, and halogen.

[0126] PTM is coupled to ULM via L.

[0127] In any aspect or embodiment described herein, PTM is covalently coupled to one or more ULM (VLM or CLM) groups, or to a connector to which one or more ULM (VLM or CLM) groups are attached, as described herein.

[0128] In some embodiments, PTM is represented by the following chemical structure:

[0129]

[0130]

[0131] in:

[0132] R 1 R 2 and R 3 Independently selected from H, optionally substituted alkyl groups, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and

[0133] R 7 R 8 R 9 and R 10 It is independently selected from 1 to 8 substituents of H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetamino, trifluoromethyl or cyano, and wherein PTM is coupled to ULM (VLM or CLM) via L.

[0134] In some other embodiments, PTM is represented by the following chemical structure:

[0135]

[0136]

[0137] In some embodiments, the connector attachment point to the PTM is shown as indicated by dashed lines:

[0138]

[0139] Example VLM:

[0140] In one respect, ULM is VHL.

[0141] In some embodiments of the compounds described herein, the ULM is a VLM and comprises a chemical structure selected from ULM-a:

[0142]

[0143] in:

[0144] The dashed line indicates at least one PTM, another ULM or VLM or CLM (i.e., ULM' or VLM' or CLM'), or the attachment of a chemical connector portion that couples at least one PTM, ULM' or VLM' or CLM' to the other end of the connector.

[0145] X 1 X 2 Each is independently selected from the bond, O, and NR. Y3 CR Y3 R Y4 , C=O, C=S, SO, SO and SO2;

[0146] R Y3 R Y4 Each is independently selected from H, and straight-chain or branched C, optionally substituted with one or more halogens. 1-6 Alkyl, C 1-6 Alkyl groups);

[0147] R P It consists of one, two, or three groups, each independently selected from H, halogens, -OH, C. 1-3 alkyl;

[0148] W 3 Selected from the arbitrarily replaced –TN(R) 1a R 1b ), Optional replacement of –TN(R) 1a R 1b )X 3-T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-heterocyclic, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocyclic rings;

[0149] X 3 It is C=O, R 1 R 1a R 1b

[0150] R 1 R 1a R 1b Each is independently selected from H, straight-chain or branched C1-C6 alkyl groups optionally substituted with one or more halogen or -OH groups, R Y3 C = O, R Y3 C = S, R Y3 SO, R Y3 SO2, N(R) Y3 R Y4 C = O, N(R) Y3 R Y4 C = S, N(R) Y3 R Y4 )SO and N(R Y3 R Y4 SO2;

[0151] T is covalently bonded to X1;

[0152] W 4 It is optionally substituted -NR1-T-aryl, optionally substituted -NR1-T-heteroaryl, or optionally substituted -NR1-T-heterocyclic, wherein -NR1 is covalently bonded to X2, and R1 is H or CH3, preferably H.

[0153] In any of the embodiments described herein, T is selected from optionally substituted alkyl groups, –(CH2). n - groups, wherein each of the methylene groups is optionally substituted with one or two substituents selected from: halogen, methyl, straight-chain or branched C1-C6 alkyl groups optionally substituted with one or more halogen or -OH groups, or optionally substituted amino acid side chains; and

[0154] n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.

[0155] In some embodiments, W 4 yes Where R 14a R 14bEach is independently selected from H, haloalkyl, or optionally substituted alkyl;

[0156] In any aspect or embodiment described herein, W 5 Selected from phenyl or 5-10 heteroaryl groups,

[0157] R 15 Selected from H, halogens, CN, OH, NO2, NR 14a R 14b OR 14a CONR 14a R 14b NR 14a COR 14b SO2NR 14a R 14b NR 14a SO2R 14b Optionally substituted alkyl groups, optionally substituted haloalkyl groups, optionally substituted haloalkoxy groups; aryl, heteroaryl, cycloalkyl, or cyclohexaalkyl groups;

[0158] In another embodiment, W is used in this disclosure. 4 Substituents also specifically include (and are not limited to) W 4 Substituents, which were found in the compounds identified herein. These W 4 Each of the substituents can be combined with any number of Ws also disclosed herein. 3 Substituents are used in combination.

[0159] In some other embodiments, ULM-α is optionally surrounded by 1-3 R groups in the pyrrolidine moiety. P Group substitution. Each R P It can be H, halogen, -OH, or C1-3 alkyl.

[0160] In any of the embodiments described herein, W 3 W 4 It can be independently covalently coupled to a connector with one or more PTM groups attached.

[0161] And the dashed line indicates the attachment site of at least one PTM, another ULM (ULM'), or a chemical connector portion that couples at least one PTM or ULM' or both to a ULM.

[0162] In some embodiments, the ULM is a VHL and is represented by the following structure:

[0163]

[0164] in:

[0165] W3 Selected from optionally substituted aryl groups, optionally substituted heteroaryl groups, or

[0166] R9 and R 10 Independently, it is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R9, R 10 And the carbon atoms to which they are attached form optionally substituted cycloalkyl groups;

[0167] R 11 Selected from optionally substituted heterocycles, optionally substituted alkoxy groups, optionally substituted heteroaryl groups, optionally substituted aryl groups,

[0168]

[0169] R 12 Selected from H or optionally substituted alkyl groups;

[0170] R 13 Selected from H, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkyl carbonyl, optionally substituted aralkyl carbonyl, optionally substituted aryl carbonyl, optionally substituted (heterocyclic) carbonyl or optionally substituted aralkyl.

[0171] R 14a R 14b Each is independently selected from H, haloalkyl, or optionally substituted alkyl;

[0172] W 5 Selected from phenyl or 5-10 heteroaryl groups,

[0173] R 15 Selected from H, halogens, CN, OH, NO2, NR 14a R 14b OR 14a CONR 14a R 14b NR 14a COR 14b SO2NR 14a R 14b NR 14a SO2R 14b Optionally substituted alkyl groups, optionally substituted haloalkyl groups, optionally substituted haloalkoxy groups; aryl, heteroaryl, cycloalkyl, or cyclohexaalkyl groups (each optionally substituted independently);

[0174] R 16Independently selected from H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxyl or optionally substituted haloalkoxy;

[0175] o is 0, 1, 2, 3 or 4;

[0176] R 18 Independently selected from halogens, optionally substituted alkoxy groups, cyano groups, optionally substituted alkyl groups, haloalkyl groups, haloalkoxy groups, or linkers; and

[0177] p is 0, 1, 2, 3 or 4, and the dashed line indicates the attachment site of at least one PTM, another ULM (ULM'), or a chemical connector portion that couples at least one PTM or ULM' or both to a ULM.

[0178] In some embodiments, R 15 yes Where R 17 It is H, halogen, or C that can be substituted. 3-6 cycloalkyl, with optional substituted C 1-6 Alkyl group, optionally substituted C 1-6 alkenyl and C 1-6 Haloalkyl; and Xa is S or O.

[0179] In some embodiments, R 17 Selected from methyl, ethyl, isopropyl and cyclopropyl.

[0180] In some other embodiments, R 15 Selected from:

[0181]

[0182] In some embodiments, R 11 Selected from:

[0183]

[0184] In some embodiments, the ULM has a chemical structure selected from the following:

[0185]

[0186] in:

[0187] 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.

[0188] R 14a It is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0189] R 15 Selected from H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cyclohexaalkyl;

[0190] X is C, CH2, or C=O.

[0191] R3 is a bond or optionally substituted 5- or 6-membered heteroaryl group; and

[0192] The dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical connector portion that couples at least one PTM or ULM' or both to a ULM (ULM-a).

[0193] In some embodiments, the ULM contains groups according to the following chemical structures:

[0194]

[0195] in:

[0196] R 14a It is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0197] R9 is H;

[0198] R 10 It is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0199] R11 is

[0200] Or optionally, the substituted heteroaryl group;

[0201] p is 0, 1, 2, 3 or 4;

[0202] Each R 18 Independently, it is a halogen, an optionally substituted alkoxy group, a cyano group, an optionally substituted alkyl group, a haloalkyl group, a haloalkoxy group, or a linker;

[0203] R12 is H, C=O;

[0204] R13 is H, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkyl carbonyl, optionally substituted aralkyl carbonyl, optionally substituted aryl carbonyl, optionally substituted (heterocyclic) carbonyl, or optionally substituted aralkyl.

[0205] R 15Selected from H, halogens, Cl, CN, OH, NO2, optionally substituted heteroaryl groups, optionally substituted aryl groups;

[0206]

[0207]

[0208] The dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or chemical connector portions that couple at least one PTM or ULM' or both to a ULM.

[0209] In some embodiments, the ULM is selected from the following structures:

[0210]

[0211]

[0212] Where n is 0 or 1.

[0213] In some embodiments, the ULM is selected from the following structures:

[0214]

[0215]

[0216]

[0217]

[0218] The benzene ring in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15 and ULM-d1 to ULM-d9 may be optionally substituted with fluorine, lower alkyl and alkoxy groups, and the dashed line indicates the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker portion that couples at least one PTM or ULM' or both to ULM-a.

[0219] In one embodiment, the benzene rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15 and ULM-d1 to ULM-d9 may be functionalized into esters so that they become part of a prodrug.

[0220] In some embodiments, the hydroxyl groups on the pyrrolidine rings of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 each comprise an ester-linked prodrug moiety.

[0221] In any aspect or embodiment described herein, ULM and the present ULM' are each independently a group according to the following chemical structure:

[0222]

[0223] in:

[0224] ULM-g's R 1' It is an optional substituted C1-C6 alkyl group, or an optional substituted -(CH2). n OH, optionally substituted -(CH2) n SH, optionally replaced (CH2) n O-(C1-C6)alkyl, optionally substituted (CH2) containing the epoxide moiety WCOCW n -WCOCW-(C0-C6)alkyl (where each W is independently H or C1-C3 alkyl), optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)-(C1-C6 alkyl), optionally substituted -(CH2) n NHC(O)-R1, optionally substituted -(CH2) n C(O)-NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2、-(CH2O) n H. Optional substitution of -(CH2) n OC(O)-(C1-C6 alkyl), optionally substituted -(CH2) n C(O)-O-(C1-C6 alkyl)), optionally substituted -(CH2O) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), optionally substituted -(CH2O) n C(O)-(C1-C6 alkyl), optionally substituted -(OCH2) n NHC(O)-R1, optionally substituted -(CH2O) n C(O)-NR1R2、-(CH2CH2O) n H. Optional substitution of -(CH2CH2O) n COOH, optional substituents -(OCH2CH2) n O-(C1-C6 alkyl), optionally substituted -(CH2CH2O) n C(O)-(C1-C6 alkyl), optionally substituted -(OCH2CH2) nNHC(O)-R1, optionally substituted -(CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S Optional replacement of S(O)R S NO2, CN or halogens (F, Cl, Br, I, preferably F or Cl);

[0225] R1 and R2 of ULM-g are each independently H or C1-C6 alkyl, which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

[0226] ULM-g's R S It is a C1-C6 alkyl group, optionally substituted aryl, heteroaryl, or heterocyclic group, or -(CH2). m NR1R2 group;

[0227] In ULM-g, X and X' are independently C=O, C=S, -S(O), and S(O)2, respectively (preferably both X and X' are C=O);

[0228] ULM-g's R 2' It is optional to replace –(CH2). n -(C=O) u (NR1) v (SO2) w Alkyl groups, optionally substituted –(CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N Groups, optionally substituted –(CH2) n -(C=O) u (NR1) v (SO2) w -Aryl, optionally substituted –(CH2) n -(C=O) u (NR1) v (SO2) w -Heteroaryl, optionally substituted –(CH2) n -(C=O) v NR1(SO2) w - Heterocyclic, 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 Optional replacement of -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N Optional replacement of -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 - Heterocyclic, optionally substituted -X R2’ -alkyl; optionally substituted -X R2’ -Aryl; optional -X to be replaced R2’ - heteroaryl; optionally substituted -X R2’ - Heterocyclic group; optionally substituted;

[0229] ULM-g's R 3' It is an alkyl group that can be optionally substituted, or a –(CH2) group that can be optionally substituted. n -(O) u (NR1) v (SO2) w -alkyl, optionally substituted –(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N Optional substitution of –(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N Optional substitution of –(CH2) n -C(O) u(NR1) v (SO2) w -C(O)NR1R2, optionally substituted –(CH2) n -C(O) u (NR1) v (SO2) w -Aryl, optionally substituted –(CH2) n -C(O) u (NR1) v (SO2) w -Heteroaryl, optionally substituted –(CH2) n -C(O) u (NR1) v (SO2) w - Heterocyclic, 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 Optional replacement of -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N Optional replacement of -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -Aryl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -Heteroaryl, optionally substituted-NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w - Heterocyclic, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2)w -alkyl, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N The -O-(CH2)n-(C=O) component can be arbitrarily substituted. u (NR1) v (SO2) w -NR1C(O)R 1N The -O-(CH2)n-(C=O) component can be arbitrarily substituted. 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 - Heterocyclic; –(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl group, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’ -Aryl group, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’ - Heteroaryl group, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’ -heterocyclic group, arbitrarily 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 -(CH2) n -N(R 1’ (C=O) m’ -(V) n’ - Heterocyclic group, optionally substituted -X R3’ -alkyl group; optionally substituted -X R3’ -Aryl group; optionally substituted -X R3’ - Heteroaryl group; optionally substituted -X R3’ - Heterocyclic group; optionally substituted;

[0230] ULM-g's R 1N and R 2N Each is independently H, a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups and up to three halogen groups, or optionally substituted -(CH2). n -Aryl, -(CH2) n -Heteroaryl or -(CH2) n - Heterocyclic group;

[0231] The V in ULM-g is O, S, or NR1;

[0232] R1 for ULM-g is the same as above;

[0233] ULM-g's R 1 and R 1' Each is independently an H or C1-C3 alkyl group;

[0234] ULM-g's X R2' and X R3' Each is independently arbitrarily replaced –CH2) n -、–CH2) n -CH(X v )=CH(X v -(cis or trans), –CH2) n -CH≡CH-、-(CH2CH2O) n - or C3-C6 cycloalkyl, wherein X v It is H, halogen, or optionally substituted C1-C3 alkyl;

[0235] Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0236] Each m' in ULM-g is independently 0 or 1;

[0237] Each n in ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0238] Each n' in ULM-g is independently 0 or 1;

[0239] Each u in ULM-g is independently 0 or 1;

[0240] Each v in ULM-g is independently 0 or 1;

[0241] Each w in ULM-g is independently 0 or 1; and

[0242] When PTM is not ULM', the R of ULM-g can be optionally modified. 1’ R 2’ R 3’ Any one or more of X and X' to be covalently bonded to the PTM group via a linker group, or, when PTM is ULM', optionally modifying the respective R of ULM and ULM'. 1’ R 2’ R 3’ Any one or more of X and X', covalently bonded to each other directly or through a linker group, or their pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

[0243] In any aspect or embodiment described herein, ULM and the present ULM' are each independently a group according to the following chemical structure:

[0244]

[0245] in:

[0246] ULM-h's R 1' R 2' and R 3' Each is the same as above, and X is a C=O, C=S, -S(O) group or S(O)2 group, more preferably a C=O group, and

[0247] When PTM is not ULM', the R of ULM-h is optionally modified. 1' R 2' and R 3' Any one or more of them, to combine with a linker group that is further covalently bonded to the PTM group, or, when PTM is ULM', optionally modify the respective R of ULM and ULM'. 1' R 2' R 3' One or more of them are covalently bonded to each other directly or through a linker group, or

[0248] Its pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs.

[0249] In any aspect or embodiment described herein, ULM and the existing ULM' are each independently defined by their chemical structures:

[0250]

[0251] in:

[0252] When PTM is not ULM', the R of ULM-I is optionally modified. 1' R 2' and R 3' Any one or more of them, to combine with a linker group that is further covalently bonded to the PTM group, or, when PTM is ULM', optionally modify the respective R of ULM and ULM'. 1' R 2' R 3' One or more of them are covalently bonded to each other directly or through a linker group, or

[0253] Its pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, or polymorphs.

[0254] In a further preferred aspect of the invention, R of ULM-g to ULM-i 1’ Preferably, it is a hydroxyl group or a group that can be metabolized into a hydroxyl or carboxyl group, such that the compound represents a prodrug form of the active compound. An exemplary preferred R 1’ Groups include, for example, -(CH2). n OH, (CH2) n -O-(C1-C6) alkyl groups, -(CH2) n COOH, -(CH2O) n H. Optional substitution of -(CH2) n OC(O)-(C1-C6 alkyl), or optionally substituted -(CH2). n C(O)-O-(C1-C6 alkyl), where n is 0 or 1. When R 1' When it is or contains a carboxylic acid group, it may be further chemically modified with hydroxyl or amino groups, hydroxyl, carboxylic acid or amine (each of which may be optionally substituted) to provide covalent linkage with the PTM group (including ULM) and the linker group thereto.

[0255] When present, X and X' of ULM-g and ULM-h are preferably C=O, C=S, -S(O) groups or S(O)2 groups, more preferably C=O groups;

[0256] ULM-g to ULM-i R 2’ Preferred alternative is -NR. 1 -T-aryl, optionally substituted -NR 1-T-heteroaryl or optionally substituted-NR 1 -T-heterocyclic rings, where R 1 It is H or CH3, preferably H and T are optionally substituted –(CH2). n - A group, wherein each of the methylene groups may optionally be substituted with one or two substituents, said substituents preferably selected from halogens, amino acid side chains as described elsewhere herein, or C1-C3 alkyl groups, preferably one or two methyl groups, which may optionally be substituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be –(CH2O). n - group, –(OCH2) n - group, –(CH2CH2O) n - group, –(OCH2CH2) n - Groups, all of which are optionally substituted.

[0257] Regarding R for ULM-g to ULM-i 2'The preferred aryl group comprises an optionally substituted phenyl or naphthyl group, preferably phenyl, wherein the phenyl or naphthyl group is optionally linked to a PTM group (including a ULM' group) via: a linker group, a halogen (preferably F or Cl), an amine, a monoalkyl- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted at the ortho, meta, and / or para positions, preferably para, on the benzene ring), an optionally substituted phenyl group (the phenyl group itself is optionally linked to a PTM group (including a ULM' group) via a linker group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and / or para positions, preferably para, on the benzene ring), an optionally substituted naphthyl group, an optionally substituted heteroaryl group, and preferably an optionally substituted isoxazole including methyl substitution. The optional substituted oxazoles include methyl-substituted oxazoles, optional substituted thiazoles include methyl-substituted thiazoles, optional substituted isothiazoles include methyl-substituted isothiazoles, optional substituted pyrroles include methyl-substituted pyrroles, optional substituted imidazoles include methyl imidazoles, optional substituted benzimidazoles or methoxybenzyl imidazoles, optional substituted oximidazoles or methyloximidazoles, optional substituted diazolyl groups include methyl diazolyl groups, optional substituted triazolyl groups include methyl-substituted triazolyl groups, optional substituted pyridyl groups include halogen- (preferably F) or methyl-substituted pyridyl or oxapyridyl (wherein the pyridyl group is linked to a phenyl group via oxygen), optional substituted furans, optional substituted benzofurans, optional substituted dihydrobenzofurans, optional substituted indoles, inazines or azaindazines (2, 3 or 4-azaindazines), optional substituted quinolines, and optional substituted groups according to the chemical structure:

[0258]

[0259] in:

[0260] ULM-g to ULM-i S c It is CHR SS NR URE Or O;

[0261] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where Ra It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0262] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0263] ULM-g to ULM-i R URE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclic, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran);

[0264] ULM-g to ULM-i R PRO H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), selected from the following heteroaryl or heterocyclic groups: oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine;

[0265] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group; and

[0266] Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), or optionally a substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine or morpholine (when substituted, each group is preferably substituted with a methyl or halogen (F, Br, Cl), each group may optionally be connected to a PTM group (including the ULM' group) via a linker group).

[0267] In some preferred aspects, ULM-g to ULM-i is

[0268] Group,

[0269] Among them, R of ULM-g to ULM-i PRO The same applies to n as above.

[0270] Regarding R for ULM-g to ULM-i 2’ Preferred heteroaryl groups include optionally substituted quinolines (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles, optionally substituted indazines, optionally substituted azaindazines, optionally substituted benzofurans, including optionally substituted benzofurans, optionally substituted isoxazoles, optionally substituted thiazoles, optionally substituted isothiazoles, optionally substituted thiophenes, optionally substituted pyridines (2-, 3-, or 4-pyridines), optionally substituted imidazoles, optionally substituted pyrroles, optionally substituted diazoles, optionally substituted triazoles, tetraazoles, optionally substituted oximidazoles, or groups according to the following chemical structures:

[0271]

[0272] in:

[0273] ULM-g to ULM-i S c It is CHR SS NR URE Or O;

[0274] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a Among them, R of ULM-g to ULM-i a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0275] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0276] ULM-g to ULM-i R UREIt is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0277] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is an H or C1-C6 alkyl group (preferably C1-C3 alkyl group), and each of the groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[0278] For ULM-g to ULM-i R 2' Preferred heterocyclic groups include tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which may be optionally substituted, or groups according to the following chemical structures:

[0279]

[0280] Preferably, Group,

[0281] in:

[0282] ULM-g to ULM-i R PRO H is an optional substituted C1-C6 alkyl group or an optional substituted aryl, heteroaryl, or heterocyclic group;

[0283] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group, and

[0284] Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (often 0 or 1), and each group may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[0285] ULM-g to ULM-i preferred R2' The substituents also specifically (and not limited to the specific compounds disclosed) R 2' Substituents, which are found in the compounds identified herein (including the specific compounds disclosed in this specification and the accompanying figures). These R 2' Each of the substituents can be combined with any number of R also disclosed herein. 3' Substituents are used in combination.

[0286] ULM-g to ULM-i R 3’ Preferably, it is a -T-aryl group that has been optionally substituted, a -T-heteroaryl group that has been optionally substituted, a -T-heterocyclic group that has been optionally substituted, or a -NR group that has been optionally substituted. 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocyclic rings, where R 1 It is an H or C1-C3 alkyl group, preferably H or CH3, and T is optionally substituted -(CH2). n - A group, wherein each of the methylene groups may optionally be substituted with one or two substituents, the substituents preferably selected from halogens, C1-C3 alkyl groups or side chains of amino acids as described elsewhere herein, preferably methyl groups, which may optionally be substituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be –(CH2O). n - group, –(OCH2) n - group, –(CH2CH2O) n - group, –(OCH2CH2) n - Groups, each of which may be optionally substituted.

[0287] Regarding R for ULM-g to ULM-i 3’ The preferred aryl group includes optionally substituted phenyl or naphthyl groups, preferably phenyl, wherein the phenyl or naphthyl group is optionally linked to a PTM group (including a ULM' group) via: a connector group and / or a halogen (preferably F or Cl), an amine, a monoalkyl- or dialkylamine (preferably dimethylamine), or an amide (preferably –(CH2)). m -NR1C(O)R2 group, where m, R1, and R2 are the same as above), halogen (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN, or S(O)2R S Group (R) S It is a C1-C6 alkyl group, optionally substituted with an aryl, heteroaryl, or heterocyclic group, or (CH2). mThe NR1R2 group, each of which may be substituted at the ortho, meta, and / or para positions, preferably para, on the benzene ring, or an aryl (preferably phenyl), heteroaryl, or heterocyclic group. Preferably, the substituent phenyl is an optionally substituted phenyl (i.e., the substituent phenyl itself is preferably substituted by at least one of the following: F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or a linker group (including the ULM' group) to which it is attached, wherein the substitution occurs at the ortho, meta, and / or para positions, preferably para, on the benzene ring), optionally substituted including naphthyl as described above, optionally substituted heteroaryl (preferably, optionally substituted isoxazoles include methyl-substituted isoxazoles, optionally substituted oxazoles include methyl-substituted oxazoles, optionally substituted thiazoles include methyl-substituted thiazoles, optionally substituted pyrroles include methyl-substituted pyrroles). The substituted pyrrole, optionally substituted imidazole including methylimidazolium, benzylimidazolium or methoxybenzylimidazolium, oximidazole or methyloximidazole, optionally substituted diazolyl including methyldiazolyl, optionally substituted triazolyl including methyl-substituted triazolyl, pyridyl including halogen- (preferably F) or methyl-substituted pyridyl or oxapyridyl (wherein the pyridyl group is linked to a phenyl group via oxygen) or optionally substituted heterocyclic (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or thiane). Each of the aryl, heteroaryl or heterocyclic groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

[0288] Regarding R for ULM-g to ULM-i 3’ Preferred heteroaryl groups include optionally substituted quinolines (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles (including dihydroindoles), optionally substituted indazines, optionally substituted azaindazines (2, 3, or 4-azaindazines), optionally substituted benzimidazoles, benzodiazoles, benzofurans, optionally substituted imidazoles, optionally substituted isoxazoles, optionally substituted oxazoles (preferably methyl-substituted), optionally substituted diazoles, optionally substituted triazoles, tetraazoles, optionally substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl and / or thiol-substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably methyl, triisopropylsilyl, optionally substituted (CH2)). m -O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), optionally substituted pyridine (2-, 3- or 4-pyridine) or groups according to the following chemical structures:

[0289]

[0290] in:

[0291] ULM-g to ULM-i S c It is CHR SS NR URE Or O;

[0292] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0293] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0294] ULM-g to ULM-i R URE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0295] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R aIt is an H or C1-C6 alkyl group (preferably C1-C3 alkyl). Each of the heteroaryl groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

[0296] For ULM-g to ULM-i R 3’ Preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, and thiane, each of which may be optionally substituted, or groups according to the following chemical structures:

[0297] Preferably

[0298] Group,

[0299] in:

[0300] ULM-g to ULM-i R PRO H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), selected from the following heteroaryl or heterocyclic groups: oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine;

[0301] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group, and

[0302] Each n in ULM-g to ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), wherein each of the heterocyclic groups may optionally be connected to the PTM group (including the ULM' group) via a linker group.

[0303] ULM-g to ULM-i preferred R 3’ The substituents also specifically (and not limited to the specific compounds disclosed) R 3’ Substituents, which are found in the compounds identified herein (including the specific compounds disclosed in this specification and the accompanying figures). These R 3’ Each of the substituents can be combined with any number of R also disclosed herein. 2’ Substituents are used in combination.

[0304] In some alternative preferred embodiments, the R of ULM-g to ULM-i 2’It is optional to replace -NR1-X R2’ -alkyl group, -NR1-X R2’ -Aryl group; optionally substituted -NR1-X R2’ -HET, optional replacement -NR1-X R2’ -Aryl-HET or optionally replaced -NR1-X R2’ -HET-aryl,

[0305] in:

[0306] R1 in ULM-g to ULM-i is H or C1-C3 alkyl (preferably H);

[0307] X from ULM-g to ULM-i R2' (It is optional to be replaced –CH2) n -、–CH2) n -CH(X v )=CH(X v (cis or trans), –(CH2) n -CH≡CH-、-(CH2CH2O) n -or C3-C6 cycloalkyl; and

[0308] X from ULM-g to ULM-i v It is H, halogen, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups;

[0309] The alkyl groups from ULM-g to ULM-i are optionally substituted C1-C. 10 Alkyl (preferably C1-C6 alkyl) group (in some preferred embodiments, the alkyl group is often end-capped with a halogen group, Cl or Br);

[0310] The aryl group in ULM-g to ULM-i is optionally substituted phenyl or naphthyl (preferably phenyl); and

[0311] HET in ULM-g to ULM-i is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, inazine, azainazine, quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl) or a group according to the following chemical structure:

[0312]

[0313] ULM-g to ULM-i S c It is CHRSS NR URE Or O;

[0314] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0315] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0316] ULM-g to ULM-i R URE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0317] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0318] ULM-g to ULM-i R PROH, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), selected from the following heteroaryl or heterocyclic groups: oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine;

[0319] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group, and

[0320] Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0321] Each of the groups may optionally be connected to a PTM group (including a ULM' group) via a linker group.

[0322] In certain alternative preferred embodiments of the invention, the R of ULM-g to ULM-i 3' It is optional to replace –(CH2). n -(V) n’ -(CH2) n -(V) n’ -R S3’ Group, optionally substituted -(CH2) n -N(R 1’ (C=O) m’ -(V) n’ -R S3’ Group, optionally substituted -X R3’ -alkyl, optionally substituted -X R3’ -Aryl; optional -X to be replaced R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or optionally substituted -X R3’ -HET-aryl group,

[0323] in:

[0324] R S3’ It is an alkyl group that is optionally substituted (C1-C) 10 (preferably C1-C6 alkyl), optionally substituted aryl or HET groups;

[0325] R 1' It is an H or C1-C3 alkyl group (preferably H);

[0326] V is O, S, or NR 1’ ;

[0327] X R3' It is –(CH2) n -、-(CH2CH2O) n -、–CH2) n -CH(X v )=CH(X v -(cis or trans), –CH2) n -CH≡CH- or C3-C6 cycloalkyl groups, all of which can be substituted at will;

[0328] X V It is H, halogen or C1-C3 alkyl, which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups;

[0329] Alkyl groups are optional substituted C1-C 10 Alkyl (preferably C1-C6 alkyl) group (in some preferred embodiments, the alkyl group is often end-capped with a halogen group, Cl or Br);

[0330] The aryl group is optionally substituted with a phenyl or naphthyl group (preferably phenyl); and

[0331] HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, inazine, azainazine, quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl) or a group according to the following chemical structure:

[0332]

[0333] ULM-g to ULM-i S c It is CHR SS NR URE Or O;

[0334] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0335] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0336] ULM-g to ULM-i R URE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0337] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0338] ULM-g to ULM-i R PRO H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), selected from the following heteroaryl or heterocyclic groups: oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine;

[0339] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group;

[0340] Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

[0341] Each m' from ULM-g to ULM-i is 0 or 1; and

[0342] Each n' from ULM-g to ULM-i is 0 or 1;

[0343] Each of the compounds is preferably attached to an alkyl, aryl, or Het group, optionally via a linker group to a PTM group (including a ULM' group).

[0344] In an alternative embodiment, R of ULM-g to ULM-i 3 'is – (CH2) n -Aryl, –(CH2CH2O) n -Aryl, –(CH2) n -HET or –(CH2CH2O) n -HET,

[0345] in:

[0346] The aryl group in ULM-g to ULM-i is a phenyl group optionally substituted with one or two substituents, wherein the substituents are preferably selected from -(CH2). n OH, a C1-C6 alkyl group optionally substituted with CN, a halogen (up to three halogen groups), OH, -(CH2) n O(C1-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halogen (preferably F, Cl) groups, or

[0347] The aryl groups in ULM-g to ULM-i are substituted with: -(CH2) n OH, -(CH2) n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine (wherein the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halogen (preferably F, Cl) groups) CN, NO2, optionally substituted -(CH2) n -(V) m’ -CH2)n -(V) m’ -(C1-C6)alkyl, –(V) m’ -(CH2CH2O) n -R PEG Group, wherein V is O, S or NR 1' R 1' It is an H or C1-C3 alkyl group (preferably H), and R PEG It is an H or an optionally substituted (including optional carboxyl-substituted) C1-C6 alkyl group, or

[0348] The aryl groups of ULM-g to ULM-i are optionally substituted with heterocyclic rings, which include heteroaryl groups selected from oxazoles, isoxazoles, thiazoles, isothiazoles, imidazoles, diazoles, oximidazoles, pyrroles, pyrrolidines, furans, dihydrofurans, tetrahydrofurans, thiophenes, dihydrothiophenes, tetrahydrothiophenes, pyridines, piperidines, piperazines, morpholine, quinoline, benzofurans, indole, inazines, azaindazines (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl), or groups according to the following chemical structures:

[0349]

[0350] ULM-g to ULM-i S c It is CHR SS NR URE Or O;

[0351] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0352] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0353] ULM-g to ULM-i RURE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0354] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0355] ULM-g to ULM-i R PRO H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), selected from the following heteroaryl or heterocyclic groups: oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine;

[0356] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group;

[0357] The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, inazine, azaindazine, or a group according to the following chemical structure:

[0358]

[0359] ULM-g to ULM-i S c It is CHRSS NR URE Or O;

[0360] ULM-g to ULM-i R HET It is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0361] ULM-g to ULM-i R SS It is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O) (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0362] ULM-g to ULM-i R URE It is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0363] ULM-g to ULM-i Y C Is it N or CR? YC , where R YC It is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O (C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted alkynyl -C≡CR a , where R a It is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0364] ULM-g to ULM-i R PRO H is an optional substituted C1-C6 alkyl group or an optional substituted aryl, heteroaryl, or heterocyclic group;

[0365] ULM-g to ULM-i R PRO1 and R PRO2 Each is independently H, optionally substituted C1-C3 alkyl groups, or together forming a ketone group;

[0366] Each m' from ULM-g to ULM-i is independently 0 or 1; and

[0367] Each n from ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0368] Each of the compounds is preferably attached to a PTM group (including a ULM' group) via a linker group on the alkyl or Het group.

[0369] In yet another embodiment, preferred compounds include those with the following chemical structures:

[0370]

[0371] in:

[0372] ULM-i's R 1’ It is an OH group or a group that is metabolized or subjected to OH in the patient;

[0373] ULM-i's R 2' It is -NH-CH2-aryl-HET (preferably, a phenyl group directly linked to a methyl-substituted thiazole);

[0374] ULM-i's R 3' Yes – CHR CR3’ -NH-C(O)-R 3P1 Group or –CHR CR3’ -R 3P2 Group;

[0375] ULM-i's R CR3' It is a C1-C4 alkyl group, preferably methyl, isopropyl or tert-butyl;

[0376] ULM-i's R 3P1 It is a C1-C3 alkyl group (preferably methyl), or optionally substituted oxecyclobutane group (preferably methyl-substituted, –(CH2)). n The OCH3 group, wherein n is 1 or 2 (preferably 2), or Groups (the ethyl ether group is preferably substituted on the phenyl moiety), morpholino groups (attached to the carbonyl group at the 2- or 3-position);

[0377] ULM-i's R 3P2 yes Group;

[0378] The aryl group of ULM-i is phenyl;

[0379] The HET of ULM-i is either a substituted thiazole or an isothiazole; and

[0380] ULM-i's R HET It is an H or halogen group (preferably H);

[0381] Or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein each of the compounds is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0382] In some respects, bifunctional compounds contain a ubiquitin E3 ligase-binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[0383]

[0384] in:

[0385] 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 group;

[0386] R7 in ULM-j is H or an substituted alkyl group;

[0387] In ULM-j, E is a bond, C=O, or C=S;

[0388] In ULM-j, G is a bond, an substituted alkyl group, -COOH, or C=J;

[0389] J in ULM-j is O or N-R8;

[0390] R8 of ULM-j is H, CN, an optionally substituted alkyl group, or an optionally substituted alkoxy group;

[0391] In ULM-j, M is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group, or...

[0392] ULM-j's R9 and R 10 Independently, it is H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R9, R 10 And the carbon atoms to which they are attached form optionally substituted cycloalkyl groups;

[0393] ULM-j's R 11It is an optionally substituted heterocycle, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, an optionally substituted aryl group, or...

[0394] ULM-j's R 12 It is H or an alkyl group that is optionally substituted;

[0395] ULM-j's R 13 It is H, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkyl carbonyl, optionally substituted aralkyl carbonyl, optionally substituted aryl carbonyl, optionally substituted (heterocyclic) carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl) carbamate,

[0396] ULM-j for each R 14 Independently, it is H, a haloalkyl, an optionally substituted cycloalkyl, an optionally substituted alkyl, or an optionally substituted heterocyclic alkyl;

[0397] ULM-j's R 15 It is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy or optionally substituted heterocyclic group;

[0398] ULM-j for each R 16 Independently, it is a halogen, an optionally substituted alkyl group, an optionally substituted haloalkyl group, CN, or an optionally substituted haloalkoxy group;

[0399] ULM-j for each R 25 Independently H or optionally substituted alkyl; or two R 25 The groups can together form oxo or optionally substituted cycloalkyl groups;

[0400] ULM-j's R 23 It is H or OH;

[0401] Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; and

[0402] The o in ULM-j is 0, 1, 2, 3, or 4, or its pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph.

[0403] In some embodiments, where G of ULM-j is C=J, J is O, R7 is H, and each R 14 It is H, and o is 0.

[0404] In some embodiments, where G of ULM-j is C=J, J is O, R7 is H, and each R 14 It is H, R 15It is an optional heteroaryl group that is substituted, and o is 0. In other cases, E is C=O and M is

[0405] In some embodiments, where E of ULM-j is C=O, R 11 Is it an optional substituted heterocycle or And M is

[0406] In some embodiments, where E of ULM-j is C=O, and M is And R 11 yes Each R 18 Independently, it is a halogen, an optionally substituted alkoxy group, a cyano group, an optionally substituted alkyl group, a haloalkyl group, or a haloalkoxy group; and p is 0, 1, 2, 3, or 4.

[0407] In some embodiments, ULM and the existing ULM' are each independently a group according to the following chemical structure:

[0408]

[0409] in:

[0410] In ULM-k, G is C=J, and J is O;

[0411] R7 in ULM-k is H;

[0412] ULM-k for each R 14 It is H;

[0413] The o in ULM-k is 0;

[0414] ULM-k's R 15 yes and

[0415] ULM-k's R 17 It is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[0416] In other cases, ULM-k's R 17 It is an alkyl group (e.g., methyl) or a cycloalkyl group (e.g., cyclopropyl).

[0417] In other embodiments, ULM and the existing ULM' are each independently a group according to the following chemical structure:

[0418]

[0419] in:

[0420] In ULM-k, G is C=J, and J is O;

[0421] R7 in ULM-k is H;

[0422] ULM-k for each R 14 It is H;

[0423] The o in ULM-k is 0; and

[0424] ULM-k's R 15 Selected from:

[0425] Among them, ULM-k's R 30 It is H or an alkyl group that is optionally substituted.

[0426] In other embodiments, ULM and the existing ULM' are each independently a group according to the following chemical structure:

[0427]

[0428] in:

[0429] E for ULM-k is C=O;

[0430] The M in ULM-k is and

[0431] ULM-k's R 11 Selected from:

[0432]

[0433]

[0434] In other embodiments, the chemical structure of the compound,

[0435]

[0436] in:

[0437] E for ULM-k is C=O;

[0438] ULM-k's R 11 yes and

[0439] The M in ULM-k is

[0440] The q of ULM-k is 1 or 2;

[0441] ULM-k's R 20H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or;

[0442] ULM-k's R 21 It is H or an alkyl group that is optionally substituted; and

[0443] ULM-k's R 22 It is H, an optionally substituted alkyl group, an optionally substituted alkoxy group, or a haloalkyl group.

[0444] In any of the embodiments described herein, the R of ULM-j or ULM-k 11 Selected from:

[0445]

[0446]

[0447] In some embodiments, the R of ULM-j or ULM-k 11 Selected from:

[0448]

[0449]

[0450]

[0451] In some embodiments, the ULM (or the existing ULM') is a group based on the following chemical structure:

[0452]

[0453] in:

[0454] X in ULM-l is O or S;

[0455] In ULM-l, Y is H, methyl, or ethyl;

[0456] ULM-l's R 17 It is H, methyl, ethyl, hydroxymethyl, or cyclopropyl;

[0457] In ULM-l, M is an optionally substituted aryl group, an optionally substituted heteroaryl group, or...

[0458] R9 in ULM-l is H;

[0459] ULM-l's R 10 It is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;

[0460] R11 of ULM-l is an optionally substituted heteroaromatic compound, optionally substituted heterocyclic compound, optionally substituted aryl compound, or...

[0461] ULM-l's R 12 It is H or an alkyl group that is optionally substituted; and

[0462] ULM-l's R 13 It is H, optionally substituted alkyl, optionally substituted alkyl carbonyl, optionally substituted (cycloalkyl)alkyl carbonyl, optionally substituted aralkyl carbonyl, optionally substituted aryl carbonyl, optionally substituted (heterocyclic) carbonyl or optionally substituted aralkyl; optionally substituted (oxoalkyl) carbamate.

[0463] In some embodiments, ULM and the present ULM' are each independently groups according to the following chemical structures:

[0464]

[0465] in:

[0466] The Y in ULM-m is H, methyl, or ethyl;

[0467] The R9 of ULM-m is H;

[0468] R 10 It is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;

[0469] ULM-m's R 11 It can be an amide that is optionally substituted, an isoindolineone that is optionally substituted, an isoxazole that is optionally substituted, or a heterocyclic compound that is optionally substituted.

[0470] In other preferred embodiments of the invention, ULM and the existing ULM' are each independently a group according to the following chemical structure:

[0471]

[0472] in:

[0473] ULM-n's R 17 It is methyl, ethyl, or cyclopropyl; and

[0474] ULM-n's R9, R 10 and R 11 As defined above. In other cases, R9 is H; and

[0475] ULM-n's R 10 It is H, alkyl or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[0476] In any aspect or embodiment described herein, the ULM (or ULM' present herein) may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any aspect or embodiment described herein, the ULM (or ULM' present herein) may be directly coupled to the PTM via a bond or chemical linker.

[0477] In some aspects of this invention, the ULM portion is selected from:

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] The VLM can be connected to the PTM at any suitable location via a connector as described herein, including, for example, an aryl, heteroaryl, phenyl, or phenyl group of indole, optionally via any suitable functional group, such as an amine, ester, ether, alkyl, or alkoxy group.

[0501] Example CLM:

[0502] In any aspect or embodiment described herein, the specification provides compounds that can be used to bind and / or inhibit cereblon (e.g., ULM is CLM, PTM is CLM, or both ULM and PTM are CLM).

[0503] In some embodiments, the ULM is a CLM, which is thalidomide, lenalidomide, pomalidomide, its analogues, its isotopes or derivatives thereof.

[0504] New imide compounds

[0505] In some embodiments, the CLM is selected from the following chemical structures:

[0506]

[0507]

[0508] in:

[0509] W is selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0510] Each X is independently selected from O, S, and H2;

[0511] Y is selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclic, O, and S;

[0512] Z is selected from O, S, and H2;

[0513] G and G' are independently selected from H, alkyl (straight chain, branched chain, optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclic group optionally substituted with R', and benzyl group optionally substituted with R';

[0514] Q1, Q2, Q3, and Q4 represent carbon Cs that are substituted by groups independently selected from R', N, or N-oxides;

[0515] A is independently selected from H, alkyl, cycloalkyl, Cl, and F;

[0516] R includes, but is not limited to: -CONR'R”, -OR', -NR'R”, -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, -aryl, -heteroaryl, -alkyl (straight-chain, branched, optionally substituted), -cycloalkyl, -heterocyclic, -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;

[0517] R' and R" are independently selected from bonds, H, N, N-oxides, alkyl (straight-chain, branched-chain), cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R or heterocyclic groups, each of which may be optionally substituted;

[0518] This indicates that the bond can be stereospecific ((R) or (S)) or non-stereospecific; and

[0519] R n Contains functional groups or atoms.

[0520] Where n is an integer from 1 to 4, and where:

[0521] When n is 1, modify R n It is covalently linked to the linker group (L), and

[0522] When n is 2, 3, or 4, it modifies an R. n It is covalently linked to the linker group (L) and optionally modified with any other R. n It is covalently linked to PTM, CLM, a second CLM having the same chemical structure as CLM, CLM', a second connector, or any combination thereof.

[0523] Exemplary CLM

[0524] In any of the compounds described herein, the CLM comprises a chemical structure selected from the following:

[0525]

[0526] in:

[0527] W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0528] X is independently selected from O, S, and H2;

[0529] Y is independently selected from CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclic, O, and S;

[0530] Z is independently selected from O, S or H2, except that neither X nor Z is H2;

[0531] G and G' are independently selected from H, alkyl (straight chain, branched chain, optionally substituted with R'), OH, R'OCOOR, R'OCONRR", CH2-heterocyclic group optionally substituted with R', and benzyl group optionally substituted with R';

[0532] Q1–Q4 represent carbon Cs that are substituted by groups independently selected from R', N, or N-oxides;

[0533] A is independently selected from H, alkyl, cycloalkyl, Cl, and F;

[0534] R includes, but is not limited to: -CONR'R”, -OR', -NR'R”, -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, -aryl, -heteroaryl, -alkyl (straight-chain, branched, optionally substituted), -cycloalkyl, -heterocyclic, -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-NO 2) 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;

[0535] R' and R" are independently selected from bonds, H, N, N-oxides, alkyl (straight-chain, branched-chain), cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R or heterocyclic groups, each of which may be optionally substituted;

[0536] n is an integer from 1 to 4;

[0537] This indicates that the bond can be stereospecific ((R) or (S)) or non-stereospecific; and

[0538] Rn contains 1-4 independent functional groups or atoms, and optionally, one of them is modified to be covalently linked to ABM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0539] In some embodiments described herein, the CLM or ULM comprises a chemical structure selected from the following:

[0540]

[0541] in:

[0542] W is independently selected from CH2, C=O, NH and N-alkyl;

[0543] R is independently selected from H, methyl, and alkyl;

[0544] This indicates that the bond can be stereospecific ((R) or (S)) or non-stereospecific; and

[0545] Rn contains 1-4 independently selected functional groups or atoms, and optionally, one of them is modified to be covalently linked to PTM, chemical linker group (L), CLM (or CLM') or a combination thereof.

[0546] In some embodiments, the CLM is represented by the following structure, where dashed lines indicate connector attachment points:

[0547]

[0548] More specifically, non-limiting examples of CLMs include those shown below and those “hybrid” molecules that originate from combinations of one or more different features shown in the molecules below.

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] In any of the compounds described herein, the CLM comprises a chemical structure selected from the following:

[0560]

[0561]

[0562] in:

[0563] The W in formulas (h) to (ab) is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0564] In formulas (h) to (ab), Q1, Q2, Q3, Q4, and Q5 independently represent carbon C substituted by groups independently selected from R', N, or N-oxides;

[0565] R from (h) to (ab) 1 Selected from H, CN, and C1-C3 alkyl groups;

[0566] R from (h) to (ab) 2 Selected from H, CN, C1-C3 alkyl groups, CHF2, CF3, and CHO;

[0567] R from (h) to (ab) 3 Selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;

[0568] R from (h) to (ab) 4 Selected from H, alkyl, and substituted alkyl;

[0569] R from (h) to (ab) 5 It is H or a lower alkyl group;

[0570] X in equations (h) to (ab) is C, CH, or N;

[0571] R' in formulas (h) to (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0572] R in formulas (h) to (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halo-lower alkoxy or halo-lower alkyl;

[0573] Formulas (h) to (ab) contain either single or double bonds; and

[0574] CLM is covalently linked to PTM, chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0575] In any aspect or embodiment described herein, CLM or CLM' is via an R group of formula (h) to (ab) (e.g., R, R). 1 R 2 R 3 R 4 The R, W, X or Q groups (e.g. Q1, Q2, Q3, Q4 or Q5) are covalently attached to PTM, chemical linker group (L), ULM, CLM, CLM' or combinations thereof.

[0576] In any of the embodiments described herein, CLM or CLM' is defined via W, X, R, R of formulas (h) to (ab). 1 R 2 R 3 R 4 R 5 R', Q1, Q2, Q3, Q4 and Q5 are covalently linked to PTM, chemical linker group (L), ULM, CLM, CLM' or combinations thereof.

[0577] In any of the embodiments described herein, W, X, R in equations (h) to (ab) 1 R 2 R 3 R 4 R', Q1, Q2, Q3, Q4 and Q5 can be independently covalently coupled to a connector and / or attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0578] More specifically, non-limiting examples of CLMs include those shown below and “hybrid” molecules or compounds that originate from combining one or more different features of the following compounds:

[0579]

[0580]

[0581] in:

[0582] The W in formulas (ac) to (an) is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl;

[0583] R from (ac) to (an) 1 Selected from H, CN, and C1-C3 alkyl groups;

[0584] R from (ac) to (an) 3Selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;

[0585] R in equations (ac) to (an) is H;

[0586] Is it a single bond or a double bond; and

[0587] Rn in formulas (ac) to (an) contains functional groups or atoms.

[0588] In any of the embodiments described herein, W and R in formulas (ac) to (an) 1 R 2 Q1, Q2, Q3, Q4 and Rn can be independently covalently coupled to the connector and / or attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0589] In any of the embodiments described herein, R of equations (ac) to (an) 1 R 2 Q1, Q2, Q3, Q4 and Rn can be independently covalently coupled to the connector and / or attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0590] In any of the embodiments described herein, Q1, Q2, Q3, Q4 and Rn of formulas (ac) to (an) may be independently covalently coupled to a connector and / or to a connector attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0591] In any aspect or embodiment described herein, the R modified (ac) to (an) n It is covalently linked to a linker group (L), PTM, ULM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any combination thereof.

[0592] In any aspect or embodiment described herein, CLM is selected from:

[0593]

[0594] Where R' is a halogen, and R 1 As described above with respect to equations (h) to (ab) or (ac) to (a).

[0595] In some cases, CLMs can be imides that bind to cereblon E3 ligase. These imides and adapter attachment sites can be, but are not limited to, the following structures:

[0596]

[0597] Where R' is a halogen.

[0598] Example connector:

[0599] In any aspect or embodiment containing the ULM-L-PTM structure, the connector (L) comprises a chemical structural unit represented by the following formula:

[0600] -(A) q -,

[0601] in:

[0602] A is a group attached to the ULM or PTM portion; and

[0603] q is an integer greater than or equal to 1.

[0604] Where A is selected from bond, CR L1 R L2 ,O,S,SO,SO2,NR L3 SO2NR L3 ,SONR L3 CONR L3 ,NR L3 CONR L4 ,NR L3 SO2NR L4 CO, CR L1 =CR L2 ,C≡C,SiR L1 R L2 ,P(O)R L1 ,P(O)OR L1 ,NR L3 C(=NCN)NR L4 ,NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , Select any 0-6 R L1 and / or R L2 C with substituent group 3-11 cycloalkyl, optionally with 0-6 R L1 and / or R L2 C with substituent group 3-11 Heterocyclic groups, optionally with 0-6 R groups L1 and / or R L2 Group-substituted aryl groups, optionally with 0-6 R groups L1 and / or R L2 Group-substituted heteroaryl groups, wherein R L1 or R L2 Each can be independently and optionally linked to other groups to form a group optionally bounded by 0-4 R groups. L5Group-substituted cycloalkyl and / or heterocyclic moieties;

[0605] R L1 R L2 R L3 R L4 and R L5 Each is independently H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C) 1-8 cycloalkyl)2, N(C) 1-8 cycloalkyl)(C 1-8 Alkyl groups, OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C) 1-8 Alkyl), C(C) 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl groups, CO2H, halogens, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C) 1-8 Alkyl)2, CONHC 1-8 Alkyl, CON(C) 1-8 Alkyl)2, N(C) 1-8 Alkyl)CONH(C 1-8 alkyl), N(C) 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON (C 1-8 Alkyl)2, NHCONH2, N(C)1-8 alkyl)SO2NH(C 1-8 alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NH SO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2, NH SO2NH2.

[0606] In any aspect or embodiment described herein, the connector (L) comprises the following chemical structure:

[0607]

[0608] in:

[0609] W L1 and W L2 Each is independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ being independently H, halogen, OH, CN, CF3, C1-C6 alkyl (straight chain, branched, optionally substituted), C1-C6 alkoxy (straight chain, branched, optionally substituted), or two RQ groups together with the atoms to which they are attached to form a 4-8 membered ring system containing 0-4 heteroatoms;

[0610] Y L1 Each is independently a bond, a C1-C6 alkyl group (straight-chain, branched, optionally substituted) and optionally one or more C atoms replaced by O; or a C1-C6 alkoxy group (straight-chain, branched, optionally substituted); and

[0611] The dashed line indicates the attachment point to the PTM or ULM section.

[0612] In any aspect or embodiment described herein, the connector (L) comprises the following chemical structure:

[0613]

[0614] in:

[0615] W L1 and W L2 Each is independently an aryl, heteroaryl, cyclol, heterocyclic, C 1-6 Alkyl, bicyclic, diaryl, diheteroaryl, or diheterocyclic, each optionally R Q Replace, each R Q Independently, it can be H, halogen, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 alkenyl, C 2-6 Alkynyl, C1-C6 alkyl (straight-chain, branched, optionally substituted), C1-C6 alkoxy (straight-chain, branched, optionally substituted), OC1-3 Alkyl groups (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN, or 2 R Q The groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[0616] Y L1 Each is an independent key, NR YL1 O, S, NR YL2 CR YL1 R YL2 C=O, C=S, SO, SO2, C1-C6 alkyl (straight-chain, branched, optionally substituted), and optionally one or more C atoms are replaced with O; C1-C6 alkoxy (straight-chain, branched, optionally substituted);

[0617] Q L It is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally bounded by 0-6 R atoms. Q Replace, each R Q H and C independently 1-6 Alkyl groups (straight-chain, branched, optionally substituted with one or more halogens, C) 1-6 alkoxy group), or two R groups Q Groups, together with the atoms to which they are attached, form 3-8 membered ring systems containing 0-2 heteroatoms.

[0618] R YL1 R YL2 Each is independently H, OH, C 1-6 Alkyl groups (straight-chain, branched, optionally substituted with one or more halogens, C) 1-6 alkoxy), or R 1 R 2 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms;

[0619] n is 0-10; and

[0620] The dashed line indicates the attachment point to the PTM or ULM section.

[0621] In some embodiments, the linker group (L) comprises a group represented by a general structure selected from:

[0622] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2)r -OCH2-,

[0623] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[0624] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[0625] -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[0626] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-;

[0627] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[0628]

[0629] Each of m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, there is no NO or OO bond; R is selected from H, methyl, or ethyl, and X is selected from H or F;

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636] In some other embodiments, the connector (L) is selected from:

[0637]

[0638]

[0639]

[0640] In some preferred embodiments, the connector (L) is selected from:

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] Each n and m is independently 0, 1, 2, 3, 4, 5, or 6.

[0653] In some embodiments, L is an optionally substituted polyvinyl group comprising 1 to 10 units.

[0654] In some other embodiments, L is a polyethylene group optionally substituted with aryl or phenyl groups comprising 1 to 10 ethylene glycol units.

[0655] In any embodiment, the compound comprises multiple ULMs, multiple PTMs, multiple connectors, or any combination thereof.

[0656] Exemplary Tau-PROTAC compounds

[0657] As described above, in some respects, this specification provides bifunctional PROTAC compounds comprising at least one PTM group, a linker, and at least one ULM (VLM or CLM) group as described herein.

[0658] In some embodiments, the compounds are selected from compounds 1-330 (e.g., selected from Table 1 or 2), their salts, and polymorphs.

[0659] In some embodiments, the compounds are selected from Table 1 or 2 (i.e., the compounds are selected from compounds 1-330), their salts and polymorphs.

[0660] In any aspect or embodiment described herein, the compounds are selected from formulas C1 to C1:

[0661]

[0662]

[0663] in:

[0664] R 101 It consists of 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano;

[0665] R 102 Selected from H, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl;

[0666] R 103 It consists of 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano;

[0667] R 104 It consists of 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano;

[0668] R 105 It consists of 1-2 substituents independently selected from H, alkyl, halogen, haloalkyl, or cyano;

[0669] R 106 R 107 R 109 R 110 R 111 R 112 R113 R 114 R 116 R 117 R 120 R 121 R 126 R 127 R 122 and R 123 Each is independently selected from H, alkyl, halogen, or haloalkyl;

[0670] R 108 It is one or two substituents independently selected from H, alkyl, halogen, haloalkyl, cyano or methoxy;

[0671] R 115 Selected from H, alkyl, and haloalkyl;

[0672] R 118 and R 119 Independently selected from H, alkyl, halogen or haloalkyl, or R 118 and R 119 Together with the carbon atoms to which they are attached, they represent 3-6 membered cycloalkyl or heterocycloalkyl rings, such as cyclopropane or oxetane;

[0673] R 124 and R 125 Independently selected from H, alkyl, halogen or haloalkyl, or R 124 and R 125 Together with the carbon atoms to which they are attached, they represent 3-6 membered cycloalkyl or heterocycloalkyl rings, such as cyclopropane or oxetane;

[0674] G is a phenyl or a 5- or 6-membered heteroaryl ring; and

[0675] Z is CH2 or C=O.

[0676] In any aspect or embodiment described herein, at least one of the following:

[0677] R 101 It is H, F, or Cl;

[0678] R 102 It is H, CH3, or CF2H;

[0679] R 103 It is H or F;

[0680] R 104 It is H, CH3, F, or CN;

[0681] R 105 It is H, CN, CH3 or CF3;

[0682] R 106 and R107 Each can be independently H, F, or CH3;

[0683] R 108 It is H, F, or CH3O;

[0684] R 109 and R 110 Each is independently H or CH3;

[0685] R 111 and R 112 Each can be independently H, F, or CH3;

[0686] R 113 and R 114 Each is independently H or CH3;

[0687] R 115 It is H or CH3;

[0688] R 116 and R 117 Each is independently H or CH3;

[0689] R 118 and R 119 Each of them independently is H, CH3, F, or R. 118 and R 119 Together with the carbon atoms to which they are attached, they represent cyclopropane or oxobutane rings;

[0690] R 120 and R 121 Each is independently H or CH3;

[0691] R 122 and R 123 Each is independently H or CH3;

[0692] R 124 and R 125 Each of them independently is H, CH3, F, or R. 124 and R 125 Together with the carbon atoms to which they are attached, they represent cyclopropane or oxobutane rings;

[0693] R 126 and R 127 Each is independently H or CH3;

[0694] A is pyridine or pyrimidine;

[0695] Z is CH2 or C=O; or

[0696] Its combination.

[0697] In any aspect or embodiment described herein, the compound is selected from: (2S,4R)-1-((S)-14-(5-(5H-pyridino[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-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (1); 4-(2-(2-(2-(2-(5-(5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoin Dolin-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)isoindolline-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)isoindolline-1,3-dione (4); (2S,4R)-1-((S)-2-(2-(2-(2-(5-(5H- Pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (5); (2S,4R)-1-((S)-17-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (6); (2S,4R)-1-((S) (7) -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-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-4-oxo-6,9,12-trioxa-3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazolyl-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-methylthiazolyl- 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-tetraoxo (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)pyrrolidin-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)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidin-2-carboxamide (14) (2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazine-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-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-oxo-6,9,12,15-tetraoxa-3-azaheptadecanyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-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-azatetradecanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (17); (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-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (18); (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-6,9,12,15-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-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide ]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (21); (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-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (22);(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-azaheptocetanoyl)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (23); (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-azaheptocetanoyl)-4-hydroxy-N-(4- (4-Methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (24); 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-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26); (2S,4R)- 1-((S)-2-(2-(2-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)ethoxy)ethoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (27); (2S,4R)-1-((S)-2-(2-(2-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)ethoxy)ethoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (28); (2 (29) (2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (30)(2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-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)quinoline-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (31); (32) pyrrolidine-2-carboxamide; (33) pyrrolidine-2-carboxamide; (34) pyrrolidine-2-carboxamide; (35) pyrrolidine-2-carboxamide; (36) pyrrolidine-2-carboxamide; (37) pyrrolidine-2-carboxamide; (38) pyrrolidine-2-carboxamide; (39) pyrrolidine-2-carboxamide; (30) pyrrolidine-2-carboxamide; (31) pyrrolidine-2-carboxamide; (32) pyrrolidine-2-carboxamide; (32) pyrrolidine-2-carboxamide; (33) pyrrolidine-2-carboxamide; (34) pyrrolidine-2-carboxamide; (38) pyrrolidine-2-carboxamide; (39) pyrrolidine-2-carboxamide; (30) pyrrolidine-2-carboxamide; (32) pyrrolidine-2-carboxamide; (32) pyrrolidine-2-carboxamide; (33) pyrrolidine-2-carboxamide; (34) pyrrolidine-2-carboxamide; (35) pyrrolidine-2-carboxamide; (36) pyrrolidine-2-carboxamide; (37) pyrrolidine-2-carboxamide; (38) pyrrolidine-2-carboxamide; (39) pyrrolidine-2-carboxamide; (32 ... Amine (34); (2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)propoxy)propoxy)acetamyl)-3,3-dimethylbutyryl)-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)quinoline-6-yloxy)propoxy)propoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-Carboxamide (36); (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)pentoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (37); (2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)pentoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (38);(2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (39); 4-(15-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-3,6,9,12-tetraoxapentadecanylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40); 4-((2-(2-(2-(2-(4-(benzo[4] ,5]imidazo[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)quinoline-6-yloxy) )-14-hydroxy-4-oxo-6,9,12-trioxa-3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide (43); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)propoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (44); 4-(15-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-14-hydroxy-3,6,9,12-tetraoxapentadecanylamino)-2-(2,6-dioxopiperidin-3-yl) (45) isoindoline-1,3-dione; (2S,4R)-1-((2S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-17-hydroxy-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide (46); 4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinoline-6-yloxy)-2-hydroxypropoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (47);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-tetraoxatetradecylamino)isoindololin-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-oxoisoindololin-2-yl)piperidin-2,6-dione (49); 3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-1-oxoisoindololin-2-yl)piperidin-2,6-dione Tetraalkyloxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (50); 5-((14-((5-(5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (51); 5-((5-(4-(2-(3-(5-(5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin-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-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (53); 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)isoindolline-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)pyridin-3-yl)propyl 5-((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-dioxopiperdol-3-yl)isoindol-1,3-dione (56); 5-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)piperdol-1-yl)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperdol-3-yl)isoindol-1,3-dione (57);5-((5-(2-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)ethoxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindololin-1,3-dione (58); 5-((5-(4-(2-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindololin-1,3-dione (59); 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)isoindolline-1,3-dione (60); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindolline-1,3-dione (61); 3-(5-((5-(4-(3-(5-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindolline-1,3-dione 2-(2,6-dioxonyl)pentyl)oxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (62); 2-(2,6-dioxonyl-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione (63); 5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxonyl- 3-yl)isoindoline-1,3-dione (64); 5-((5-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (65); 5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (66);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindolline-1,3-dione (67); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindolline-1,3-dione (68); 2-(2,6-dioxopiperidin-3-yl)-5-((14 -((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindolline-1,3-dione (69); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-(1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindolline-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-tetraoxapentadecan-14-yn-1-yl)oxy)isoindolline-1,3-dione (71); 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)-4,6,7-trifluoroisoindolline-1,3-dione (72); [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- [[2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione](73); 2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin2-yl)-3,6,9,12-tetraoxapentadecanyl)oxy)isoindoline-1,3-dione (74); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((5-(5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin2-yl)oxy)pentyl)oxy)pentyl)piperidin-1-yl)isoindoline-1,3-dione (75);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(3-(5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)propoxy)azacyclobutane-1-yl)isoindolline-1,3-dione (76); 5-(3-(5-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (77); 2-(2,6-dioxopiperidin-3-yl)-5-(4-( 6-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)piperazin-1-yl)isoindolline-1,3-dione (78); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azacyclobutane-1-yl)isoindolline-1,3-dione (79); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(5-((5-((5-methyl-5H-pyridano[4,3-b]indol-7-yl)oxy)pentyl)oxy)azonyl)butane-1-yl)isoindolline-1,3-dione 3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azacyclobutane-3-yl)oxy)isoindolline-1,3-dione (80); 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-fluoroisoindolline-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)cyclobutoxy)piperidin 1-pyridyl)pentyl)oxy)isoindoline-1,3-dione (82); 5-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indoline-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]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione (84);2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione (85); 4-((14-(4-(5H-pyridino[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-pyridino[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)pyridin2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindolline-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)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindolline-1,3-dione (89); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)but-2-yn-1-yl)oxy)butoxy)butoxy)isoindolline-1,3-dione (90); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyridino[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]indoline-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (92); 5-((6-((5-(2,2-difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indoline-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-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindolline-1,3-dione (94); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)isoindolline-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)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindolline-1,3-dione (96); 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)isoindolline-1,3-dione (97); 2-(2 ,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hexyl)oxy)isoindolline-1,3-dione (98); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azacyclobutane-3-yl)oxy)isoindolline-1,3-dione (99); 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]heptane-2-yl)isoindolline-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)azacyclobutane-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (101);2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)pyridin3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (102); 5-((14-((5-(8,9-difluoro-5H-pyridino[4,3-b]indol-7-yl)pyridin2-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)isoindoline-1,3-dione 2-(2,6-dioxadiazin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)propoxy)propoxy)azicyclobutane-1-yl)isoindolline-1,3-dione (104); 2-(2,6-dioxadiazin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin2-yl)oxy)cyclobutoxy)propoxy)propyl)azicyclobutane-3-yl)oxy)isoindolline-1 ,3-Diketone (105); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-(3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azacyclobutane-1-yl)pentyl)oxy)pentyl)oxy)isoindoline-1,3-diketone (106); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptane-2-yl)butoxy)butoxy)isoindoline-1,3-diketone (107) ;2-(2,6-dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindolline-1,3-dione (108); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindolline-1,3-dione (109);2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[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-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azacyclobutane-1-yl)isoindoline Dolin-1,3-dione (111); 5-((14-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (112); 5-((14-((4-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-dioxopiperidin-3-yl)isoindolin-1,3-dione (113) ); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindolline-1,3-dione (114); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-((1-(5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)azacyclobutane-3-yl)oxy)pentyl)oxy)pentyl)oxy)isoindolline-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]heptane-6-yl)oxy)isoindolline-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)prop-2-yn-1-yl)oxy)isoindolline-1,3-dione (117);2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azacyclobutane-1-yl)isoindoline-1,3-dione(118); (2S,4R)-1-((S)-17-((5-(5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azahepta-hepta-oc ... Acyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (119); (2S,4R)-1-((S)-2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (120); (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-azaeicosaeyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (121); (2S,4R)-1-((S)-23-((5-(5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azaeicosaeyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (122); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)isoindolline-1,3-dione (123); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hex-5-yn-1-yl)oxy)isoindolline-1,3-dione (124);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)isoindoline-1,3-dione (125); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3. 3] heptane-2-yl)pentyl)oxy)isoindoline-1,3-dione (126); 3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (127); 3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (128); 2-(2, 6-Dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexyl-2-yl)oxy)isoindolline-1,3-dione (129); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)propoxy)propoxy)azacyclobutane-1-yl)isoindolline- 1,3-Diketone (130); 2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentoxaheptadecyl)oxy)isoindoline-1,3-Diketone (131); 2-(2,6-dioxopiperidin-3-yl)-5-((20-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15,18-hexaoxaeicosyl)oxy)isoindoline-1,3-Diketone (132);2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azacyclobutane-1-yl)isoindololin-1,3-dione (133); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazine-3-yl)hex-5-yn-1-yl)oxy)isoindololin-1,3-dione (134); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazine-3-yl)hex-5-yn-1-yl)oxy)isoindololin-1,3-dione (134); 2-(2,6-dioxadiazin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptane-6-yl)oxy)butoxy)isoindolin-1,3-dione (135); 2-(2,6-dioxadiazin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptane-6-yl)oxy)butoxy)isoindolin 1,3-Dionone (136); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3,3]heptane-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-Dionone (137); 5-((14-((5-(5-(difluoromethyl)-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl) -yl)isoindoline-1,3-dione (138); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indo-7-yl)pyridin2-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]indo-7-yl)pyridin2-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-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione (141); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)aza Cyclobutane-3-yl)oxy)isoindoline-1,3-dione (142); 2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyridino[4,3-b]indo-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-pyridino[4,3-b]indo-7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hex-5-acetyloxy) Isoindolin-1,3-dione (144); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hexyloxy)isoindololin-1,3-dione (145); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindololin-1,3-dione (146) ;2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hexyl)oxy)isoindolline-1,3-dione (147); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (148);2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hexyl)oxy)isoindolline-1,3-dione](149); 5-(6-(2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione(150); 2-(2, 6-Dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hexyl)oxy)isoindolline-1,3-dione (151); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azacyclobutane-3-yl)oxy)isoindolline-1,3-dione (152); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azacyclobutane-3-yl)oxy)isoindolline-1,3-dione (152); Piperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)propyl)azacyclobutane-1-yl)isoindololin-1,3-dione (153); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2,2,2-trifluoro-1-((6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)ethyl)azacyclobutane-1-yl)isoindololin-1,3-dione (154) ); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azacyclobutane-1-yl)isoindolline-1,3-dione (155); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azacyclobutane-1-yl)isoindolline-1,3-dione (156);2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptane-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-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazine-4-yl)oxy)ethoxy)isoindoline-1,3- Dione (158); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azacyclobutane-1-yl)isoindoline-1,3-dione (159); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azacyclobutane-1-yl)iso Indoline-1,3-dione (160); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azacyclobutane-1-yl)isoindoline-1,3-dione (161); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)butoxy)azacyclobutane-1-yl )Isoindoline-1,3-dione (162); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)azacyclobutane-1-yl)isoindoline-1,3-dione (163); 5-(6-(4-((1r,3r)-3-(5-(5H-pyridino[4,3-b]indol-7-yl)pyridin2-yloxy)cyclobutoxy)piperidin-1-yl)-6-oxohexyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (164);5-((5-((1-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (165); 5-((5-((1-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (166); 2-(2,6- Dioxopiperidin-3-yl)-5-(3-((3-(5-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azacyclobutane-1-yl)isoindolline-1,3-dione (167); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azacyclobutane-1-yl)isoindolline-1,3-dione (168); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azacyclobutane-1-yl)isoindolline-1,3-dione Piperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)azacyclobut-3-yl)methoxy)propoxy)azacyclobutane-1-yl)isoindololin-1,3-dione (169); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((1s,3s)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)isoindololin-1,3-dione ( 170); 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)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (171); 5-((6-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hex-5-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-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)isoindololin-1,3-dione(173); 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]pent-1-yl)methoxy)butoxy)isoindololin-1,3-dione( 174); 2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azacyclobutane-1-carbonyl)bicyclo[1.1.1]pent-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione (175); 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (176); 3-(5-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (177); 2-(2,6-dioxopiperidine-3-yl)-5-(3-(((6-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)methyl)azacyclobutane-1-yl)isoindolin-1,3-dione Ketone (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)isoindolline-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-oxoisoindolline-2-yl)piperidin-2,6-dione (180);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)pentyl)oxy)ethyl)azacyclobutane-1-yl)isoindoline-1,3-dione (181); 5-(3-(3-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (182); 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)isoindolline-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)azacyclobutane-1-carbonyl)bicyclo[1.1.1]pent-1-yl)heptyl)oxy)isoindolline-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-methylthiazolyl-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butyryl)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-methylthiazolyl-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butyryl)pyrrolidine-2-carboxamide (186); (2S,4R)-N-( 2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazolyl-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butyryl)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-3-yl)isoindolin-1,3-dione (188);5-((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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (189); 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)azacyclobutane-1-yl)isoindoline-1,3-dione (190); 2-(2,6-dioxopiperidin -3-yl)-5-(3-((3-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)propoxy)methyl)azacyclobutane-1-yl)isoindolline-1,3-dione (191); 2-(2,6-dioxopiperidine-3-yl)-5-(3-((2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)methyl)azacyclobutane-1-yl)isoindolline-1,3-dione (192); 2-(2,6-dioxopiperidine- 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]heptane-2-yl)-2-oxoethoxy)propoxy)azacyclobutane-1-yl)isoindolline-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)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (194); 5-((1 4-((5-(4-chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (195); (2S,4R)-N-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)4-(4-methylthiazolyl-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolline-2-yl)butyryl)pyrrolidine-2-carboxamide (196);5-(6-((2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptane-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-pyridino[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-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butoxy)methyl)-N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridino)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide (199); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((7-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridino)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide (199); pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)heptyl)oxy)azacyclobutane-1-yl)isoindololin-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-methylthiazolyl-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindololin-2-yl)butyryl)pyrrolidine-2-carboxamide (201); 2-((1-(2-(2,6-di) 2-((1r,3r)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methoxy)-N-methyl-N-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide (202); 2-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-5-(5-methyl-5H-pyrido[4,3-b]indoline-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-dioxopiperidin-3-yl)isoindolline-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)isoindolline-1,3-dione (205) ; 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)methyl)azacyclobutane-1-yl)isoindolline-1,3-dione (206); 5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (207); 2-( 2,6-Dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)azacyclobutane-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindolline-1,3-dione(208); 2-(2,6-Dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pent-1-yl)methoxy)ethoxy)ethoxy)isoindolline- 1,3-Diketone (209); 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-tetraoxapentadecanyl)oxy)isoindoline-1,3-diketone (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]heptane-2-yl)ethoxy)propoxy)azacyclobutane-1-yl)isoindoline-1,3-diketone (211);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azacyclobutane-1-yl)isoindoline-1,3-dione(212); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)-2-azaspiro[3,3]heptane-2-yl)iso Indoline-1,3-dione (213); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-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-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy )Isoindoline-1,3-dione (215); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indo-7-yl)pyridin2-yl)oxy)cyclobutoxy)propoxy)ethoxy)piperidin-1-yl)isoindoline-1,3-dione (216); 2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-((2-(3-((1r,3R)-3-((5-(5-methyl-5H-pyridino[4,3-b]indo-7-yl)pyridin2-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]indoline-7-yl)pyridin2-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]indoline-7-yl)pyridin2-yl)oxy)cyclobutoxy)pyridin2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (219);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-oxoisoindololin-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)azacyclobutane-1-yl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (220); Ketone (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)piperidin-2,6-dione (222); 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)piperidin-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)piperidin-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)prop-2-yn-1-yl)oxy)propyl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (225); 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-oxoisoindololin-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)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (227);3-(5-(4-(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)piperazin-1-yl)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (228); 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-oxoisoindololin-5-yl)-N-methylacetamide (2 29); 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-oxoisoindololin-2-yl)piperidine-2,6-dione (230); 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazine-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (231); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrazin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (232); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (233); 3- (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)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (234); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-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 (235);5-(2-((3-(5-((1r,3r)-3-((5-(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-oxoisoindoline-5-yl)oxy)ethoxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indo-7-yl)nicotinonitrile (238); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indo-7-yl) pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (239); 3-(5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindololin-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)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (241); 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)isoindololin-1,3-dione (242);3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolline-2-yl)piperidin-2,6-dione(243); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)isoindolline-1,3 -Diketone (244); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (245); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy) )Isoindoline-1,3-dione (246); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (247); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)isoindoline 1,3-dione (248); 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-oxoisoindololin-2-yl)piperidin-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)isoindololin-1,3-dione (250);3-(5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione(251); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azacyclobutane-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoin Dolin-1,3-dione (252); N-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-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)butyramide (253); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl) 2-(2,6-dioxopiperidin-3-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethyl)azacyclobutane-3-yl)oxy)isoindoline-1,3-dione (254); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethoxy)azacyclobutane-1-yl)isoindoline-1,3-dione (255); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1 r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenoxy)azacyclobutane-1-yl)isoindolline-1,3-dione (256); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(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)azacyclobutane-1-yl)isoindolline-1,3-dione (257);2-(2,6-dioxopiperidin-3-yl)-5-(2-(9-(2-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)ethoxy)isoindoline-1,3-dione (258); 2-(2,6-dioxopiperidin-3-yl)-5-((4-(9-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-1- 2-(2,6-dioxane-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-pyridino[4,3-b]indoline-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)isoindolline-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)isoindolline-1,3-dione (262); 2-(2,6-dioxopiperidin-3-yl)-5 -(2-(3-(3-((3-hydroxy-1-(5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridinyl-2-yl)azacyclobutane-3-yl)methoxy)propoxy)propoxy)ethoxy)isoindolline-1,3-dione (263); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((5'-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)-3'H-spiro[cyclobutane-1,2'-furano[2,3-b]pyridinyl]-3-yl)oxy)propoxy)propoxy)azacyclobutane-1-yl)isoindolline-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-dioxopiperidin-3-yl)isoindolline-1,3-dione (265); 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)isoindolline-1,3-dione (266); 2-(2,6- Dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(2-((1r,3R)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)cyclobutyl)ethoxy)azacyclobutane-1-yl)isoindololin-1,3-dione(267); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((1S,2R)-2-((4-((1r,3R)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy) Butoxy)methyl)cyclopropyl)azacyclobutane-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-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropyl)methoxy)butoxy)azacyclobutane-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)cyclopropyl)methoxy)ethoxy)ethoxy)azacyclobutane-1-yl)isoindololin-1,3-dione (270); 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)cyclobutoxy)ethoxy)azacyclobutane-1-yl)isoindololin-1,3-dione (271);5-(3-(3-(2,2-difluoro-3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (272); 5-(3-(2,2-difluoro-3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione Ketone (273); 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)propoxy)isoindolline-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)but-3-yn-2-yl)oxy)ethoxy)isoindolline- 1,3-Diketone (275); 5-(2-((1,1-difluoro-3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[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)isoindololin-1,3-diketone (276); 3-(5-((4-(5-((1r,3r)-3-((5-(5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6 -Diketone (277); 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)methyl)-1-oxoisoindololin-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)but-3-yn-1-yl)oxy)azacyclobutane-1-yl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (279);5-(3-((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)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-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)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolline-1,3-dione (281); 3-(5-(3-((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)azacyclobutane-1-yl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (282); 2-(2,6-dioxopiperidine-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)azacyclobutane-3-yl)oxy)isoindol 1,3-Pyrin-1,3-dione (283); 3-(5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)azacyclobutane-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (284); 5-(2-(2,2-difluoro-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine-1-yl)propoxy)ethoxy)-2-(2,6-dioxopiperidine-3- 2-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5H-pyrido[4,3-b]indo-7-yl)nicotinonitrile (286); 3-(5-((3-(5-((1r,3r)-3-((3-methyl-5-(5H-pyrido[4,3-b]indo-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindoline-2-yl)piperidin-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-oxoisoindololin-2-yl)piperidine-2,6-dione (288); 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-oxoisoindololin-2-yl)piperidine-2,6 -Diketone (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-oxoisoindololin-2-yl)piperidin-2,6-dione (290); 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]pent-1-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-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]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutyl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione (292); 3-(5-(4-((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)piperidin-2,6-dione (293); 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)ethoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridin-1,3(2H)-dione (294);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pent-1-yl)methoxy)ethoxy)azacyclobutane-1-yl)isoindololin-1,3-dione (295); 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyridino) 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indo-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isoniconitrile (297); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indo-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isoniconitrile (297); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indo-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isoniconitrile 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-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindoline-2-yl)piperidin-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)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (300); 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)isoindololin-1,3-dione (301);6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picoline nitrile (302); 6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indoline -7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinenitrile (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)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindolline-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) 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridano[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindolin-1,3-dione (306); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl) 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-yne-2-yl)oxy)ethoxy)isoindolin-1,3-dione (307);3-(5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (309); 3-(5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)-1-oxo 2-(2,6-dioxopiperidin-3-yl)-5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)isoindolin-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)benzyl nitrile (312); 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-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)benzyl nitrile (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-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (314); 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)piperidin-2,6-dione (315);3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[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)piperidin-2,6-dione (316); 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indolin) -7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)nicotinonitrile (317); 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)prop-1-yn-1-yl)-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzylnitrile (318); 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-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)piperidin-1-yl)benzyl nitrile (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-oxoisoindololin-2-yl)piperidin-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)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (320); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)oxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (321); 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)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione (322);3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[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-oxoisoindololin-2-yl)piperidin-2,6-dione (323); 2-(2,6-dioxopiperidin-3-yl)-5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1- 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)piperidin-1-yl)phenyl)but-3-yn-2-yl)oxy)-1-oxoisoindol-2-yl)piperidin-2,6-dione (325); 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl) 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-oxoisoindolin-2-yl)piperidin-2,6-dione (327); 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)piperidin-2,6-dione (328); 6-(3-((2-(2,6-dioxopiperidin-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-((2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxy)ethoxy)-3-methylbut-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indoline-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile (330).

[0698] Where applicable, this specification includes compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds disclosed herein.

[0699] Where applicable, the term "pharmaceutically acceptable salt" is used throughout the specification to describe the salt form of one or more compounds described herein, which is used to increase the solubility of the compound in the gastric juices of a patient's gastrointestinal tract, thereby promoting the dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, and a host of other acids and bases well known in the pharmaceutical industry. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to this disclosure.

[0700] The acids used to prepare pharmaceutically acceptable acid addition salts that can be used in the above-described basic compounds in this disclosure are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, hydrogen tartrates, succinates, maleates, fumarates, gluconates, sucrose, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl) salts [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarboxylic acid)] salts, etc.

[0701] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of compounds or derivatives according to this disclosure. Chemical bases that are acidic in nature and can be used as reagents for preparing pharmaceutically acceptable basic salts of the compounds herein are those chemical bases that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such 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-methylglucosamine-(glucosamine), and other basic salts of lower alkanol ammonium and pharmaceutically acceptable organic amines, etc.

[0702] Composition:

[0703] In another aspect, this specification provides compositions comprising compounds as described herein, including their salts and pharmaceutically acceptable carriers. In some embodiments, the compositions are therapeutic or pharmaceutical compositions comprising effective amounts of the compounds as described herein and pharmaceutically acceptable carriers.

[0704] The amount of compounds in the pharmaceutical compositions of this disclosure, which can be combined with carrier materials to produce a single dosage form, will vary depending on the host and disease being treated and the specific administration modality. Generally, the amount of active ingredient administered ranges from 0.1 mg / kg to 1000 mg / kg body weight / day, depending on the potency of the agent. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell culture or laboratory animals, for example, to determine the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxicity and efficacy is the therapeutic index, and it can be expressed as the LD50 / ED50 ratio. Compounds exhibiting a large therapeutic index are preferred. While compounds exhibiting toxic side effects can be used, delivery systems targeting such compounds to affected tissue sites should be carefully designed to minimize potential damage to uninfected cells and thus reduce side effects. Data obtained from cell culture assays and animal studies can be used to formulate a range of doses for human use. The doses of such compounds are preferably within a cyclic concentration range including the ED50, exhibiting little or no toxicity. The dosage can vary within this range, depending on the dosage form and route of administration used. For any compound used in the methods of this disclosure, the therapeutically effective dose can initially be estimated from cell culture assays. Doses can be formulated in animal models to achieve circulating plasma concentration ranges, including IC50 (i.e., the concentration of the test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine the useful dose in humans. For example, plasma levels can be measured by high-performance liquid chromatography.

[0705] The compositions disclosed herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in controlled-release formulations. 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, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes such as lysodium sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0706] In any aspect or embodiment described herein, PTM, ULM, or both have an affinity (IC50) 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, or lower. 50 In view of this disclosure, ICs can be implemented using methods well known to those skilled in the art. 50 The determination.

[0707] In any aspect or embodiment, the compounds described herein achieve ubiquitination of the target protein at sufficient levels or amounts to achieve or induce the degradation of the target protein.

[0708] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient for the desired indication without causing serious toxic effects in the treated patient. Preferred doses of the active compound for all conditions mentioned herein range from about 10 ng / kg to 300 mg / kg, preferably from 0.1 to 100 mg / kg / day, and more generally from 0.5 to about 25 mg / kg of recipient / patient body weight / day. Typical local dose ranges are 0.01–5% wt / wt in a suitable carrier.

[0709] This compound can be conveniently administered in any suitable unit dosage form, including but not limited to unit dosage forms containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. Oral doses of about 25-250 mg are often convenient.

[0710] The active ingredient is preferably administered to achieve a peak plasma concentration of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient in saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for achieving an effective plasma concentration of the active agent.

[0711] The concentration of the active compound in a pharmaceutical composition will depend on the rates of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be alleviated. It should also be understood that, for any given subject, a particular dosage regimen should be adjusted over time based on individual needs and the professional judgment of the individual administering or supervising the administration of the composition, and the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered once or divided into many smaller doses administered at different time intervals.

[0712] If administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS).

[0713] In one embodiment, the active compound is prepared together with a carrier that protects the compound from rapid elimination from the body, such as in controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0714] Liposome suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving a suitable lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an organic solvent, followed by evaporation of the organic solvent, leaving a film of dried lipids on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0715] Application mode

[0716] In any aspect or embodiment described herein, a therapeutic composition comprising the compounds described herein may be any suitable dosage form configured for delivery via any suitable route. For example, the compounds may be administered via any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically (including transdermal, in liquid, cream, gel, or solid form), rectally, nasally, buccally, vaginally, or via an implanted reservoir or in aerosol form.

[0717] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intra-traumatic, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

[0718] The compounds described herein can be administered in single or fractionated doses via oral, parenteral, or topical routes. Administration of the active compound can range from continuous (intravenous infusion) to several times daily oral administration (e.g., QID), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, sublingual, and suppository administration, as well as other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration. The most effective dosage form depends on the pharmacokinetics of the specific agent chosen and the severity of the patient's disease.

[0719] Compounds can also be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary use. Compounds described herein can be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Sustained- or controlled-release forms are preferably administered orally, but can also be administered as suppositories and transdermal or other local forms. Intramuscular injection in liposome form can also be used to control or maintain the release of the compound at the injection site.

[0720] The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, can be used to prepare injectable formulations, as can natural, pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0721] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is mixed with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if desired. Oral compositions generally include an inert diluent or an edible carrier. These can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, an active compound or its prodrug derivative can be mixed with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binders and / or adjuvant materials are included as part of the composition.

[0722] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit is in capsule form, in addition to the materials of the above types, it may also contain a liquid carrier such as fatty oil. Furthermore, the dosage unit form may contain various other substances that modify the physical form of the dosage unit, such as sugar coating, shellac, or enteric solvent.

[0723] Active compounds or their pharmaceutically acceptable salts can be applied as components of elixirs, suspensions, syrups, chips, chewing gum, etc. In addition to active compounds, syrups may also contain sucrose as a sweetener, along with certain preservatives, dyes, colorings, and flavorings.

[0724] Alternatively, the pharmaceutical compositions described herein can be administered in suppository form for rectal administration. These can be prepared by mixing the reagent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0725] The pharmaceutical compositions of this disclosure can also be applied topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestine can be achieved as a rectal suppository formulation (see above) or as a suitable enema formulation. Topically acceptable transdermal patches can also be used. For topical application, the pharmaceutical compositions can be formulated as suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. In some preferred aspects of this disclosure, the compounds can be coated onto a stent to be surgically implanted in a patient to inhibit or reduce the likelihood of stent occlusion in the patient.

[0726] Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0727] For ocular 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, with or without preservatives such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.

[0728] The pharmaceutical compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0729] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and tonic agents such as sodium chloride or glucose. Parenteral preparations may be encapsulated in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0730] It should 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, age, weight, general health, sex, diet, timing of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the specific disease or condition to be treated.

[0731] Patients or subjects requiring treatment with compounds as described herein may be treated by administering to the patient (subject) an effective amount of the compound, alone or in combination with other known agents, including pharmaceutically acceptable salts, solvates, or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent.

[0732] Co-application

[0733] Disease conditions that can be treated with the compounds or compositions according to this specification include, but are not limited to, cancer (e.g., prostate cancer) and Kennedy's disease. In some embodiments, the therapeutic or pharmaceutical composition contains an effective amount of additional biological or bioactive agents, such as co-administered agents effective for cancer treatment.

[0734] The terms "co-administration" or "combination therapy" should mean the simultaneous administration of at least two compounds or compositions to a patient such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time point. Although the compounds according to this disclosure can be co-administered to a patient simultaneously, the term includes the simultaneous or different administration of two or more agents, provided that an effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In some preferred aspects of this disclosure, one or more of the compounds described above are co-administered in combination with at least one additional bioactive agent, particularly including anticancer agents. In a particular preferred aspect of this disclosure, the co-administration of the compounds results in synergistic therapy, including anticancer therapy.

[0735] In another aspect, this specification provides compositions comprising an effective amount of two or more PROTAC compounds as described herein and a pharmaceutically acceptable carrier. In some embodiments, the composition also comprises an effective or synergistic amount of another bioactive agent that is not a PROTAC compound.

[0736] The pharmaceutical composition represents a further aspect of this disclosure, comprising, in combination with a pharmaceutically effective amount of at least one bifunctional compound according to this disclosure and one or more compounds otherwise described herein, in combination with a carrier, additive or excipient.

[0737] The term "bioactive agent" is used to describe agents other than the PROTAC compounds described herein, which, in combination with the compounds described herein, are used as bioactive agents to help achieve the intended therapeutic, inhibitory, and / or preventative / prophylactic effects of the use of the compounds described herein. Preferred bioactive agents used herein include those that help achieve the intended therapeutic effect, such as P-gp inhibitors or agents having similar pharmacological activity to that of the compounds described herein, and include, for example, anti-neurodegenerative agents.

[0738] The term "P-gp" is used to describe a "permeability glycoprotein," or P-glycoprotein (ABCB1), discovered in rodent cells in 1976. The presence of "endogenous or physiological" P-gp is a potential problem for achieving targeted exposure with therapeutic agents. P-gp is expressed in barrier tissues targeting protected sites (e.g., the blood-brain barrier) and secretory / absorbatory tissues (e.g., the gastrointestinal tract) (Cordon-Cardo et al., 1989, 1990). This protein acts as a cellular defense agent and affects the overall pharmacokinetic profile of numerous drugs by actively pumping them out of the intracellular environment (efflux), thereby reducing drug penetration through barrier tissues. In particular, P-gp efflux reduces drug permeability across the gastrointestinal membrane and can lead to reduced systemic drug exposure. P-gp efflux can also reduce drug entry across the blood-brain barrier. P-gp inhibitors can indirectly contribute to efficacy by increasing PROTAC exposure, particularly CNS exposure.

[0739] The term "another anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that can be combined with the PROTAC compound according to this specification to treat neurodegenerative diseases.

[0740] In some embodiments, PROTAC is used in conjunction with a P-gp inhibitor.

[0741] In some other embodiments, the P-gp inhibitor is selected from, but not limited to, amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, taribeda, ecrimethamine, and verapamil.

[0742] Treatment

[0743] In another aspect, this disclosure provides a method for modulating protein ubiquitination and degradation in a subject (e.g., cells, tissues, mammals, or human patients), the method comprising administering to the subject an effective amount of a PROTAC compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising thereof effectively modulates protein ubiquitination and protein degradation in the subject. In some embodiments, the protein is a Tau protein.

[0744] In some embodiments, this specification provides a method for modulating the protein activity of Tau protein by degrading Tau aggregates in a patient in need, comprising administering to the patient an amount of a compound as described herein.

[0745] In yet another embodiment, this specification provides a method for treating a disease state or condition in a patient, wherein dysregulated protein activity (Tau aggregation and accumulation) is responsible for the disease state or condition, the method comprising administering to the patient an effective amount of a compound as described herein to modulate the protein activity in the patient. In some embodiments, the protein is Tau.

[0746] As used herein, the terms “treat,” “treating,” and “treatment,” etc., refer to any action that provides benefit to a patient to whom the compounds described herein may be administered, and the benefit includes treatment of any disease state or condition regulated by proteins to which the compounds of this invention bind. Disease states or conditions that may be treated with the compounds according to this disclosure include neurological and neurodegenerative diseases, as set forth above.

[0747] In another aspect, this disclosure provides a method for 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 as described herein or a composition comprising an effective amount of a compound as described herein, wherein the compound or composition comprising thereof effectively modulates Tau protein ubiquitination and protein degradation in the subject.

[0748] In another aspect, this disclosure provides a method for treating or improving 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 an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising thereof effectively treats or improves symptoms of a disease associated with TAU aggregation in the subject.

[0749] In some embodiments, the disease or condition is a neurological condition, including but not limited to: septum pellucidum absence, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Addison's pupils, Addison's syndrome, adrenoleukodystrophy, corpus callosum dysplasia, agnosia, Eckhardt syndrome, AIDS-neurological complications, Alexander disease, Alpert disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, hemangioma, hypoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Argives-Gilles malformation, arteriovenous malformation, Asperger's syndrome, ataxia, telangiectasia, ataxia and cerebellar / spinocerebellar degeneration, injection Attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Bartholomew's syndrome, Barten's disease, Becker's muscle rigidity, Behcet's disease, Bell's palsy, benign primary blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhardt-Robber syndrome, Binswanger disease, blepharospasm, Brønsted-Sud syndrome, brachial plexus birth injury, brachial plexus injury, Bradbury-Eggleston syndrome, brain and spinal tumors, cerebral aneurysms, brain injury, Brown-Seckal syndrome, bulbar muscular atrophy, Canavan's disease, carpal tunnel syndrome burning pain, cavernous malformation, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central cord syndrome, central pain syndrome, cranial diseases, cerebellar degeneration, cerebellar hypoplasia. Cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral gigantism, cerebral hypoxia, cerebral palsy, brain-ocular-facial-bone syndrome, Sharma-Tutus disease, Chiari malformation, chorea, chorea-acanthosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, type II chronic pain, Cocaine syndrome, Kohl's syndrome, COFS, cavitary brain, coma and persistent vegetative state, complex regional pain syndrome, congenital facial palsy, congenital myasthenia gravis, congenital myopathy, congenital cavernous vascular malformation, cortical-basal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus infection Oculofoot syndrome, Dan Wolverine syndrome, Dawson's disease, Demosie syndrome, deep brain stimulation for Parkinson's disease, Dejerine-Klumpke paralysis, dementia, dementia with multiple cerebral infarctions, dementia with semantic function, dementia with subcortical function, Lewy body dementia, dentate nucleus-cerebellar ataxia, dentate nucleus-red nucleus atrophy, dermatomyositis, developmental motor disorders, Dervec syndrome, diabetic neuropathy, diffuse sclerosis, familial autonomic dysfunction, writing difficulties, dyslexia, dysphagia, motor disorders, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early infantile epilepsy, encephalopathy, empty sella syndrome, encephalitis of lethargy, encephalocele, encephalopathy, trigeminal neuralgia, epilepsy.Erb-Duchenne and Dejerine-Klumpke paralysis, Ober's paralysis, Fabry disease, Fall's syndrome, syncope, familial autonomic dysfunction, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, soft-bellied infant syndrome, Friedreich ataxia, frontotemporal dementia, Gaucher disease, Göstmann syndrome, Gschäuer syndrome, giant cell arteritis, giant cell inclusion body disease, globular cell leukodystrophy, glossopharyngeal neuralgia, Göstmann-Bartholin syndrome, Has-Schätschler syndrome, head injury, headache, persistent migraine, hemifacial spasm, hemiplegia, Alterans syndrome, hereditary neuropathies, hereditary spasm Spastic paraplegia, hereditary ataxic polyneuritis, herpes zoster, otitis herpes zoster, Hirayama syndrome, Hodgkin-Ellison syndrome, holoprosencephaly, HTLV-1 related myelopathy, Huntington's disease, hydrocephalus, hydrocephalus-normal pressure, hydramnios, ADHD, Cushing's syndrome, hypersomnia, hypertonia, hypotonia-infantile, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinence pigmentosa, infantile hypotonia, infantile axonal dystrophy, infantile phytate storage disease, infantile Reifsomm's disease, infantile spasms, inflammatory myopathy, cleft occipital bone with exposed brain, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, Isaac syndrome, Jubert syndrome, Keith-Selby syndrome Kennedy's disease, Kingsbrinner syndrome, Klebsiella pneumoniae-Lewinsky syndrome, Klebsiella pneumoniae-Ferdinandovich syndrome, Klebsiella pneumoniae-Troy syndrome (KTS), Klebsiella pneumoniae-Bruce syndrome, Korsakov amnesia, Crabbe's disease, Cushing's disease, Krugman's disease, Landau-Kleffner syndrome, lateral femoral nerve entrapment, lateral medullary syndrome, learning disabilities, Lewy body disease, Ring-Gorbachev syndrome, Lyme disease-Naphthyl syndrome, leukodystrophy, Levine-Critchley syndrome, Lewy body dementia, lipid storage disease, gyri, locked-in syndrome, Glenn disease, lupus—neurology, sequelae, Lyme disease—neurological complications, Mayo C., megalencephaly. Mania, megalencephalopathy, Milo-Ross syndrome, meningitis, meningitis and encephalitis, Menx's disease, paresthesia of the femoral head, metachromatic encephalopathy, leukodystrophy, microcephaly, migraine, Miller-Fischer syndrome, mini-stroke, mitochondrial myopathy, Murbius syndrome, unilateral limb atrophy, motor neuron disease, Moyamoya disease, mucolipid storage disease, mucopolysaccharidosis, multifocal motor neuropathy, multiple infarct dementia, multiple sclerosis, multiple system atrophy, multiple system atrophy with orthostatic hypotension, muscular dystrophy, myasthenia gravis (congenital), myasthenia gravis, demyelinating diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myopathy (congenital), myopathy (thyrotoxicosis), myotonia, congenital myotonia, narcolepsy, neuroacanthocytosis.Neurodegeneration with cerebral siderosis, neurofibromatosis, neuroleptic malignant syndrome, neurological complications of AIDS, neurological complications of Lyme disease, neurological consequences of cytomegalovirus infection, neurological manifestations of pumila disease, neurological sequelae of lupus, neuromyelitis optica, neurogenic myotonia, neuronal waxy deposits, lipofuscinosis, neuronal migration disorder, hereditary neuropathies, neurosarcoma, neurotoxicity, cavernous nevus, Niemann-Pick disease, normal pressure hydrocephalus. Occipital neuralgia, obesity, occult spinal canal closure disorder, Ōtahara syndrome, olivopontocerebellar atrophy, strabismus-clonic myoclonus, orthostatic hypotension, O'Sullivan-McLeod syndrome, overuse syndrome, chronic pain, Paine, pantothenic acid kinase-related neurodegeneration, paraneoplastic syndrome, paresthesia, Parkinson's disease, paroxysmal choreoathetosis, paroxysmal migraine, Parry-Romberg syndrome, Peyreke's disease, Pena Shokeir II syndrome, fasciculus cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent vegetative state, pervasive developmental disorder, phytate storage disease, Pick's disease, nerve pinching, piriformis syndrome, pituitary adenoma, polymyositis, pampiniformis, pore brain, postherpetic neuralgia, post-infectious encephalomyelitis, post-poliomyelitis syndrome, orthostatic hypotension, orthostatic hypotension, tachycardia syndrome, orthostatic tachycardia syndrome, primary Dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal leukoencephalopathy, progressive sclerotic gray matter encephalopathy Malnutrition, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsey Hunt syndrome I (formerly known as), Ramsey Hunt syndrome II (formerly known as), Rasmussen encephalitis, reflex sympathetic dystrophy syndrome, Reversum disease, Reversum disease in infancy, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Reid-Dell syndrome, sacral nerve root cyst, St. Vitus dance, salivary gland disease, Sandhof disease, Sheldt's disease, schizophrenia, Setterberg disease, epilepsy, semantic dementia, optic-septal dysplasia, shaken baby syndrome, Shingles Shy-Drager syndrome, Sjögren's syndrome, sleep apnea, narcolepsy, Sotos syndrome, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Sjögren's syndrome, stiff-person syndrome, striatal substantia nigra degeneration, stroke, Sjögren's syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, Suntham's headache and dysphagia, Siddenham's chorea, syncope, syphilitic spinal sclerosis, syringomyeliaSyringomyelia, systemic lupus erythematosus, tabes dorsalis varicose veins, Tarlov's cyst, Tay-Sachs disease, temporal arteritis, tethered cord syndrome, Thomsen's myotonia, thoracic outlet syndrome, thyrotoxic myopathy, trigeminal neuralgia, Todd's paralysis, Tourette syndrome, transient ischemic attack, infectious cavernous encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paralysis, tuberous sclerosis, vascular erectile neoplasms, vasculitis including temporal arteritis, Ekonomo's disease, Hey-Lin's disease (VHL), von Reckling-Hosezen's disease, Warenberg syndrome, Welch-Hosezen's disease, Welch-Colburn syndrome, West syndrome, whiplash, Whipple's disease, Williams syndrome, Wilson's disease, X-linked spinal-bulbar muscular atrophy or Zellweger syndrome.

[0750] In some embodiments, the disease or condition is at least one of the following: Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Barten disease, spinal cord and brain injury, epilepsy, seizures, 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.

[0751] In some embodiments, the disease or condition is Alzheimer's disease.

[0752] In another aspect, this disclosure provides a method for treating or improving 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 the subject in need an effective amount of a compound as described herein or a composition containing such an effective amount, and an effective or synergistic amount of another bioactive agent, wherein the composition containing such a compound effectively treats or improves symptoms of a disease associated with Tau accumulation or aggregation in the subject by Tau degradation / inhibition.

[0753] In some embodiments, the disease to be treated is a neurological condition. In a preferred embodiment, the subject is a human being.

[0754] In some other embodiments, the additional bioactive agent is an anti-neurodegenerative agent.

[0755] In an alternative, this disclosure relates to methods for treating disease states by degrading proteins or peptides, wherein the disease state or condition is modulated by said proteins or peptides, the methods comprising administering to the patient or subject an effective amount of at least one compound as described above, optionally in combination with another bioactive agent. Due to the administration of an effective amount of at least one compound described herein, the methods according to this disclosure can be used to treat a wide range of neurological states or conditions.

[0756] In another aspect, this disclosure provides a method for identifying the effects of target protein degradation in biological systems using compounds according to this disclosure.

[0757] Reagent test kit

[0758] In another aspect, this specification provides kits comprising compounds or compositions as described herein. These kits can be promoted, dispensed, or sold as units for performing the methods of this disclosure. Additionally, the kits of this disclosure may preferably contain instructions describing suitable uses. Such kits can be conveniently used, for example, in a clinical setting to treat patients with neurological conditions.

[0759] Example

[0760] The PROTAC compounds of this disclosure are effective in tau degradation. Exemplary compounds are presented in Tables 1 and 2, with in vitro data from some selected compounds in Tables 2 and 3 demonstrating tau protein degradation. In vivo studies demonstrating tau protein degradation were conducted in... Figure 1 As shown in the image.

[0761] General methods of chemical synthesis

[0762] The synthesis of the claimed chimeric compound can be performed according to general synthetic procedures known in the literature. The synthetic route shown in this disclosure is described as one of the methods that can be used to obtain the desired compound. Other methods may also be useful to those skilled in the art of synthesis. The ULM and PTM described in the scheme represent only one of many ULMs and PTMs in this patent application.

[0763] LC-MS method for purity analysis (quality control)

[0764] LCMS method:

[0765] Instruments: Agilent Infinity 1260 LC; Agilent 6230 TOF mass spectrometer

[0766] Analysis was performed at 45 °C on a Poroshell 120 EC C18 column (50 mm x 3.0 mm inner diameter, 2.7 μm filling diameter).

[0767] The solvent used is:

[0768] A = 0.1% v / v formic acid aqueous solution.

[0769] B = 0.1% v / v formic acid in acetonitrile solution.

[0770] The gradient used is as follows:

[0771]

[0772] UV detection is an average signal with wavelengths from 210 nm to 350 nm, and the mass spectra are recorded on a mass spectrometer using positive mode electrospray ionization.

[0773] abbreviation:

[0774] ACN: Acetonitrile

[0775] Boc2O: Ditert-butyl dicarbonate

[0776] DCM: Dichloromethane.

[0777] DIPEA: N,N-Diisopropylethylamine

[0778] DMA: N,N-dimethylacetamide

[0779] DMF: N,N-dimethylformamide

[0780] EA: Ethyl acetate

[0781] HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate

[0782] HPLC: High Performance Liquid Chromatography

[0783] LC-MS: Liquid Chromatography-Mass Spectrometry

[0784] Min: minutes

[0785] MTBE: Methyl tert-butyl ether

[0786] PE: Petroleum ether

[0787] RT: Room temperature

[0788] SPB: Sodium perborate

[0789] tBu: tert-butyl

[0790] TBACl: Tetrabutylammonium chloride

[0791] TFA: Trifluoroacetic acid

[0792] THF: Tetrahydrofuran

[0793] TLC: Thin-layer chromatography

[0794] TMS: Trimethylsilyl

[0795] t R Retention time

[0796] TsCl: p-Toluenesulfonyl chloride

[0797] Intermediate products of ubiquitin E3 ligase targeting moiety (ULM) and protein targeting moiety (PTM)

[0798] Intermediate Product 1: (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

[0799]

[0800] Step 1: Preparation of 4-(4-methyl-1,3-thiazolyl-5-yl)benzylnitrile

[0801] At room temperature and under 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 to a stirred solution of 4-bromobenzyl nitrile (20 g, 109.88 mmol) in DMA (250 mL). The resulting mixture was heated to 150 °C and stirred at this temperature for 5 hours, at which point LC-MS indicated complete reaction. 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 concentrated under reduced pressure to give a crude residue, which was purified by rapid silica gel column chromatography (eluent: ethyl acetate / petroleum ether, v:v = 1:5) to give the title compound as a white solid (yield: 91%).

[0802] Step 2: Preparation of [4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methylamine

[0803] Under nitrogen atmosphere, at 0°C, LiAlH4 (20 g, 526.32 mmol) was added aliquots to a stirred solution of 4-(4-methyl-1,3-thiazolyl-5-yl)benzylnitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL). The resulting mixture was then stirred at 60°C for 3 hours, at which point LC-MS indicated complete reaction. The mixture was cooled to 0°C and then quenched by the addition of water (20 mL, slowly), an aqueous solution of NaOH (15%, 20 mL), and water (60 mL). The mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue, which was purified by rapid silica gel column chromatography (eluent: dichloromethane / methanol (v:v = 10:1)) to give the title compound as a yellow oil (yield: 56%).

[0804] Step 3: Preparation of tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylic acid ester

[0805] At room temperature, DIPEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol), and [4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methylamine (2 g, 9.79 mmol) were added 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). The resulting mixture was stirred overnight at room temperature until LC-MS indicated complete reaction. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude residue, which was purified by rapid silica gel column chromatography (eluent: dichloromethane / methanol (v:v = 20:1)) to give the title compound as a yellow solid (yield: 56%).

[0806] Step 4: Preparation of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride

[0807] To a 1 L round-bottom flask containing a solution of tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylic acid ester (45 g, 107.78 mmol) in dioxane, a solution of hydrogen chloride in dioxane (4 N, 300 mL) was added. The resulting solution was stirred at room temperature for 2 hours. The solid was collected by filtration to give the title product as a yellow solid (yield: 98%).

[0808] Step 5: Preparation of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazo-5-yl)]phenyl]methyl]carbamoyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutane-2-yl]carbamate

[0809] At room temperature, 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-thiazolyl-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol) were added to a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutyric acid (15.7 g, 68.0 mmol) in N,N-dimethylformamide (500 mL).

[0810] The resulting solution was stirred at room temperature for 16 hours, and LC-MS indicated the formation of the desired product. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride (50 mL x 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by rapid silica gel chromatography (eluent: ethyl acetate / petroleum ether (v:v = 2:1)) to give the title compound as a yellow solid (yield: 51%).

[0811] Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (ULM-1)

[0812] At room temperature, a solution of dioxane (4N, 80 mL) containing hydrogen chloride was added to a stirred solution of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]methyl]carbamoyl)pyrrolidone-1-yl]-3,3-dimethyl-1-oxobutane-2-yl]carbamate (12 g, 22.61 mmol) in dioxane (20 mL). The resulting solution was stirred at room temperature for 2 hours, at which point LC-MS indicated that the reaction was complete. The precipitated solid was collected by filtration to give the title product as a yellow solid (yield: 48%).

[0813] d: 48%) as a yellow solid.

[0814] 1 HNMR (400MHz, CD3OD): δ9.84-9.82(s,1H),7.58-7.54(m,4H),4.71-4.41(m,4H),4.13-4.08(m,1H) ,3.86-3.71(m,2H),3.36(s,1H),2.60-2.58(s,3H),2.35-2.07(m,2H),1.19-1.12(m,9H).LC-MS(ES + ):m / z 431.11[MH + ],t R = 0.73 minutes.

[0815] Intermediate Product 2: (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamide hydrochloride (ULM-2)

[0816]

[0817] Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate

[0818] At 5 °C, (Boc)₂O (5.20 g, 23.8 mmol) was added to a mixture of (S)-1-(4-bromophenyl)ethylamine (3.98 g, 19.9 mmol) and NaHCO₃ (1.24 g, 14.8 mmol) in H₂O (10 mL) and ethyl acetate (10 mL). The reaction was allowed to proceed for 2 h. TLC showed the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 mL) and H₂O (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 (5.9 g, 98.7%) as a white solid.

[0819] 1 HNMR (400MHz, DMSO-d6): δ1.28(d,J=7.2Hz,3H),1.36(s,9H),4.55-4.60(m,1H),7.25(d,J=8.4Hz,2H),7.39(br,1H),7.49(d,J=8.4Hz,2H).

[0820] Step 2: Preparation of (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethylamine hydrochloride

[0821] A mixture of (S)-tert-butyl-1-(4-bromophenyl)-ethylcarbamate (4.0 g, 13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium(II) acetate (29.6 mg, 0.13 mmol), and potassium acetate (2.61 g, 26.6 mmol) in DMF (10 mL) was stirred at 90 °C under N2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. H2O (50 mL) was added to the filtrate, and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50 °C to give (S)-tert-butyl-1-(4-(4-methylthiazole-5-yl)phenyl)-ethylcarbamate (3.48 g, 82.3%) as a gray solid.

[0822] 1 HNMR (400MHz, DMSO-d6): δ1.33(d,J=7.2Hz,3H),1.38(s,9H),2.46(s,3H),4.64-4.68(m,1H),7.23(br d,0.5H),7.39(d,J=8Hz,2H),7.44(d,J=8.4Hz,2H),7.50(br d,0.5H),8.99(s,1H); LC-MS[M+1] + 319.5

[0823] The solid material (1.9 g, 6.0 mmol) was dissolved in a methanol solution of 4N hydrochloride (5 mL, 20 mmol, prepared from acetyl chloride and methanol), and the mixture was stirred at ambient temperature for 3 hours, then concentrated and ground with diethyl ether. The mixture was filtered, and the solid was collected and dried in an oven at 60 °C to give (S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethylamine hydrochloride (1.3 g, 85%) as a light green solid.

[0824] 1 HNMR (400MHz, DMSO-d6): δ1.56 (d, J=6.8Hz, 3H), 2.48 (s, 3H), 4.41-4.47 (m, 1H) ,7.57(d,J=8.4Hz,2H),7.67(d,J=8.4Hz),8.75(s,3H),9.17(s,1H); LC-MS[M+1] + :219.2

[0825] Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyryl}-4-hydroxypyrrolidine-2-carboxylic acid

[0826] Under nitrogen and at 0 °C, HATU (2.15 g, 5.7 mmol) was added to a solution of (S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutyric acid (1.25 g, 5.4 mol), (2S,4R)-methyl-4-hydroxypyrrolidine-2-carboxylic acid hydrochloride (0.98 g, 5.4 mmol), and DIPEA (2.43 g, 18.9 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature for 18 hours. TLC showed that the reaction was complete. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layers were washed with 5% citric acid (10 mL x 2), saturated NaHCO3 solution (10 mL x 2), brine (10 mL x 2), and dried over Na2SO4. The organic solution was filtered and concentrated to give (2S,4R)-methyl 1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyryl}-4-hydroxypyrrolidine-2-carboxylic acid ester (1.93 g, 100% yield) as a pale yellow oil. This crude product (1.93 g) and lithium hydroxide hydrate (2.2 g, 54 mmol) were added to THF (20 mL) and H2O (10 mL). The resulting mixture was stirred at ambient temperature for 18 hours. THF was removed by concentration. The residue was diluted with ice water (10 mL) and slowly adjusted to pH 2–3 with 3N HCl. The resulting suspension was filtered and washed with H2O (6 mL × 2). The solid was collected by filtration and dried in an oven at 50 °C to give the title compound (1.4 g, 75% for both steps) as a white solid.

[0827] 1 HNMR (400MHz, DMSO-d6): δ6.50 (d, J=9.6Hz, 1H), 5.19 (br s, 1H), 4.32 (br s,1H),4.25(t,J=8.4Hz,1H),4.16(d,J=9.2Hz,1H),3.57-3.66(m,2H),2.08-2.13(m,1H),1.85-1.91(m,1H),1.38(s,9H),0.94(s,9H).

[0828] Step 4: Preparation of (2S,4R)-1-[(S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazolyl)-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamide hydrochloride (ULM-2)

[0829] At 0 °C, HATU (1.6 g, 4.2 mmol) was added to a stirred solution containing (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyryl}-4-hydroxypyrrolidine-2-carboxylic acid (1.21 g, 3.5 mmol), (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylamine hydrochloride (0.9 g, 3.5 mmol), and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 mL). The resulting mixture was allowed to heat to ambient temperature and stirred 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. The solid was added to methanol (10 mL) and activated carbon (150 mg). The resulting mixture was heated at 80 °C and stirred for 1 hour. The mixture was filtered while hot. Water (5 mL) was added to the filtrate at 80 °C. The resulting mixture was cooled to ambient temperature and stirred for another 18 hours. The suspension was filtered. The solid was collected and dried in an oven at 50 °C to give tert-butyl-{(S)-1-[(2S,4R)-4-hydroxy]-2-[(S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)-ethylcarbamoyl]pyrrolidine-1-yl}-3,3-dimethyl-1-oxobutane-2-yl-carbamate (1.41 g, 74.2%) as a white solid.

[0830] 1 H NMR (400MHz, CDCl3): δ1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J = 7.2Hz, 3H), 2.04-2.10 (m,1H),2.53(s,3H),2.58-2.64(m,1H),3.23(s,1H),3.58(dd,J=11.2Hz,3.2Hz,1 H),4.11(d,J=11.6Hz,1H),4.22(d,J=9.2Hz,1H),4.51(br,1H),4.79(t,J=8.0Hz, 1H),5.04-5.11(m,1H),5.22(d,J=8.8Hz,1H),7.36-7.42(m,4H),7.61(d,J=7.6Hz 1H), 8.68(s,1H).

[0831] The solid (1.04 g, 1.9 mmol) was dissolved in a methanol (3.0 mL) solution of 4 N hydrogen chloride, and the mixture was stirred at ambient temperature for 3 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated to remove all volatiles under reduced pressure to give a pale yellow solid. The solid was added to TBME (5 mL), and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered, and the solid was collected and dried in an oven at 50 °C to give the title compound (0.92 g, 100%).

[0832] 1 H NMR (400MHz, DMSO-d6): δ1.03 (s, 9H), 1.38 (d, J = 7.2Hz, 3H), 1.72-1.79 (m, 1H), 2.09-2.14(m,1H),2.49(s,3H),3.48-3.52(m,1H),3.75-3.79(m,1H),3.88-3.9 0(m,1H),4.31(br,1H),4.56(t,J=8.4Hz,1H),4.89-4.95(m,1H),7.41(d,J=8.4 Hz,2H),7.47(d,J=8.4Hz,2H),8.20(br,3H),8.67(d,J=7.6Hz,1H),9.22(s,1H); 13 C NMR (400MHz, DMSO-d6): δ170.7,167.1,153.0,146.5,145.7,132.5,129.4,129. 3,126.9,69.4,59.3,58.5,56.9,48.3,38.4,34.8,26.6,23.0,15.7; LC-MS[M+1] + 445.6

[0833] Intermediate product 3: (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazolyl-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxamide (ULM-3)

[0834]

[0835] Step 1: Preparation of 2-hydroxy-4-(4-methylthiazolyl-5-yl)benzyl nitrile

[0836] Under a nitrogen atmosphere, a mixture of 4-bromo-2-hydroxybenzyl nitrile (15 g, 76 mmol), 4-methylthiazole (14 mL, 152 mmol), KOAc (14.9 g, 152 mmol), and Pd(OAc)₂ (0.34 g, 1.52 mmol) in anhydrous NMP (125 mL) was stirred at 110 °C 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 organic fractions were filtered, and the filtrate was washed with water and brine, dried on anhydrous Na₂SO₄, and concentrated. The residue was dissolved in toluene (100 mL) and evaporated again to give the crude product. The crude product was treated with cold MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL), and dried under vacuum to give the title compound (10.5 g, 64%) as a pale yellow solid.

[0837] LC / MS: 217.2 [M+1] + .

[0838] 1 HNMR (400MHz, DMSO-d6): δ2.49(s,3H),7.07(dd,J=8.0,1.6Hz,1H),7.13(d,J=1.6Hz,1H),7.70(d,J=8.0Hz,1H),9.07(s,1H),11.34(s,1H).

[0839] Step 2: Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

[0840] At 0 °C, LiAlH4 (1.5 g, 40.23 mmol) was added aliquots to an anhydrous THF (150 mL) solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzyl nitrile (2.9 g, 13.41 mmol). The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 3 h. TLC showed the reaction was complete. The mixture was cooled in an ice-water bath, and then Na2SO4·10H2O (5 g) was carefully added, and the mixture was stirred at this temperature for 1 h. The mixture was filtered, and the filter cake was washed four times with a 10% MeOH solution of DCM. The combined filtrates were concentrated to give crude 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (2.0 g, 68%) as a pale yellow solid. It did not require further purification for the next step.

[0841] LCMS: 221.2 [M+H] + .

[0842] 1HNMR (400MHz, DMSO-d6): δ2.43(s,3H),3.54(br,2H),6.11(d,J=7.2Hz,1H),6.40(d,J=11.6Hz,1H),6.83(d,J=7.6Hz,1H),8.81(s,1H).

[0843] Step 3: Preparation of (S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyric acid

[0844] L-valine (4.37 g, 37.3 mmol) was added to a solution of phthalaldehyde (5.0 g, 37.3 mmol) in acetonitrile (350 mL). The resulting mixture was refluxed for 5 hours. The reaction mixture was filtered while hot, and the filtrate was slowly cooled to room temperature. The resulting precipitate was filtered and dried to give (S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyric acid (6.45 g, 74%) as a white solid.

[0845] 1 HNMR (400MHz, DMSO-d6): δ0.85(d,J=6.8Hz,3H),1.0(d,J=6.8Hz,3H),2.25-2.34(m,1H),4.51(d,J=4.4Hz,1H),4.54(d ,J=3.6Hz,1H),4.64(d,J=18.0Hz,1H),7.48-7.54(m,1H),7.63(d,J=3.6Hz,2H),7.72(d,J=7.6Hz,1H),13.01(br,1H).

[0846] Step 4: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxylic acid ester

[0847] HATU (3.8 g, 10 mmol) was added to an anhydrous DMF (15 mL) solution containing 4-hydroxy-L-proline methyl ester hydrochloride (1.0 g, 5.52 mmol), (S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyric acid (1.16 g, 4.97 mmol), and DIPEA (2.58 g, 20 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtoAc and water. The organic phase was washed with water and brine and dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography using a 30–50% hexane solution of EtOAc as eluent to give the title compound (1.21 g, 67.6%) as a pale yellow solid.

[0848] LCMS: 361.3 [M+1] + .

[0849] Step 5: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxylic acid

[0850] A mixture containing (2S,4R)-methyl-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxylic acid ester (1.2 g, 3.33 mmol), LiOH·H₂O (559 mg, 13.32 mmol) in THF (20 mL) and H₂O (10 mL) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction mixture was acidified to pH 1–2 with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give the title compound (1.05 g, 91% yield) as a pale yellow solid.

[0851] 1 HNMR (400MHz, CDCl3): δ0.91(d,J=6.4Hz,3H),1.05(d,J=6.8Hz,3H),2.30(dd,J =8.4,2.8Hz,2H),2.44-2.50(m,1H),3.75(dd,J=11.2,3.2Hz,1H),4.42(d,J=17 .6Hz,1H),4.50-4.55(m,2H),4.66(t,J=8.4Hz,1H),4.75(d,J=17.6Hz,1H),4.8 3(d,J=11.2Hz,1H),7.42-7.45(m,2H),7.51-7.56(m,1H),7.78(d,J=7.6Hz,1H).

[0852] Step 6: Preparation of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazolyl-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxamide

[0853] HATU (2.2 g, 5.77 mmol) was added to a 20 mL solution of DMF containing (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindoline-2-yl)butyryl)pyrrolidine-2-carboxylic acid (1.0 g, 2.89 mmol), 2-(aminomethyl)-5-(4-methylthiazolyl-5-yl)phenol (954 mg, 4.33 mmol) and DIPEA (1.5 g, 11.55 mmol). The resulting mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The mixture was partitioned between EtoAc and water. The organic phase was washed with water and brine and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography using a 2–5% MeOH solution in DCM to give the title compound (650 mg, 43% yield) as a pale yellow solid.

[0854] LCMS: 549.2 [M+H] +

[0855] 1 HNMR (400MHz, CDCl3): δ0.80(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H),1.96-2.01(m,1H),2.34-2.40(m,1H), 2.47-2.53(m,4H),3.61(dd,J=11.6,3.6Hz,1H),4.29-4.37(m,2H),4.38-4.41(m,1H),4.47-4.50(m,2H),4 .64-4.69(m,2H),4.72(s,1H),6.90(dd,J=8.0,2.0Hz,1H),7.01(d,J=2,0Hz,1H),7.14(d,J=8.0Hz,1H),7. 39-7.44(m,2H),7.51-7.54(m,1H),7.76(d,J=7.6Hz,1H),8.03(t,J=6.4Hz,1H),8.66(s,1H),9.27(br,1H).

[0856] Intermediate product 4: (2R,4S)-1-[(S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-N-[(S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamide hydrochloride (ULM-4)

[0857]

[0858] The compound was synthesized using (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylic acid ester hydrochloride, using the same method as described in the preparation of ULM-2.1 HNMR (400MHz, CD3OD): δ1.14(s,9H),1.55(d,J=6.8Hz,3H),2.00-2.05(m,1H),2.51-2.58(m,1H),2.65(s,3H),3.77-3.81(m,1H),3.88-3.92(m,1 H),4.06(br,1H),4.41-4.46(m,1H),4.56-4.60(m,1H),5.07-5.12(m,1H ),7.58(d,J=8.0Hz,2H),7.67(d,J=8.0Hz,2H),10.02(s,1H).LC-MS[M+H] + 445.3

[0859] Intermediate products 5 and 6: tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazo-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutane-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-thiazo-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutane-2-yl]carbamate (ULM-5-B)

[0860]

[0861] Step 1: Synthesis of 2-(4-bromophenyl)ethylene oxide

[0862] A mixture of 4-bromobenzaldehyde (2.52 g, 13.6 mmol), trimethylsulfonium iodide (2.87 g, 14.1 mmol), water (0.65 mL, 36.1 mmol), and potassium hydroxide (1.56 g, 27.7 mmol) in acetonitrile (20 mL) was heated to 55 °C for 4 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, dilute hydrochloric acid, and brine, and dried over sodium sulfate. The crude product of 2-(4-bromophenyl)ethylene oxide (2.20 g, 81.8% yield) was obtained by removing the organic solvent under reduced pressure, which required no purification for use in the next reaction.

[0863] 1H NMR (400MHz, CDCl3) δ2.74 (1H, q, J = 2.8Hz), 3.14 (1H, dd, J = 4.0Hz, 5.2Hz), 3.82 (1H, dd, J = 2.4Hz, 4.0Hz), 7.15 (2H, d, J = 8.4Hz), 7.47 (2H, d, J = 8.8Hz).

[0864] Step 2: Synthesis of 2-azido-2-(4-bromophenyl)ethanol

[0865] Sodium azide (3.28 g, 50.5 mmol) was added to a stirred suspension of 2-(4-bromophenyl)ethylene oxide (5.0 g, 25.3 mmol) in distilled water (70 mL). The resulting mixture was stirred at 60 °C for 4 hours, monitored by TLC. After the reaction was complete, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2-azido-2-(4-bromophenyl)ethanol (5.5 g, 90.2%) as a pale yellow oil. The crude product was used directly in the next step.

[0866] 1 H NMR (400MHz, CDCl3) δ1.94 (1H, s), 3.63-3.66 (2H, m), 4.57 (1H, dd, J = 5.2Hz, 7.6Hz), 7.15 (2H, d, J = 8.4Hz), 7.46 (2H, d, J = 8.4Hz).

[0867] Step 3: Synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride

[0868] Triphenylphosphine (4.35 g, 16.6 mmol) was added to a solution of 2-azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) in tetrahydrofuran (20.0 mL) and water (5.00 mL). The reaction mixture was stirred overnight at room temperature, and the solvent was removed under vacuum. The residue was dissolved in HCl / dioxane (4 M, 10.0 mL) and stirred at room temperature for 1 hour. After concentration, the solid was washed with dichloromethane to give 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.5 g, 72.1% yield) as a white solid.

[0869] 1 H NMR (400MHz, CDCl3) δ3.70(2H,s),4.28(1H,s),5.55(1H,s),7.47(2H,d,J=8.4Hz),7.63(2H,d,J=8.4Hz),8.61(3H,s); LC / MS 216.2[M+H]+ .

[0870] Step 4: Synthesis of 1-(4-bromophenyl)-2-(tert-butyldimethylsiloxy)ethylamine

[0871] 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-butyldimethylchlorosilane (TBSCl) (1.63 g, 10.8 mmol) were added. The reaction mixture was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted with dichloromethane (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a crude compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give 1-(4-bromophenyl)-2-(tert-butyldimethylchlorosilane)ethylamine (1.50 g, 63.6%) as a white solid.

[0872] LC / MS: 330.1 [M+H] + ;

[0873] Step 5: Synthesis of tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsiloxy)ethylcarbamate

[0874] To a solution of 1-(4-bromophenyl)-2-(tert-butyldimethylsiloxy)ethylamine (1.50 g, 4.56 mmol) in tetrahydrofuran (20 mL), triethylamine (0.69 g, 6.84 mmol) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol) were added. The reaction mixture was stirred overnight at room temperature and then quenched with water. The aqueous phase was extracted with ethyl acetate (50 mL x 3) and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a crude compound. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsiloxy)ethylcarbamate (1.80 g, 92.0%) as a pale yellow oil.

[0875] 1 H NMR(400MHz, CDCl3)δ0.01(6H,d,J=9.6Hz),0.86(9H,s),1.42(9H,s),3.65-3.70(2H,m) ,4.60-4.63(1H,m),7.34(2H,d,J=8.0Hz),7.39(1H,d,J=8.8Hz),7.56(2H,d,J=8.4Hz).

[0876] Step 6: Synthesis of tert-butyl-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)-ethylcarbamate

[0877] A mixture of tert-butyl-1-(4-bromophenyl)-2-(tert-butyldimethylsiloxy)ethylcarbamate (4.0 g, 9.32 mmol), 4-methylthiazole (1.85 g, 18.6 mmol), potassium acetate (1.82 g, 18.6 mmol), and palladium(II) acetate (0.11 g, 0.47 mmol) was dissolved in dimethylacetamide and stirred under argon. The mixture was heated to 140 °C and stirred for 15 hours, then diluted with water. The aqueous phase was extracted with ethyl acetate (50 mL x 3) and washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give a crude compound, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give tert-butyl-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethylcarbamate (1.30 g, 41.8%) as a pale yellow solid.

[0878] 1 H NMR (400MHz, CDCl3) δ1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J = 6.0Hz), 4.55-4.58 (1H, m),4.84(1H,t,J=6.0Hz),7.30(1H,d,J=8.0Hz),7.38-7.45(4H,m),8.99(1H,s); LC / MS 335.2[M+H] + Rt = 1.859 minutes

[0879] Step 7: Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride

[0880] tert-butyl-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (300 mg, 0.536 mmol) was dissolved in hydrochloric acid / dioxane (5 mL, 4 M). The resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated under vacuum to give 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride as a white solid, which did not require further purification for the next step.

[0881] Step 8: Synthesis of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazo-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutane-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-thiazo-5-yl)phenyl]ethyl]carbamoyl}pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutane-2-yl]carbamate (ULM-5-B)

[0882] A solution of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride (1000 mg, 3.70 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (995 mg, 5.19 mmol), 1-hydroxybenzotriazole (HOBT) (695 mg, 5.19 mmol), (2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutyryl)4-hydroxypyrrolidine-2-carboxylic acid (1273 mg, 3.70 mmol) and triethylamine (747 mg, 7.40 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight under argon 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 layers were washed with brine (50 mL x 3), dried on anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (dichloromethyl / methanol = 15:1) to obtain tert-butyl(S)-1-((2S,4R)-4-hydroxy-2-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-ylcarbamate (700 mg) as a pale yellow oil, and tert-butyl(S)-1-((2S,4R)-4-hydroxy-2-((S)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidine-1-α)-3,3-dimethyl-1-oxobutane-2-ylcarbamate (500 mg) as a pale yellow oil.

[0883] ULM-5-A: 1H NMR(400MHz, CDCl3)δ0.93(9H,s),1.39(9H,s),1.77-1.83(1H,m),2.01-2.06(1 H,m),2.46(3H,s),3.54-3.60(4H,m),4.13-4.19(1H,m),4.29-4.36(1H,m),4.50 (1H,t,J=8.0Hz),4.78(1H,t,J=5.6Hz),4.81-4.88(1H,m),5.12-5.16(1H,m),6. 46(1H,d,J=9.2Hz),7.36-7.46(4H,m),8.41(1H,d,J=8.0Hz),8.99(1H,s); LC / MS 561.2[M+H] + Rt = 1.897 min

[0884] ULM-5-B: 1 H NMR(400MHz, CDCl3)δ0.87(9H,s),1.38(9H,s),1.92-2.06(2H,m),2.45(3H,s),3.56 -3.69(4H,m),4.06-4.14(1H,m),4.36(1H,s),4.56(1H,t,J=7.6Hz),4.76-4.81(1H,m ),4.87(1H,t,J=5.6Hz),5.146(1H,d,J=2.8Hz),6.47(1H,d,J=8.8Hz),7.37(2H,d,J =8.0Hz),7.51(2H,d,J=8.0Hz),8.37(1H,d,J=7.6Hz),8.98(1H,s); LC / MS561.2[M+H] + Rt = 1.887 minutes

[0885] Intermediate product 7: (2S,4R)-N-[(4-chloro-2-hydroxyphenyl)methyl]-4-hydroxy-1-[3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butyryl]pyrrolidine-2-carboxamide (ULM-6)

[0886]

[0887] The key intermediate was prepared using the above synthetic route. The desired 3-methylisoxazol-5-acetic acid was prepared according to the literature (J. Org. Chem. 66, 6595-6603, 2001). Alkylation with 2-iodopropane has been described in the literature. The desired ULM-6 was prepared using the same synthetic method as described in the preparation of intermediate ULM-3.

[0888] 1 H NMR (400MHz, CDCl3): δ9.33 (s, 0.5H), 9.20 (s, 0.5H), 8.07 (t, J = 6.4Hz, 0.5H), 7.83 (t, J = 6.0Hz, 0.5H), 6.99 (dd, J =2.4,8.0Hz,1H),6.89-6.90(m,1H),6.76-6.78(m,1H),6.02(s,0.5H),5.99(s,0.5H),5.80-5.83(m,0.5H),4.35( q,J=6.4Hz,1.5),4.16-4.25(m,2H),3.72-3.76(m,0.5H),3.61(d,J=9.2Hz,1.0H),3.51-3.55(m,1.5H),2.30-2.4 6(m,2.5H),2.26(s,1.5H),2.24(s,1.5H),1.95-2.05(m,1H),1.01(d,J=6.8Hz,1.5H),0.82-0.87(m,4.5H); LC-MS 436.1[M+1] + Rt = 3.57 minutes.

[0889] PTM synthesis:

[0890] Preferred PTM embodiments of this disclosure can be prepared according to the synthetic routes described in Schemes 1–3 below. These routes can be modified using general methods known to those skilled in the art and adapted to the synthesis of specific PTM embodiments.

[0891]

[0892]

[0893] Example PROTAC synthesis:

[0894] Intermediate product 1

[0895]

[0896] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

[0897]

[0898] At 25 °C, K₂CO₃ (756 mg, 5.47 mmol) and 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (832 mg, 2.73 mmol) were added to a DMF (10 mL) solution of 2-(2,6-dioxadiidine-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol) (832 mg, 2.73 mmol). 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 layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the desired product (95 mg, 13% yield).

[0899] Step 2: 2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethoxy)ethoxy)acetaldehyde

[0900]

[0901] At 25°C, IBX (130 mg, 0.46 mmol) was added to a CH3CN (5 mL) solution of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (95 mg, 0.23 mmol). The reaction was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated to give the crude intermediate 1,2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethoxy)ethoxy)acetaldehyde (90 mg), which was used without further purification.

[0902] Intermediate product 2

[0903]

[0904] To a solution of 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (10 g, 36.2 mmol) in NMP (70 mL), tert-butylpiperazine-1-carboxylic acid ester (13.47 g, 72.5 mmol) and DIPEA (18.6 g, 14.5 mmol) were added. The resulting mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (100 mL), and the mixture was extracted with ErOAc (300 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 100–2 / 1) to obtain the desired product 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (14 g, 31.67 mmol, 87.5% yield) as a pale yellow solid.

[0905] Synthesis scheme of exemplary compound 51

[0906] Step 1: 3-(4-bromophenyl)-4-nitropyridine

[0907]

[0908] At room temperature and under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (14.8 g, 12.8 mmol) was added to a stirred solution of 3-bromo-4-nitropyridine (100 g, 492.6 mmol), (4-bromophenyl)boronic acid (98.6 g, 492.6 mmol), and potassium carbonate (203.9 g, 1.47 mol) in toluene (1000 mL)-water (100 mL); the mixture was degassed three times with nitrogen. The resulting mixture was stirred overnight at 50 °C. TLC showed that the reaction was complete. The solid was removed by filtration and washed with ethyl acetate (100 mL x 3). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (400 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel pad (eluting with a hexane solution of 10-33% ethyl acetate) to give 3-(4-bromophenyl)-4-nitropyridine (89 g, 65% yield) as a yellow solid.

[0909] Step 2: 7-Bromo-5H-pyrido[4,3-b]indole

[0910]

[0911] Under a nitrogen atmosphere, a mixture of 3-(4-bromophenyl)-4-nitropyridine (20.0 g, 71.7 mmol) in triethyl phosphate (400 ml) was stirred at 110 °C for 2 h. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure to give a residue, which was purified by recrystallization (methanol) to give 7-bromo-5H-pyrido[4,3-b]indole (11.0 g, 62% yield) as a brown solid.

[0912] Step 3: 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

[0913]

[0914] A mixture of 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 dioxane / water (20 mL, 20:1) was heated to 90 °C for 4 hours under N2. The solid was filtered and the filtrate was evaporated. The residue was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH = 30:1) to give 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (250 mg, 59% yield).

[0915] Step 4: 14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxaundecane-1-ol

[0916]

[0917] At 0 °C, NaH (45 mg, 60%, 1.13 mmol) was added to a THF (10 mL) solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (270 mg, 1.13 mmol). After stirring at 20 °C for 1 hour, a DMF (2.0 mL) solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (150 mg, 0.57 mmol) was added. The resulting solution was stirred at 80 °C for 4 hours. After cooling to room temperature, the reaction was diluted with EA (30 mL) and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel (DCM / MeOH = 4 / 1) to give the desired product (200 mg, 72.89% yield) as a colorless oil.

[0918] Step 5: tert-butyl 7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylic acid ester

[0919]

[0920] To a solution of 150 mg (0.31 mmol) of 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxaundecane-1-ol (10 mL) in DCM, NET3 (94.5 mg, 0.93 mmol) and Boc2O (102.0 mg, 0.47 mmol) were added. The resulting solution was stirred at ambient temperature for 12 hours. The solvent was removed under vacuum. The residue was diluted with EA (30 mL) and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired product (120 mg, 66% yield), which required no further purification for use in the next step.

[0921] Step 6: tert-butyl 7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylic acid ester

[0922]

[0923] At 0 °C, MsCl (38.9 mg, 0.34 mmol) was added to a DCM (10 mL) solution of tert-butyl 7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylic acid ester (120 mg, 0.31 mmol) and NEt3 (93.9 mg, 0.93 mmol). After stirring at 30 °C for 1 hour, the solvent was removed. The residue was diluted with EA (30 mL) and washed with brine. The organic phase was concentrated to give the intermediate methanesulfonate.

[0924] To a stirred solution of methanesulfonate (100 mg, 0.15 mmol) in anhydrous DMF (10 mL), 2-(2,6-dioxadiidine-3-yl)-5-hydroxyisoindoline-1,3-dione (45.6 mg, 0.17 mmol) and K₂CO₃ (31.4 mg, 0.23 mmol) were added. The resulting mixture was stirred at 68 °C for 4 hours. The mixture was diluted with EtOAc (40 mL), washed twice with brine, and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the desired product (15 mg, 23.6% yield) as a yellow solid.

[0925] 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)isoindololin-1,3-dione

[0926]

[0927] TFA (5 mL) was added to a 2 mL solution of tert-butyl 7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylic acid ester (30 mg, 0.036 mmol). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10 mg, 38% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ12.34–12.48(m,1H),9.19–9.29(m,1H),8.80(s,1H),8.29–8.4 2(m,1H),8.02–8.14(m,1H),7.95(s,1H),7.69–7.81(m,1H),7.60(s,2H),7.17(s,1H), 7.09(s,1H),6.62(s,1H),4.97(s,1H),4.43(s,2H),4.14(s,2H),3.88(d,J=24.1Hz,3H ),3.78(d,J=8.2Hz,3H),3.69(d,J=10.0Hz,6H),2.80(m,4H),1.99–2.29(m,4H).(M+H) + 738.3.

[0928] Compound 50 was also prepared using a similar procedure to that used for compound 51.

[0929] Synthesis scheme of exemplary compound 52

[0930] Step 1: tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylic acid ester

[0931]

[0932] A solution of 2-(piperazin-1-yl)ethanol (5 g, 38.5 mmol) and TEA (12 g, 115 mmol) was stirred in DCM at 0 °C, Boc₂O was added, and the mixture was stirred overnight at 10 °C. Water was added. The mixture was then extracted with DCM, dried, concentrated, and filtered through a silica gel pad to give 8.1 g of product (92% yield).

[0933] Step 2: tert-butyl 4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylic acid ester

[0934]

[0935] A THF solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylic acid ester (3 g, 13 mmol) was stirred at 0 °C. NaH (624 mg, 15.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 3-bromoprop-1-yne (1.85 g, 15.6 mmol) was added, and stirring continued overnight at 70 °C. The mixture was then cooled to room temperature. Water was added, and the mixture was extracted with EA, dried over Na₂SO₄, and concentrated. The product was filtered through a silica gel pad (EA) to give 1.5 g (43% yield).

[0936] Step 3: tert-butyl 4-(2-((3-(5-bromopyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)piperazine-1-carboxylic acid ester

[0937]

[0938] tert-butyl 4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylic acid ester (500 mg, 1.86 mmol), 2,5-dibromopyridine (442 mg, 1.86 mmol), Pd(PPh3)2Cl2 (10%), CuI (11%), DIPEA, and CH3CN were stirred overnight at 5 °C, and EA was added. The mixture was washed with water and concentrated. It was then filtered through silica gel (EA) to give 450 mg of product (57% yield).

[0939] Step 4: tert-butyl 4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazine-1-carboxylic acid ester

[0940]

[0941] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylic acid ester [prepared using a procedure similar to step 1 of exemplary compound 63] (300 mg, 0.76 mmol), Pd(aMphose)Cl2 (50 mg, 10%), and CsF (450 mg, 2.96 mmol) were stirred in a microwave oven at 120 °C for 40 min in CH3CN / H2O (10:1). The mixture was cooled to room temperature and EA was added. The organic layer was washed with water and then filtered through a silica gel pad (DCM:MeOH = 20:1) to give 100 mg of tert-butyl 4-(2-(3-(5-(5H-pyrido[4,3-b]indole-7-yl)pyridin-2-yl)prop-2-kynyloxy)ethyl)piperazine-1-carboxylic acid ester. The crude product was dissolved in MeOH, Pd / C was added, and the mixture was stirred at 30°C under 2 MPa H2 for 2 hours. The mixture was then filtered and concentrated to obtain 100 mg of product (26% yield).

[0942] Step 5: 7-(6-(3-(2-(piperazin-1-yl)ethoxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole

[0943]

[0944] 100 mg (0.2 mmol) of tert-butyl 4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazine-1-carboxylic acid ester was stirred at 5 °C for 1 hour in HCl / dioxane solution (2 mL). The solution was concentrated to give 100 mg of crude product.

[0945] Step 6: 5-((5-(4-(2-(3-(5-(5H-pyridino[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindololin-1,3-dione

[0946]

[0947] 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yloxy)pentanal (86 mg, 0.24 mmol), NaBH4CN (55 mg, 0.48 mmol), and CH3COOH (saturated) were stirred in MeOH at 5 °C for 3 hours. DCM was then added. The organic layer was washed with water, concentrated, and filtered through a silica gel pad (DCM:MeOH = 8:1) to give 11 mg of product.

[0948] 1 HNMR (400MHz, MeOD): δ9.25(s,1H),8.79(s,1H),8.37-8.39(d,J=8Hz,1H),8.28-8.30(d,J=8Hz,1H),8.11-8.13(d, J=8Hz,1H),7.80(s,1H),7.75-7.77(d,J=8Hz,1H),7.60(s,1H),7.49-7.51(d,J=8Hz,1H),7.43-7.45(d,J=8Hz,1H) ,7.33(s,1H),5.07-5.09(m,1H),4.06-4.09(m,2H),3.57-3.60(m,2H),3.51-3.54(m,2H),2.93-2.95(m,2H),2.91- 2.93(m,1H),2.59-2.75(m,12H),2.37-2.41(m,2H),2.04-2.06(m,3H),1.78-1.80(m,2H),1.46-1.55(m,5H).(M+H) + 758.3.

[0949] Synthesis scheme of exemplary compound 53

[0950] Step 1: (((1s,3s)-3-(allyloxy)cyclobutoxy)methyl)benzene

[0951]

[0952] At 0 °C, NaH (60%, 0.336 g, 8.4 mmol) was added to a DMF (10 mL) solution of (1s,3s)-3-(benzyloxy)cyclobutanol (1.0 g, 5.61 mmol). After stirring for 30 minutes, 3-bromoprop-1-ene was added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 hours. After quenching with a saturated solution of NH4Cl (20 mL), the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE / EA = 10–1 as eluent to give the desired product (1.0 g, 82%) as a colorless oil.

[0953] Step 2: 3-((1s,3s)-3-(benzyloxy)cyclobutoxy)prop-1-ol

[0954]

[0955] At 0 °C, a THF solution (1.0 M, 9.0 mL) of dicyclohexylborane was added to a THF solution (20 mL) of (((1s,3s)-3-(allyloxy)cyclobutoxy)methyl)benzene (1.0 g, 4.58 mmol). After stirring at room temperature for 4 hours, NaOH (37%, 3.0 mL) and H₂O₂ (30%, 3.0 mL) were added to the mixture at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was quenched ...

Claims

1. A compound having the following chemical structure: ULM―L―PTM, Or its pharmaceutically acceptable salt. in: (a) The L is selected from: -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 -O-; in: Each m, n, o, p, q, and r of L is independently 0, 1, 2, 3, 4, 5, or 6, provided that no NO or OO bond is formed when any of m, n, o, p, q, or r is zero. as well as Each n and m is independently 0, 1, 2, 3, 4, 5, or 6; (b) The ULM is: in: W is CH2 or C=O; Each X is O; Z is O; G is H; Q1, Q2, and Q4 are each independently CH or CR; Q3 is N, CH, or CR; A is H; n is 1, 2, 3 or 4; R is -OR', C 1-6 Alkyl, -Cl, -F, -Br, or -I, wherein one of the R is covalently attached to the L; R' is H; and Indicate whether the bond is stereospecific or non-stereospecific; and (c) The PTM is selected from: in: R 1 Selected from H and C, which may be substituted with 1, 2 or 3 halogens. 1-6 Alkyl; and R 7 R 8 and R 9 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, hydroxyl, C 1-6 Alkyl and cyano groups.

2. The compound according to claim 1, wherein R 1 It is selected from methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl.

3. The compound according to claim 1, wherein the PTM is selected from:

4. The compound according to claim 1, wherein the ULM is: in: W is selected from CH2 and C=O; A is H; and This indicates whether the bond is stereospecific or non-stereospecific.

5. The compound according to claim 1, wherein the ULM is: in Indicates the attachment point of L.

6. A compound, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

7. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the composition further comprises at least one additional bioactive agent.

9. The pharmaceutical composition according to claim 8, wherein the additional bioactive agent is an anti-neurodegenerative agent.

10. The pharmaceutical composition according to claim 8, wherein the additional bioactive agent is a P-gp inhibitor.

11. The pharmaceutical composition according to claim 10, wherein the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, taribeda, ecrimethamine, or verapamil.

12. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating Tau-related diseases or conditions.

13. The use according to claim 12, wherein the Tau-related disease or condition is selected from the neurological conditions of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Barten's disease, spinal cord and brain injury, epilepsy, brain tumor, meningitis, multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformation, cerebral aneurysm, dural arteriovenous fistula, headache, memory impairment, peripheral neuropathy, postherpetic neuralgia, spinal cord tumor, stroke, and combinations thereof.

14. The use according to claim 12, wherein the Tau-related disease or condition is dementia.

15. The use according to claim 12, wherein the Tau-related disease or condition is selected from: subcortical dementia, frontotemporal dementia, Lewy body dementia, multi-infarct dementia, and semantic dementia.

16. The use according to claim 12, wherein the Tau-related disease or condition is an autoimmune disease.

17. The use according to claim 12, wherein the Tau-related disease or condition is Alzheimer's disease.

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