Compounds for tau protein degradation

Abstract

To provide compounds that bind tau protein and / or promote targeted ubiquitination for the degradation of tau protein.SOLUTION: Provided is a bifunctional compound having a tau protein binding moiety and a ubiquitin ligase binding moiety, as exemplified by the following structural formula.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application USSN 62 / 531,773, filed July 12, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] FIELD OF THE INVENTION The present invention relates generally to bifunctional compounds that bind to tau protein and promote its degradation through the recruitment of E3 ubiquitin ligases, and the use of such compounds in the treatment of neurological disorders (e.g., Alzheimer's disease).

[0003] Background of the Invention Alzheimer's disease (AD) is characterized by the progressive loss of memory and other mental functions. Approximately 35 million people worldwide suffer from AD. Although the exact mechanism of AD is not fully understood, the deposition of two characteristic proteins, senile plaques and neurofibrillary tangles (NFTs), defines the causative events of AD. While senile plaques contain extracellular aggregates of amyloid-β peptide (Aβ), NFTs consist of hyperphosphorylated tau protein. Because tau accumulation begins before widespread neuronal loss, targeting tau protein has become a strategy for treating AD. Therefore, tau is not only a drug target but also a biomarker for the early diagnosis of AD by measuring brain tau loading. Positron emission tomography (PET) is a molecular imaging technique that provides a noninvasive diagnostic method for the detection of tau aggregation. Therefore, several tau radiotracers have been developed and tested in humans.

[0004] Recently, a new therapeutic strategy to reduce and / or eliminate proteins associated with certain pathological conditions, PROTACs (Protein Degradation Targeting Chimeras; see, for example, 2015 U.S. Patent Application No. USSN 14 / 792,414, filed July 6, 2015), has been developed by creating bifunctional compounds that recruit target proteins to E3 ubiquitin ligases, which subsequently induce proteasome-mediated degradation of the target protein. E3 ubiquitin ligases, in combination with E2 ubiquitin-conjugating enzymes, are proteins that facilitate the attachment of ubiquitin to lysines on target proteins via an isopeptide bond (e.g., an amide bond not present on the protein backbone). Ubiquitination of the protein generally leads to proteasome-targeted degradation of the protein.

[0005] Currently, there is no clinically approved compound that targets tau for the treatment of AD, and the overall clinical failure rate is higher for AD compared with other diseases.As a result, there is a continuing need to identify drugs that effectively treat neurological disorders such as AD.In particular, drugs that utilize the cellular mechanisms involved in protein homeostasis (such as ubiquitination, proteasome degradation) can find particular use as therapeutic agents. Summary of the Invention

[0006] PROTACs rely on the strategy of recruiting target proteins to E3 ubiquitin ligases and subsequently inducing proteasome-mediated degradation of the target proteins. The present disclosure describes the conjugation of a tau-binding moiety with an E3 ubiquitin ligase-binding moiety (e.g., lenalidomide, thalidomide), providing compounds that can induce ubiquitination of tau proteins and promote their degradation in cells. Thus, the present disclosure arises from the recognition that aggregation of tau protein, particularly hyperphosphorylated tau protein, causes certain neurological disorders (e.g., tauopathies such as AD), and that a single bifunctional compound can promote the degradation of tau protein by targeting both tau protein or any post-translationally modified form of tau and recruiting an E3 ubiquitin ligase (e.g., cereblon), ubiquitinating tau protein and marking it for proteasomal degradation, thereby providing new compounds, compositions, and methods for the treatment of neurological diseases (e.g., tauopathies such as AD). Thus, the present disclosure represents an important advance in the treatment of neurological diseases, particularly tauopathies.

[0007] In one aspect, provided is a compound of formula I: [ka] is expressed as During the ceremony: T is a tau protein-binding moiety; E is the E3 ubiquitin ligase binding moiety; L is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted heteroalkylene, a bond, -O-, -N(R A )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)RA -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR A S(O)2-, or combinations thereof; and R A each occurrence independently represents hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, when attached to a nitrogen protecting group, a nitrogen atom, or two R A the groups are linked to form a substituted or unsubstituted heterocyclic ring, The compound or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [Problem to be solved by the invention]

[0008] In some embodiments, T has the formula TI: [ka] is expressed as During the ceremony: L is N or CR 5 and; M is N or CR 6 and; P is N or CR 7 and; Q is N or CR 8 and; X is one or more carbons, optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be replaced by alkyl1-6 A single bond or a substituted or unsubstituted C, which may be replaced by alkyl 1-12 is alkylene, R 9 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, where aryl and heteroaryl are halogen, optionally SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, —CH3, aryl, or heteroaryl; and n is 0 to 12; where R 1-8 one or more carbons may optionally be C(O), O, S, SO, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl). [Means for solving the problem]

[0009] In some embodiments of formula TI: L is N or CR 5 and; M is N or CR 6 and; P is N or CR 7 and; Q is N or CR 8 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, where aryl and heteroaryl are halogen, optionally SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 1 , R2 , and R 4 ~R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; and n is 0 to 12; where R 1-8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl). [Effects of the Invention]

[0010] In some embodiments, T has formula T-II: [ka] is expressed as During the ceremony: X 1 is CH, N, NH, O, or S; X 2 is CH, C, or N; X 3 is CR 15 or N; X 4 is CR 15 or N; X 5 is CR 15 or N; R 13 and R 15each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15 one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0011] In some embodiments of Formula T-II: X 1 is CH, N, O, or S; X 2 is CH, C, or N; X 3 But, CR 15 or N; X 4 But, CR 15 or N; X 5 But, CR 15 or N; R 13 and R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2)n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0012] In some embodiments, T has formula T-III or T-IV: [ka] is expressed as During the ceremony: R 20 and R 21 are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, -NR x Ry , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 is -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A - or -(CH2) n -S(O)2NR A - and; R 23 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 is an unsubstituted alkylene, an alkylene substituted with one or more halogen or hydroxy groups, an unsubstituted alkoxylene, or an alkoxylene substituted with one or more halogen or hydroxy groups; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; n is 0 to 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0013] In some embodiments, E is a cereblon E3 ubiquitin ligase binding moiety or a VHL E3 ubiquitin ligase binding moiety.

[0014] In some embodiments, E is a cereblon E3 ubiquitin ligase binding moiety.

[0015] Exemplary compounds of Formula I include, but are not limited to: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, provided is a radiolabeled compound comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.

[0017] In another aspect, provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In another aspect, provided is a method of treating a neurological disorder in a subject in need thereof, the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the neurological disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a tauopathy (e.g., Alzheimer's disease).

[0019] In another aspect, provided is a method of promoting the degradation of tau protein in a subject in need thereof, the method comprising administering to the subject a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I.

[0020] In another aspect, provided is a method of detecting a neurological disorder, the method comprising contacting a tissue with a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I.

[0021] In another aspect, provided is a method for detecting pathological aggregation of tau protein in a tissue, the method comprising contacting the tissue with a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I.

[0022] In another aspect, provided is a method of diagnosing a neurological disorder in a subject, the method comprising contacting a tissue of the subject with a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I.

[0023] In another aspect, provided is a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, for use in treating a neurological disorder in a subject in need thereof; and / or promoting the degradation of tau protein.

[0024] In another aspect, provided is a kit comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the kit further comprises instructions for administration (e.g., administration to a human) and / or use.

[0025] Details of certain embodiments of the invention are set forth in the detailed description below. Other features, objects, and advantages of the invention will be apparent from the definition, examples, drawings, and claims. [Brief explanation of the drawings]

[0026] Brief description of the drawings [Figure 1A]FIG. 1A is a series of Western blot stainings showing the effect of exemplary compounds on tau protein levels in a human tau A152T neuronal cell model after 24 hours of treatment. [Figure 1B] Figure 1B is a series of bar graphs quantifying total tau and hyperphosphorylated tau from the Western blot in Figure 1A. The figures demonstrate the significant tau-reducing effects of the exemplary compounds, but not lenalidomide, a compound that binds only to CRBN.

[0027] [Figure 2A] FIG. 2A is a series of Western blot stainings showing the effect of exemplary compounds on tau protein levels in the human tau P301L neuronal cell model after 24 hours of treatment. [Figure 2B] Figure 2B is a series of bar graphs quantifying total tau and hyperphosphorylated tau from the Western blot in Figure 2A. The figures demonstrate the significant tau-reducing effects of the exemplary compounds, but not lenalidomide, a compound that binds only to CRBN.

[0028] [Figure 3] Figure 3 is a series of Western blot stainings showing the effect of a known tau-binding compound, T807, on the levels of tau protein in non-mutant human neurons (control) and human tau A152T neurons. The graph on the right shows quantification of the blots. No significant tau-reducing effect of T807 was observed in either cell line.

[0029] [Figure 4A] Figure 4A is a series of Western blot stainings showing the effects of exemplary compounds on the levels of the E3 ubiquitin ligases cereblon (CRBN), von Hippel-Lindau tumor suppressor (VHL), and C-terminus of HSC70-interacting protein (CHIP) in human tauA152T and tauP301L neurons after 24 hours of treatment. [Figure 4B-C]Figure 4B is a series of bar graphs quantifying CRBN from the Western blot in Figure 4A; CRBN levels in TauA152T neurons are on the left (medium gray bars) and CRBN levels in TauP301L neurons are on the right (black bars). Figure 4C is a series of bar graphs quantifying total tau from the Western blot in Figure 4A; Tau5 (total tau) levels in TauA152T neurons are on the left (medium gray bars) and Tau5 levels in TauP301L neurons are on the right (black bars). [Figure 4D-E] Figure 4D is a series of bar graphs quantifying CHIP from the Western blot in Figure 4A; CHIP levels in tau A152T neurons are on the left (medium gray bars) and CHIP levels in tau P301L neurons are on the right (black bars). Figure 4E is a series of bar graphs quantifying VHL from the Western blot in Figure 4A; VHL levels in tau A152T neurons are on the left (medium gray bars) and VHL levels in tau P301L neurons are on the right (black bars).

[0030] [Figure 5A] FIG. 5A shows a series of Western blot stainings showing the effects of exemplary compounds on tau protein levels in human non-mutated (control), human tau A152T, and human tau P301L neurons at 6 weeks of differentiation. [Figure 5B] FIG. 5B is a series of bar graphs quantifying total tau, hyperphosphorylated tau (top graph), and CRBN (bottom graph) from the Western blot in FIG. 5A. [Figure 5C] FIG. 5C quantifies total tau, hyperphosphorylated tau (top graph), and CRBN (bottom graph) from the average of three experiments of Western blots as represented in FIG. 5A.

[0031] [Figure 6A] FIG. 6A is a series of Western blot stainings showing the effects of exemplary compounds in 6-week differentiated human tau A152T neurons. [Figure 6B] FIG. 6B is a series of bar graphs quantifying total tau, hyperphosphorylated tau, and CRBN from the Western blot in FIG. 6A.

[0032] [Figure 7] Figure 7 is a bar graph quantifying the results of a neuronal cell viability assay for the ability of exemplary compounds to provide protection from a toxic stimulus associated with neurodegeneration, selected here as β-amyloid(1-42), as a functional readout of the effectively degraded tau peptide (at 8 weeks of differentiation). As shown by Silva et al. (Stem Cell Reports, 2016, 7(3), 325-40; doi: 10.1016 / j.stemcr.2016.08.001), the reduction in viability upon β-amyloid(1-42) exposure is due to tau. Left: Schematic of the experimental design; Right: Viability graph.

[0033] [Figure 8A-B] Figure 8A is a series of Western blot stainings showing the effects of exemplary compounds and T-807 on tau protein levels in the human tau A152T neuronal cell model after 24 hours of treatment. The control is non-mutated neurons (8330-8-RC1). Figure 8B is a series of graphs quantifying total tau and hyperphosphorylated tau from the Western blot in Figure 8A.

[0034] [Figure 9A-B] Figure 9A is a series of Western blot stainings showing the effects of exemplary compounds and T-807 on a human tau P301L neuronal model after 24 hours of treatment. The control is a non-mutated neuron (CTR2-L17-RC2). Figure 9B is a series of graphs quantifying total tau and hyperphosphorylated tau from the Western blot in Figure 9A.

[0035] [Figure 10]FIG. 10 is a series of bar graphs quantifying total tau and hyperphosphorylated tau from the Western blots in FIGS. 8A and 9A.

[0036] definition Chemical Definition The definitions of specific functional groups and chemical terms are described in more detail below.Chemical elements are identified according to the CAS version of the Periodic Table of the Elements in the inside cover of Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as described therein.In addition, the general rules of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0037] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Additionally, the present invention encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0038] During the ceremony, [ka] is a single bond in which the configuration of the moiety directly bonded thereto is not specified, [ka] is absent or a single bond, and [ka] or [ka] is a single or double bond.

[0039] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ in the presence of one or more isotopically enriched atoms, for example, replacement of hydrogen by deuterium or tritium; 18 By F 19 Substitution of F, or 13 C or 14 By C 12 Within the scope of this disclosure are compounds having the present structures except for the substitution at C. Such compounds can be useful, for example, as analytical tools or probes in biological assays.

[0040] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be encompassing.

[0041] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0042] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 alkyl (unsubstituted C 1-6Alkyl, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (I-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (I-Bu), etc. In some embodiments, the alkyl group is substituted C 1-10 Alkyl (substituted C 1-6 Alkyl, for example -CF3, Bn).

[0043] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0044] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the backbone (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the backbone ("heteroC").1-20 In some embodiments, heteroalkyl groups are saturated groups having 1 to 9 carbon atoms and one or more heteroatoms within the backbone ("heteroC 1-9 In some embodiments, heteroalkyl groups are saturated groups having 1 to 18 carbon atoms and one or more heteroatoms within the backbone ("heteroC 1-18 In some embodiments, heteroalkyl groups are saturated groups having 1 to 16 carbon atoms and one or more heteroatoms within the backbone ("heteroC 1-16 In some embodiments, heteroalkyl groups are saturated groups having 1 to 14 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-14 In some embodiments, heteroalkyl groups are saturated groups having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, heteroalkyl groups are saturated groups having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkyl groups are saturated groups having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms within the backbone ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the backbone ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom within the backbone ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom within the backbone ("heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC alkyl"). In some embodiments, a heteroalkyl group, as defined herein, is a partially unsaturated group, having one or more heteroatoms in the parent chain and at least one unsaturated carbon, e.g., a carbonyl group. For example, a heteroalkyl group may contain an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-20 In some embodiments, the heteroalkyl group is a substituted heteroC 1-20 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0045] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In some embodiments, the alkenyl group is a substituted C 2-10 In alkenyl groups, the C=C double bond does not specify the stereochemistry (e.g., -CH=CHCH3 or [ka] ) may be an (E) or (Z) double bond.

[0046] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the backbone (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s). In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms within the backbone, at least one double bond, and one or more heteroatoms ("heteroalkenyl C"). 2-10In some embodiments, heteroalkenyl groups have 2-9 carbon atoms in the backbone, at least one double bond, and one or more heteroatoms ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms in the backbone, at least one double bond, and one or more heteroatoms ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms in the backbone, at least one double bond, and one or more heteroatoms ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms in the backbone, at least one double bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the backbone ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2-4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the backbone ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms within the backbone, at least one double bond, and one heteroatom ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the backbone ("heteroC 2-6 Unless otherwise specified, each heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0047] The term "alkynyl" refers to the radical of a hydrocarbon group having from 2 to 10 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds), and a straight-chain or branched chain. In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2- In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkynyl groups include pentynyl (C), hexynyl (C), and the like. Additional examples of alkynyl include heptynyl (C), octynyl (C), and the like. Unless otherwise specified, each alkynyl group is independently either unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In some embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0048] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the backbone (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s). In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms within the backbone, at least one triple bond, and one or more heteroatoms ("heteroalkynyl groups"). 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms within the main chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms in the main chain, at least one triple bond, and one or more heteroatoms ("heteroC 23-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms in the main chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms in the main chain, at least one triple bond, and one or more heteroatoms ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the main chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the backbone ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms within the backbone, at least one triple bond, and one heteroatom ("heteroC 2-3In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the backbone ("heteroC 2-6 Unless otherwise specified, each heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0049] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("C 3-14 In some embodiments, the carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms (C 3-8 In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6Carbocyclyl groups include, without limitation, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3-8 Carbocyclyl groups include, without limitation, C 3-6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 Carbocyclyl groups include, without limitation, C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (containing fused, bridged, or spiro ring systems, such as, for example, a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to designate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14It is a carbocyclyl.

[0050] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups are the C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups are the C 3-6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, cycloalkyl groups are unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0051] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms ("3- to 14-membered heterocyclyl"), each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") ring systems), saturated, or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the heterocyclyl or the carbocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0052] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl , 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0054] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the cyclic array). 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracyl). "Aryl" also encompasses ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, and the radical or point of attachment is on the aryl ring. In such instances, the number of carbon atoms is designated through the number of carbon atoms in the aryl ring system. Unless otherwise specified, each aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0055] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, with the point of attachment on the alkyl portion.

[0056] The term "heteroaryl" refers to a radical of a 5-14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 (e.g., 6, 10, or 14 π-electrons shared in a cyclic arrangement) aromatic ring system having ring carbon atoms and one to four ring heteroatoms provided within the aromatic ring system ("5-14-membered heteroaryl"), each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0057] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0058] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, putrellidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0059] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, with the point of attachment on the alkyl portion.

[0060] The term "unsaturated bond" refers to a double or triple bond.

[0061] The terms "unsaturated" or "partially unsaturated" refer to a moiety that includes at least one double or triple bond.

[0062] The term "saturated" refers to a moiety that does not contain double or triple bonds, ie, the moiety contains only single bonds.

[0063] The addition of the suffix "-ene" to a base indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0064] Unless otherwise specified, a group is optionally substituted. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that can be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). Typically, the term "substituted" means that at least one hydrogen atom present on a group is replaced with a suitable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions within the group; when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all reasonable substituents of organic compounds and includes any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in a stable moiety. The present invention is not intended to be limited in any way by the exemplary substituents described herein.

[0065] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )3、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-SI(R aa )3、-OSI(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa, -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(OR cc )2, -P(R cc )3 + X - , -P(OR cc )3 + X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc )3 + X - , -OP(R cc )2, -OP(R cc )3 + X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted by a group; where X - is the counterion; Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc be replaced by; R aa Each of the 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb each independently represents hydrogen, —OH, —OR aa , -N(Rcc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; R cc each independently represents hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NRff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -SI(R ee )3, -OSI(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg groups), or two geminal R dd The substituents may be linked to form =O or =S; where X - is the counterion; R ee Each of the 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff each independently represents hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups are linked to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3+ X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(=NH)NH(C 1-6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -SI(C 1-6alkyl)3, -OSI(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0066] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0067] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxy", by extension, refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(Rbb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa ,-OSI(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2)2), where X - , R aa , R bb , and R cc is as defined herein.

[0068] The term "amino" refers to the group -NH. By extension, the term "substituted amino" refers to a mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0069] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, such as -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2 and -NHP(=O)(N(R bb )2)2)2, wherein R aa , Rbb and R cc is as defined herein, and —NH(R bb ) group R bb is not hydrogen.

[0070] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2 and -NR bb P(=O)(N(R bb )2)2)2, wherein R aa , R bb and R cc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0071] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0072] The term "sulfinyl" refers to the group -S(=O)R aa where R aa is as defined herein.

[0073] The term "sulfinyl" refers to the group -S(=O)Raa where R aa is as defined herein.

[0074] The term "acyl" refers to -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 and -C(=NR X1 )N(R X1 )2, wherein R X1 is hydrogen, halogen, substituted or unsubstituted hydroxyl, substituted or unsubstituted thiol, substituted or unsubstituted amino, substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic, cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Substituents for the acyl group include, without limitation, any of the substituents described herein that result in a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, imino, oxo, isocyano, thioxo, cyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which can be further substituted or unsubstituted).

[0075] The term "carbonyl" refers to a group in which the carbon directly attached to the parent molecule is hybridized with an oxygen, nitrogen, or sulfur atom, e.g., a ketone (e.g., -C(=O)R aa ), carboxylic acids (e.g., -COH), aldehydes (-CHO), esters (e.g., -COR aa , -C(=O)SR aa , -C(=S)SR aa ) and amides (e.g., —C(═O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2)), and imides (e.g., -C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb ) 2), wherein R aa and R bbis as defined herein.

[0076] The term "silyl" refers to the group -SI(R aa )3, where R aa is as defined herein.

[0077] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0078] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, OH, OR aa , N(R cc )2, CN, C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C6-14 aryl, and 5- to 14-membered heteroaryl, or two R attached to the N atom cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group, where R aa , R bb , R cc , and R dd is as defined herein.

[0079] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, without limitation, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R CC )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C6-14 and aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group, wherein R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999.

[0080] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (Ν'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamic acid amide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0081] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), ...Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate (Tmoc), 2-trichloroethyl carbamate ( Methylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t -Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrilebenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

[0082] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide amide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (IMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0083] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyl Disilylazacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3)-ones, -yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethyl Thiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0084] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, without limitation, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb)N(R bb )2, -S(=O)R aa , -SO2R aa , -SI(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, wherein X - , R aa , R bb and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0085] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl, and the like. Methyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl] [Chemical]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloro ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl 1,1-bis(4-methoxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl-t-hexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formic acid, benzoyl formate, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, Phenoxyacetic acid, p-chlorophenoxyacetic acid, 3-phenylpropionic acid, 4-oxopentanoate (levuriate), 4,4-(ethylenedithio)pentanoate (levurinoyl dithioacetal), pivalic acid, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate Examples of suitable amines include aromatic acid, 2-formylbenzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyric acid, monosuccinic acid, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoate, nitric acid, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenic acid, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts). In some embodiments, the oxygen protecting group is silyl. In some embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), isoisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (PIv).

[0086] In certain embodiments, the protecting group present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -SI(R aa )3, -P(R cc )2, -P(R cc )3 + X-, -P(OR cc )2, -P(OR cc )3 + X-, -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition (John Wiley & Sons, 1999), incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0087] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electrical neutrality. Anionic counterions may be monovalent (i.e., containing one formal negative charge). Anionic counterions may be multivalent (i.e., containing more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4 - , B(C6F5)4 - , BPh4- , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - An exemplary counterion, which may be multivalent, is CO 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0088] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, e.g., Smith, March's Advanced Organic Chemistry, 6th Edition (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate. In some cases, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nonaflate, such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphine oxide (e.g., one formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), and activated substituted hydroxyl groups (e.g., —OC(═O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NRbb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein).

[0089] As used herein, the use of the phrase "at least one" refers to 1, 2, 3, 4 or more instances, but also encompasses ranges, for example, 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 instances, inclusive.

[0090] A "non-hydrogen group" refers to any group defined for a specific variable other than hydrogen.

[0091] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

[0092] Other definitions The following definitions are of more general terms used throughout this application.

[0093] As used herein, the term "salt" refers to any and all salts and includes pharmaceutically acceptable salts.

[0094] The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the bounds of sound medical wisdom, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0095] The term "solvate" refers to a compound or its salt form associated with a solvent, usually via a solvolysis reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In some instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0096] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O (where R is the compound and x is a number greater than 0). A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 but less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0097] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., reactions that provide tautomeric pairs) may be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different)enamine tautomerizations.

[0098] It will also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0099] Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center (e.g., it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0100] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0101] The term "prodrug" refers to a compound that has a cleavable group and becomes a compound described herein by solvolysis or under physiological conditions, which is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but the acid-labile form often offers advantages of solubility, tissue compatibility, or delayed release to mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 alkyl esters of the compounds described herein are also suitable. 12 Substituted aryl and C7-C 12 Aryl alkyl esters are sometimes preferred.

[0102] The terms "composition" and "formulation" are used interchangeably.

[0103] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female, at any stage of development. The non-human animal may be a transgenic or genetically modified animal. The term "patient" refers to a human subject in need of treatment for a disease. The subject may also be a plant. In some embodiments, the plant is a terrestrial plant. In some embodiments, the plant is a non-vascular terrestrial plant. In some embodiments, the plant is a vascular terrestrial plant. In some embodiments, the plant is a seed plant. In some embodiments, the plant is a cultivated plant. In some embodiments, the plant is a dicotyledonous plant. In some embodiments, the plant is a monocotyledonous plant. In some embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, e.g., a soybean plant. In some embodiments, the plant is a tree or shrub.

[0104] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and centrifuging or otherwise separating their components). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0105] The term "tissue" refers to any biological tissue (including a group of cells, a body part, or an organ) of a subject, including blood vessels and / or lymphatic vessels, or a portion thereof, to which the compounds, particles, and / or compositions of the present invention are delivered. The tissue may be an abnormal or unhealthy tissue that may need to be treated. The tissue may also be a normal or healthy tissue that is at higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In some embodiments, the tissue is the central nervous system. In some embodiments, the tissue is the brain.

[0106] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into, in, or on a subject.

[0107] The terms "treatment," "treat," and "treating" refer to halting, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0108] The terms "condition," "disease," and "disorder" are used interchangeably.

[0109] The "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventive treatment. In some embodiments, the effective amount is the amount of a compound described herein in a single dose. In some embodiments, the effective amount is the combined amount of a compound described herein in multiple doses.

[0110] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a condition or delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, alleviates or avoids a condition, or its symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent. In some embodiments, a therapeutically effective amount is an amount sufficient to promote tau protein binding and / or tau protein degradation. In some embodiments, a therapeutically effective amount is an amount sufficient to treat a neurological disorder (e.g., AD). In some embodiments, a therapeutically effective amount is an amount sufficient to promote tau protein binding and / or tau protein degradation and treat cancer (e.g., DLBCL).

[0111] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent. In some embodiments, a prophylactically effective amount is an amount sufficient to promote tau protein binding and / or tau protein degradation. In some embodiments, a prophylactically effective amount is an amount sufficient to treat a neurological disorder (e.g., AD). In some embodiments, a prophylactically effective amount is an amount sufficient to promote tau protein binding and / or tau protein degradation and treat a neurological disorder (e.g., AD).

[0112] The term "neurological disorder" refers to any disorder, disease, or condition of the nervous system.

[0113] The term "tau protein" refers to a class of proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and, less commonly, are also expressed at very low levels in CNS astrocytes and oligodendrocytes. Tau protein is the product of alternative splicing from a single gene, named MAPT (microtubule-associated protein tau) in humans and located on chromosome 17. The tau protein described herein encompasses all post-translationally modified forms of the protein.

[0114] The term "tauopathy" refers to a class of neurodegenerative diseases associated with pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Primary tauopathies, i.e., conditions in which neurofibrillary tangles (NFTs) are predominantly observed, include, but are not limited to, primary age-related tauopathy (PART) / neurofibrillary tangle predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, and argyrophilic grain disease.

[0115] The terms "biologic," "biologic drug," and "biological product" refer to a wide range of products, including vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins. Biologicals may contain sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living organisms such as cells and tissues. Biologicals may be isolated from a variety of natural sources (e.g., human, animal, microbial) or may be produced by biotechnological and other techniques.

[0116] The term "small molecule" or "small molecule therapeutic agent" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially created (e.g., via chemical synthesis). Typically, it is a small organic compound (i.e., it contains carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, etc.). In some embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol, or about 100 g / mol or less. In some embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as an "organometallic small molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In some embodiments, small molecules are drugs. Preferably, but not necessarily, drugs have already been deemed safe and effective for use in humans or animals by appropriate government agencies or regulatory authorities.For example, drugs approved for human use are listed by the FDA under 21 CFR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 CFR §§ 500-589, which are incorporated herein by reference. All listed drugs are considered acceptable for use according to the present invention.

[0117] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired (usually beneficial) effect. For example, a therapeutic agent can treat, ameliorate, and / or prevent a disease. A therapeutic agent as disclosed herein can be a biologic or a small molecule therapeutic agent.

[0118] The term "E3 ubiquitin ligase" or "E3 ligase" refers to any protein that recruits an E2 ubiquitin-conjugating enzyme, is loaded with ubiquitin, recognizes a protein substrate, and assists in or directly catalyzes the transfer of ubiquitin from the E2 protein to the protein substrate.

[0119] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Provided herein are bifunctional compounds that bind to tau protein and recruit specific E3 ligases (e.g., cereblon) to promote tau protein degradation. In one aspect, the present disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, radiolabeled derivatives, prodrugs, and pharmaceutical compositions thereof. The compounds are useful for treating and / or preventing diseases associated with tau protein aggregation (e.g., tauopathies (e.g., AD)) in subjects in need thereof.

[0120] compound The compounds described herein interact with tau protein and E3 ubiquitin ligase (e.g., cereblon). As described herein, the therapeutic effect may be the result of the degradation, regulation, binding, or modification of tau protein by the compounds described herein. Without wishing to be bound by any particular theory, the therapeutic effect may be the result of the regulation, targeting, binding, or modification of E3 ubiquitin ligase (e.g., cereblon) by the compounds described herein. The therapeutic effect may be the result of the recruitment of E3 ubiquitin ligase (e.g., cereblon) by the compounds inhibiting, targeting, binding, or modifying E3 ubiquitin ligase, thereby ubiquitinating tau protein and marking it for proteasomal degradation. The compound may be provided as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof for use in any composition, kit, or method described herein.

[0121] In one aspect, disclosed is a compound of formula I: [ka] T is the tau protein binding moiety; E is the E3 ubiquitin ligase binding moiety: L is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted heteroalkylene, a bond, -O-, -N(R A )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR AC(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A ), -S(O)NR A -, -NR A S(O)2-, or a combination thereof; and R A are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, if attached to a nitrogen atom, a nitrogen protecting group, or two R A The groups are linked to form a substituted or unsubstituted heterocyclic ring.

[0122] Group T In some embodiments, T is any tau protein binding moiety, in some embodiments, derived from the tau protein binding compounds described in U.S. patent applications USSN 13 / 447,095, filed May 22, 2012; USSN 13 / 035,405, filed February 25, 2011; USSN 13 / 881,872, filed October 28, 2011; USSN 09 / 378,662, filed August 20, 1999; and USSN 14 / 346,914, filed March 24, 2014, each of which is incorporated herein by reference.

[0123] In some embodiments, T has the formula TI: [ka] is expressed as During the ceremony: L is N or CR 5 and; M is N or CR 6 and; P is N or CR 7 and; Q is N or CR 8 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -A-NR A -(CH2) n-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 1 , R 2 , and R 4 ~R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, —CH3, aryl, or heteroaryl; and n is 0 to 12; where R 1-8 One or more carbons may optionally be C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0124] In some embodiments, the compound of formula TI: is expressed as L is N or CR 5 and; M is N or CR 6 and; P is N or CR 7 and; Q is N or CR 8 and; X is a bond or a substituted or unsubstituted C 1-12alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 1 , R2 , and R 4 ~R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; and n is 0 to 12; where R 1~8 One or more carbons of the formula may optionally be C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0125] In some embodiments, L is N or CR 5 and M is N or CR 6 and P is CR 7 and Q is CR 8 In some embodiments, L is CR 5 and M is N or CR 6 and P is CR 7 and Q is CR 8 In some embodiments, L is CR 5 M is N; P is CR 7 and Q is CR 8 is.

[0126] In some embodiments, X is a bond.

[0127] In some embodiments, R 9 is hydrogen.

[0128] In some embodiments, R 3 is -(CH2) n -NRA -, -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -(CH2) n -NR A -, -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -NR A - or -(CH2) n -A-NR A In some embodiments, R 3 is -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A - or -(CH2) n -A-(C=O)NR A -; and A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n-(C=O)NR A -, -(CH2) n -A-(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -; and A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A - or -(CH2) n -A-(C=O)NR A -; and A is substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -; and A is substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -(CH2) n -(C=O)NR A-; and A is substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -; and A is substituted or unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A - or -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A -or-A-(CH2) n -NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A In some embodiments, R 3 is -A-(CH2) n -NR A In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A - or -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -(C=O)NR A -or-A-(CH2)n -NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -A-(CH2) n -NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -A-(CH2) n -NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 3 is -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene.

[0129] In some embodiments, R 1 , R 2 , and R 4 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, aryl, heteroaryl, NHR 12 , N(R 12 )2C3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and R 12は、 is hydrogen, -CH, aryl, or heteroaryl. 1 , R 2 , and R 4 Each of is independently hydrogen.

[0130] In some embodiments, T has the formula TIa: [ka] is expressed as During the ceremony: L is N or CR 5 and; M is N or CR 6 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2)n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 8 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, —CH3, aryl, or heteroaryl; and n is 0 to 12; where R 2 , R 3 , R 7 , and R8 One or more carbons may optionally be C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0131] In some embodiments of Formula TIa: L is N or CR 5 and; M is N or CR 6 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NRA -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; and n is 0 to 12; where R 2 , R 3 , R 7 , and R 8 One or more carbons of the formula may optionally be C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0132] In some embodiments, T has the formula TIb: [ka] is expressed as In the formula, R 3 is -(CH2) n -O-, -A-(CH2) n-O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A -It is.

[0133] In some embodiments of Formula TIb, R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NRA -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A -It is.

[0134] In some embodiments of Formula TIb, R 3 But -(CH2) n -NR A -, -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -AO-(CH2) n -(C=O)NR A -It is.

[0135] In some embodiments of Formula TIb, R 3 But -(CH2) n -NR A -, -(CH2) n -(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -NR A - or -(CH2) n -A-NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A - or -AO-(CH2) n -(C=O)NR AIn some embodiments, R 3 is -(CH2) n -(C=O)NR A -or-A-(CH2) n -NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A In some embodiments, R 3 is -A-(CH2) n -NR A In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A In some embodiments, R 3 is -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A - or -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -(CH2) n -(C=O)NR A -or-A-(CH2) n -NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -A-(CH2) n -NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -A-(CH2) n -NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 3 is -(CH2) n -(C=O)NRA - or -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 3 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene.

[0136] In some embodiments, T has the formula: [ka] It is expressed as:

[0137] In some embodiments, T has the formula: [ka] It is expressed as:

[0138] In some embodiments, T has the formula: [ka] It is expressed as:

[0139] In some embodiments, T has the formula: [ka] It is expressed as:

[0140] In some embodiments, T has the formula: [ka] It is expressed as:

[0141] In some embodiments, T has the formula: [ka] It is expressed as:

[0142] In some embodiments, T has the formula: [ka] It is expressed as:

[0143] In some embodiments, T has the formula: [ka] It is expressed as:

[0144] In some embodiments, T has the formula: [ka] . It is expressed as:

[0145] In some embodiments, T has formula T-II: [ka] is expressed as During the ceremony: X 1 teeth 、 CH, N, NH, O, or S; X 2 teeth 、 CH, C, or N; X 3 teeth 、 CR 15 or N; X4 teeth 、 CR 15 or N; X 5 teeth 、 CR 15 or N; R 13 and R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -;-(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -;-(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -;-(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n-A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15 one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0146] In some embodiments of Formula T-II: X 1 is CH, N, O, or S; X 2 is CH, C, or N; X 3 But, CR 15 or N; X 4 But, CR 15 or N; X 5 But, CR 15 or N; R 13 and R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A(C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0147] In one embodiment, X 1 and X2 is N.

[0148] In one embodiment, X 3 , X 4 , or X 5 At least one of is N.

[0149] In one embodiment, X 5 is N; and X 3 and X 4 is CH.

[0150] In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, -AO-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A -; and A is unsubstituted heterocyclylene. In some embodiments, R 14 is -A-(CH2) n -(C=O)NR A In some embodiments, R 14 is -A-(CH2) n -(C=O)NR A -; and A is unsubstituted heterocyclylene. In some embodiments, R14 is -A-(CH2) n -(C=O)NR A -; and A is unsubstituted piperidinylene or piperazinylene. In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene.

[0151] In some embodiments, T has formula T-II-a: [ka] is expressed as During the ceremony: X 3 is CR 15 or N; X 4 is CR 15 or N; X 5 is CR 15 or N; R 13 and R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A(C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0152] In some embodiments of Formula T-II-a: X 3 But, CR 15 or N; X 4 But, CR 15 or N; X 5 But, CR 15 or N; R 13 and R 15 Each occurrence of 、 independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NRA -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and n is 0 to 12; where R 13 , R 14 , and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0153] In some embodiments, T has formula T-II-b: [ka] is expressed as In the formula, R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NRA -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A -It is.

[0154] In some embodiments of Formula T-II-b, R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A -It is.

[0155] In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, -AO-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A In some embodiments, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A -; and A is unsubstituted heterocyclylene. In some embodiments, R 14 is -A-(CH2) n -(C=O)NR A In some embodiments, R 14 is -A-(CH2) n -(C=O)NR A -; and A is unsubstituted heterocyclylene. In some embodiments, R 14 is -A-(CH2) n -(C=O)NR A -; and A is unsubstituted piperidinylene or piperazinylene. In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted heteroarylene. In some embodiments, R14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In some embodiments, R 14 is -AO-(CH2) n -(C=O)NR A -; and A is unsubstituted pyridinylene.

[0156] In some embodiments, T has the formula: [ka] It is expressed as:

[0157] In some embodiments, T has the formula: [ka] It is expressed as:

[0158] In some embodiments, T has the formula: [ka] It is expressed as:

[0159] In some embodiments, T has the formula: [ka] It is expressed as:

[0160] In some embodiments, T has formula T-III or T-IV: [ka] is expressed as During the ceremony: R 20 and R 21 are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, -NR xR y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 is -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A - or -(CH2) n -S(O)2NR A - and; R 23 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 is a substituted or unsubstituted alkylene or a substituted or unsubstituted alkoxylene; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; n is 0 to 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0161] In some embodiments, T has formula T-III: [ka] is expressed as During the ceremony: R 20 and R 21 are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 is -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A - or -(CH2) n -S(O)2NR A - and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; n is 0 to 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0162] In some embodiments, T has formula T-III-a: [ka] is expressed as During the ceremony: R 20 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 is -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A - or -(CH2) n -S(O)2NR A - and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and n is 0 to 12.

[0163] In some embodiments, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -It is.

[0164] In some embodiments, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -It is.

[0165] In some embodiments, G is unsubstituted arylene. In some embodiments, G is unsubstituted phenylene. In some embodiments, G is unsubstituted heteroarylene. In some embodiments, G is unsubstituted pyridinylene, pyrimidinylene, pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or thiazolylene. In some embodiments, G is unsubstituted pyridinylene or pyrazolinylene. G is unsubstituted pyridinylene. In some embodiments, G is unsubstituted phenylene, pyridinylene, or pyrazonylylene.

[0166] In some embodiments, R 20is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -It is.

[0167] In some embodiments, R 20 teeth, [ka] is; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -It is.

[0168] In some embodiments, R 20 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -It is.

[0169] In some embodiments, R 20 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R22 is -(CH2) n -NR A -It is.

[0170] In some embodiments, R 20 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -It is.

[0171] In some embodiments, R 20 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is -(CH2) n -NR A -It is.

[0172] In some embodiments, T has the formula: [ka] It is expressed as:

[0173] In some embodiments, T has the formula: [ka] It is expressed as:

[0174] In some embodiments, T has the formula: [ka] It is expressed as:

[0175] In some embodiments, T has formula T-IV: [ka] is expressed as During the ceremony: R 21 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 is a substituted or unsubstituted alkylene or a substituted or unsubstituted alkoxylene; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and r is 0, 1, or 2.

[0176] In some embodiments, T has formula T-IV-a: [ka] is expressed as During the ceremony: G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R24 is a substituted or unsubstituted alkylene or a substituted or unsubstituted alkoxylene; and R x and R y are independently hydrogen or substituted or unsubstituted alkyl.

[0177] In some embodiments, R 24 is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y is.

[0178] In some embodiments, G is unsubstituted arylene. In some embodiments, G is unsubstituted phenylene. In some embodiments, G is unsubstituted heteroarylene. In some embodiments, G is unsubstituted pyridinylene, pyrimidinylene, pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or thiazolylene. In some embodiments, G is unsubstituted pyridinylene or pyrazolinylene. In some embodiments, G is unsubstituted pyridinylene. In some embodiments, G is unsubstituted phenylene, pyridinylene, or pyrazolinylene.

[0179] In some embodiments, R 24 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y is.

[0180] In some embodiments, R 24 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y is.

[0181] In some embodiments, R 24 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y is.

[0182] In some embodiments, R 24 teeth, [ka] and; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y is.

[0183] In some embodiments, T has the formula: [ka] [ka] It is expressed as:

[0184] In some embodiments, T has the formula: [ka] It is expressed as:

[0185] In some embodiments, T has the formula: [ka] It is expressed as:

[0186] In some embodiments, T has the formula: [ka] It is expressed as:

[0187] In some embodiments, T has the formula: [ka] It is expressed as:

[0188] In some embodiments, T has the formula: [ka] [ka] It is expressed as:

[0189] In some embodiments, T has the formula: [ka] It is expressed as:

[0190] In some embodiments, the tau binding moiety has a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. dIt binds to tau protein.

[0191] In some embodiments, the tau-binding moiety selectively binds to tau protein over other tau proteins. In some embodiments, the compound of Formula I selectively binds to tau protein over amyloid beta. In some embodiments, the selectivity is between about 2-fold and about 5-fold. In some embodiments, the selectivity is between about 5-fold and about 10-fold. In some embodiments, the selectivity is between about 10-fold and about 20-fold. In some embodiments, the selectivity is between about 20-fold and about 50-fold. In some embodiments, the selectivity is between about 50-fold and about 100-fold. In some embodiments, the selectivity is between about 100-fold and about 200-fold. In some embodiments, the selectivity is between about 200-fold and about 500-fold. In some embodiments, the selectivity is between about 500-fold and about 1000-fold. In some embodiments, the selectivity is at least about 1000-fold.

[0192] Group L L is a divalent moiety connecting T and E. In certain embodiments, L is a substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, —O—, —N(R A )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR A -, -NR A C(=O)-, -NR A C(=O)R A -, -C(=O)R A -, -NR A C(=O)O-, -NR A C(=O)N(R A )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R A )-, -S(O)NR A -, -NR A S(O)2-, or a combination thereof.

[0193] In some embodiments, L is any "L" group described in U.S. Patent Application No. USSN 14 / 792,414, filed July 6, 2015, and incorporated herein by reference. In some embodiments, L is any "linker" group described in U.S. Patent Application No. USSN 14 / 707,930, filed May 8, 2015, and incorporated herein by reference. In some embodiments, L contains up to 50 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 40 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 30 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 20 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 15 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 12 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 10 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 6 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 5 atoms, excluding hydrogen atoms. In some embodiments, L contains up to 3 atoms, excluding hydrogen atoms. In some embodiments, any carbon atom in L can be substituted.

[0194] In some embodiments, L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene.

[0195] In some embodiments, L is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In some embodiments, L is substituted or unsubstituted C 1-30 In some embodiments, L is substituted or unsubstituted C 1-20 In some embodiments, L is substituted or unsubstituted C 1-10 In some embodiments, L is substituted or unsubstituted C 1-30 In some embodiments, L is substituted or unsubstituted C 1-20 In some embodiments, L is substituted or unsubstituted C 1-10 It is heteroalkylene.

[0196] In some embodiments, L is [ka] and; q is 1 to 12; u is 1 to 12; p is 1 to 10; and s is 1 to 10.

[0197] In some embodiments, L is [ka] and; q is 1 to 12; p is 1 to 10; and s is 1 to 10.

[0198] In some embodiments, L is [ka] and; q is 1 to 5; p is 2 to 5; and s is 1 to 5.

[0199] In some embodiments, L is [ka] and; and q is 1 to 12. In some embodiments, L is [ka] and; and q is 1 to 5. In some embodiments, L is [ka] and; and q is 2. In some embodiments, L is [ka] and; and q is 3. In some embodiments, L is [ka] and; and q is 4. In some embodiments, L is [ka] and; and q is 5.

[0200] In some embodiments, L is [ka] and u is 1 to 12. In some embodiments, L is [ka] and u is 1 to 5.

[0201] In some embodiments, L is [ka] and p is 1 to 10. In some embodiments, L is [ka] and p is 2 to 5. In some embodiments, L is [ka] p is 3; and s is 2.

[0202] In some embodiments, L is an unsubstituted C-C 12 alkylene, or [ka] where q is 1 to 12. In some embodiments, L is an unsubstituted C-C 12 alkylene, or [ka] where q is 1 to 11. In some embodiments, L is an unsubstituted C-C 12 alkylene or [ka] where q is 1 to 11. In some embodiments, L is an unsubstituted C-C 10 alkylene or [ka] where q is 1 to 11. In some embodiments, L is unsubstituted C5-C7 alkylene or [ka] where q is 1 to 11. In some embodiments, L is unsubstituted C5-C7 alkylene or [ka] where q is 1 to 6.

[0203] In some embodiments, L is [ka] wherein q is 1 to 12. In some embodiments, L is [ka] wherein q is 1 to 6. In some embodiments, L is [ka] wherein q is 1. In some embodiments, L is [ka] wherein q is 2. In some embodiments, L is [ka] wherein q is 3. In some embodiments, L is [ka] wherein q is 4. In some embodiments, L is [ka] wherein q is 5. In some embodiments, L is [ka] wherein q is 6. In some embodiments, L is [ka] wherein q is 7. In some embodiments, L is [ka] wherein q is 8. In some embodiments, L is [ka] wherein q is 9. In some embodiments, L is [ka] wherein q is 10. In some embodiments, L is [ka] wherein q is 11. In some embodiments, L is [ka] where q is 12.

[0204] In some embodiments, L is an unsubstituted C-C 12 In some embodiments, L is an unsubstituted C4-C 12 In some embodiments, L is an unsubstituted C4-C 10 In some embodiments, L is an unsubstituted C5-C7 alkylene. In some embodiments, L is an unsubstituted C3 alkylene. In some embodiments, L is an unsubstituted C4 alkylene. In some embodiments, L is an unsubstituted C5 alkylene. In some embodiments, L is an unsubstituted C6 alkylene. In some embodiments, L is an unsubstituted C7 alkylene. In some embodiments, L is an unsubstituted C8 alkylene. In some embodiments, L is an unsubstituted C9 alkylene. In some embodiments, L is an unsubstituted C 10 In some embodiments, L is an unsubstituted C 11 In some embodiments, L is an unsubstituted C 12 It is alkylene.

[0205] R Abase In some embodiments, R A are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, an oxygen protecting group if attached to an oxygen atom, or a sulfur protecting group if attached to a sulfur atom; or two R A The groups may be linked to form a substituted or unsubstituted heterocyclic ring. A are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom; or two R A The groups may be linked to form a substituted or unsubstituted heterocyclic ring. A are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R A The groups may be linked to form a substituted or unsubstituted heterocyclic ring. A are independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5- to 6-membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, or two R A The groups may be linked to form a substituted or unsubstituted heterocyclic ring. A are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-30heteroalkyl, substituted or unsubstituted 5- to 6-membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, or two R A The groups may be linked to form a substituted or unsubstituted heterocyclic ring. A are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 1-30 In some embodiments, R A are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 1-20 In some embodiments, R A are independently hydrogen or substituted or unsubstituted C 1-6 In some embodiments, R A are independently hydrogen.

[0206] E group E is an E3 ubiquitin ligase binding moiety. E includes all moieties that bind to or can bind to any E3 ubiquitin ligase. For example, in some embodiments, E can bind to an E3 ubiquitin ligase such as cereblon or von Hippel-Lindau tumor suppressor protein (VHL). In some embodiments, E can bind to multiple different E3 ubiquitin ligases. In some embodiments, E binds to cereblon. In some embodiments, E binds to VHL.

[0207] Human cereblon (CRBN) is a 442 amino acid protein with an apparent molecular weight of approximately 51 kDa (GenBank: AAH17419). (For the CRBN protein sequence, see Higgins et al., Neurology. 2004, 63, 1927-31. For further information on the structure of CRBN, see Hartmann et al., PLoS One. 2015, 10, e0128342.) Human CRBN contains the N-terminal portion of the ATP-dependent Lon protease domain (237 amino acids from 81 to 317) and does not contain the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites. CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain, and retina. CRBN is located in the cytoplasm, nucleus, and peripheral membranes (Chang et al., Int. J. Biochem. Mol. Biol. 2011, 2, 287-94.).

[0208] Cereblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates numerous developmental processes, such as limb and auditory vesicle formation.

[0209] In some embodiments, E is a modulator, binder, inhibitor, or ligand of cereblon. In some embodiments, E is a modulator of cereblon. In some embodiments, E is a binder of cereblon. In some embodiments, E is an inhibitor of cereblon. In some embodiments, E is a ligand of cereblon. In some embodiments, E is any modulator, binder, inhibitor, or ligand of cereblon disclosed in U.S. patent application USSN 14 / 792,414, filed July 6, 2015, U.S. patent application USSN 14 / 707,930, filed May 8, 2015, and International patent application PCT / US2013 / 054663, filed August 13, 2013, each of which is incorporated herein by reference. In some embodiments, E is a modulator, binder, inhibitor, or ligand of a variant of cereblon. In some embodiments, E is a modulator, binder, inhibitor, or ligand of an isoform of cereblon.

[0210] In some embodiments, E comprises a heteroaryl ring. In some embodiments, E comprises a fused bicyclic heteroaryl ring. In some embodiments, E comprises a fused bicyclic heteroaryl ring and a heterocyclic ring. In some embodiments, E comprises a phthalimide group, or an analog or derivative thereof. In some embodiments, E comprises a phthalimide-glutarimide group, or an analog or derivative thereof. In some embodiments, E is thalidomide, lenalidomide, pomalidomide, CC-885 (Matyskiela et al., Nature 2016, 535, 252-257), 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an analog or derivative thereof.

[0211] In some embodiments, E has the formula EI: [ka] is expressed as During the ceremony: A is a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl ring; Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (C=O)-(CH2) k -O-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0212] In some embodiments of formula EI: A is a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl ring; Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 1 or 2.

[0213] In some embodiments, Y is —(CH) k -NR B -, -O(CH2) k -(C=O)NR B -, -(CH2) k -O-, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-. In some embodiments, Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-. In some embodiments, Y is -(CH2) k -NR B -, -(CH2) k -O-, or -NR B (C=O)-(CH2) k In some embodiments, Y is —(CH) k In some embodiments, Y is -NH-. In some embodiments, Y is -(CH) k In some embodiments, Y is -O-. In some embodiments, Y is -NH(C=O)-(CH2)-O-. In some embodiments, Y is -NH-, -O-, or -NH(C=O)-(CH2)-O-.

[0214] In some embodiments, E has formula E-II or E-III: [ka] is expressed as During the ceremony: Y is -(CH2) k -, -(CH2)k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (C=O)-(CH2) k -O-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0215] In some embodiments of Formula E-II or E-III: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 1 or 2.

[0216] In some embodiments, E has formula E-II: [ka] is expressed as During the ceremony: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (C=O)-(CH2) k -O-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A)2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0217] In some embodiments of Formula E-II: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; XA is C(O) or C(R 3A )2; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0218] In some embodiments of Formula E-II: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, or 3; and n is 1 or 2.

[0219] In some embodiments of Formula E-II: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0220] In some embodiments, E has formula E-II-a: [ka] is expressed as During the ceremony: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; Each R Bare independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0221] In some embodiments of Formula E-II-a: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4Atogether with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0222] In some embodiments, E has formula E-II-b: [ka] is expressed as During the ceremony: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0223] In some embodiments of Formula E-II-b: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; X A is C(O) or C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0224] In some embodiments, E has formula E-II-c: [ka] is expressed as During the ceremony: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; Each R Bare independently hydrogen or substituted or unsubstituted alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0225] In some embodiments of Formula E-II-c: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0226] In some embodiments, E has formula E-II-d: [ka] is expressed as During the ceremony: Y is -(CH2) k -NRB -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0227] In some embodiments of Formula E-II-d: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0228] In some embodiments, E has the formula E-II-e: [ka] is expressed as During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; Each R 3A are independently H or C1-C3 alkyl; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0229] In some embodiments, E has the formula E-II-e-1: [ka] is expressed as During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; Each R 3A are independently H or C1-C3 alkyl; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0230] In some embodiments, E has the formula E-II-e-1: [ka] is expressed as During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; Each R 3A is independently H or C1-C3 alkyl; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0231] In some embodiments, E has the formula E-II-f: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0232] In some embodiments, E has the formula E-II-f-1: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0233] In some embodiments, E has formula E-II-f-2: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0234] In some embodiments, E has the formula E-II-g: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0235] In some embodiments, E has the formula E-II-g-1: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0236] In some embodiments, E has formula E-II-g-2: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0237] In some embodiments, E has formula E-III: [ka] is expressed as During the ceremony: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NRB (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (C=O)-(CH2) k -O-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0238] In some embodiments of Formula E-III: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 3′ are independently C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 1 or 2.

[0239] In some embodiments, Y is —(CH) k -NR B -, -O(CH2) k -(C=O)NR B -, -(CH2) k -O-, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-. In some embodiments, Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-. In some embodiments, Y is -(CH2) k -NR B -, -(CH2) k -O-, or -NR B (C=O)-(CH2) k In some embodiments, Y is —(CH) k In some embodiments, Y is -NH-. In some embodiments, Y is -(CH) k In some embodiments, Y is -O-. In some embodiments, Y is -NH(C=O)-(CH2)-O-. In some embodiments, Y is -NH-, -O-, or -NH(C=O)-(CH2)-O-.

[0240] In some embodiments, E has formula E-III-a: [ka] is expressed as During the ceremony: Y is -(CH2) k -, -(CH2)k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (C=O)-(CH2) k -O-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0241] In some embodiments of Formula E-III-a: Y is -(CH2) k -, -(CH2) k -O-, -O(CH2) k -, -NR B (CH2) k -, -(CH2) k -NR B -, -(CH2) k -(C=O)NR B -, -O(CH2) k -(C=O)NR B -, -O(CH2) k -NR B (C=O)-, -NR B (CH2) k -NR B (C=O)- or -(CH2) k -NR B (C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0242] In some embodiments of Formula E-III-a: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0243] In some embodiments of Formula E-III-a: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B(C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 1A are independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2 or 3.

[0244] In some embodiments, E has formula E-III-b: [ka] is expressed as During the ceremony: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X 1 -X 2 is C(R 3A)=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0245] In some embodiments of Formula E-III-b: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0246] In some embodiments, E has formula E-III-c: [ka] is expressed as During the ceremony: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, -NR B (C=O)-(CH2) k -O-, or -(CH2) k -NR B (C=O)-; X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0247] In some embodiments of Formula E-III-c: Y is -(CH2)k -NR B -, -O(CH2) k -(C=O)NR B - or -(CH2) k -NR B (C=O)-; X 1 -X 2 But C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; R 5A is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0248] In some embodiments, E has formula E-III-d: [ka] is expressed as During the ceremony: X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 3Aare independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0249] In some embodiments, E has the formula E-III-d-1: [ka] is expressed as During the ceremony: X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0250] In some embodiments, E has formula E-III-d-2: [ka] is expressed as During the ceremony: X 1 -X 2 is C(R 3A )=N or C(R 3A )2-C(R 3A )2; Each R B are independently hydrogen or substituted or unsubstituted alkyl; Each R 3A are independently H or C1-C3 alkyl; Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0251] In some embodiments, E has formula E-III-e: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0252] In some embodiments, E has the formula E-III-e-1: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0253] In some embodiments, E has formula E-III-e-2: [ka] is expressed as During the ceremony: Each R 4A are independently H or C1-C3 alkyl; or two R 4A together with the carbon atoms to which they are attached form a C(O), C3-C6 carbocyclic, or 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms selected from N and O; and R 5A is H, deuterium, C1-C3 alkyl, F, or Cl.

[0254] In some embodiments, E is thalidomide, lenalidomide, pomalidomide, CC-885 (Matyskiela et al., Nature 2016, 535, 252-257), 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an analog or derivative thereof.

[0255] In some embodiments, E is [ka] is.

[0256] In some embodiments, E is [ka] is.

[0257] In some embodiments, E is [ka] is.

[0258] In some embodiments, E is [ka] is.

[0259] In some embodiments, E is [ka] is.

[0260] In some embodiments, E is [ka] is.

[0261] In some embodiments, E is [ka] is.

[0262] Von Hippel-Lindau tumor suppressor (VHL) is a 3-ubiquitin ligase. VHL contains the substrate-recognition subunit / E3 ubiquitin ligase complex VCB, which encompasses elongins B and C, as well as a complex that includes cullin-2 and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the proangiogenic growth factor VEGF and the red blood cell-inducing cytokine erythropoietin in response to low oxygen levels. VCB is a well-known target in cancer, chronic anemia, and ischemia.

[0263] The full-length von Hippel-Lindau tumor suppressor protein (VHL) contains 213 amino acids. (For the VHL protein sequence, see Duan et al., Proc. Natl. Acad. Sci. USA 1995, 92, 6459-63. For further information on the structure of VHL, see Stebbins et al., Science 1999, 284, 455-61 and Minervini et al., Sci. Rep. 2015, 5, 12605.) A second VHL gene product arises by internal translation initiation at methionine at codon 54, producing a 160-amino acid protein ("pVHL19"). VHL has two major structural domains: an N-terminal domain (β-domain) composed primarily of β-sheets, and a smaller C-terminal domain (α-domain) between amino acids 155 and 192, composed primarily of α-helices. The α-domain consists of three α-helices, which combine with a fourth α-helix provided by Elongin C. The β-domain lies opposite the α-domain and is free to contact other proteins.

[0264] In some embodiments, E is a modulator, binder, inhibitor, or ligand of VHL. In some embodiments, E is a modulator of VHL. In some embodiments, E is a binder of VHL. In some embodiments, E is an inhibitor of VHL. In some embodiments, E is a ligand of cereblon. In some embodiments, E is any ligand of VHL listed in Galdeano, C. et al. J. Med. Chem. 2014, 57, 8657, which is incorporated herein by reference. In some embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL variant. In some embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL isoform. In some embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL gene product (e.g., pVHL19).

[0265] In some embodiments, E comprises a peptide backbone structure. In some embodiments, E has the formula: [ka] is of; In the formula, R 5 is a heteroaryl ring, and R 6 is hydrogen or C 1-4 In some embodiments, R 5 is a 5-membered heteroaryl ring containing at least one nitrogen. 5 is a substituted or unsubstituted oxazolinyl, or a substituted or unsubstituted thiazolinyl.

[0266] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0267] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0268] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0269] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0270] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0271] In some embodiments, E is a group of the formula: [ka] It is expressed as:

[0272] In some embodiments, the E3 ligase binding moiety has a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d and binds to E3 ubiquitin ligase.

[0273] In some embodiments, the E3 ligase binding moiety has a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d It then binds to cereblon.

[0274] In some embodiments, the E3 ligase binding moiety has a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d and binds to VHL.

[0275] In some embodiments, the E3 ligase binding portion selectively binds to an E3 ubiquitin ligase relative to another protein. In some embodiments, the E3 ligase binding portion selectively binds to cereblon relative to another protein. In some embodiments, the E3 ligase binding portion selectively binds to cereblon relative to another E3 ubiquitin ligase. In some embodiments, the E3 ligase binding portion selectively binds to VHL relative to another protein. In some embodiments, the E3 ligase binding portion selectively binds to VHL relative to another E3 ubiquitin ligase. In some embodiments, the selectivity is about 2-fold to about 5-fold. In some embodiments, the selectivity is about 5-fold to about 10-fold. In some embodiments, the selectivity is about 10-fold to about 20-fold. In some embodiments, the selectivity is about 20-fold to about 50-fold. In some embodiments, the selectivity is about 50-fold to about 100-fold. In some embodiments, the selectivity is about 100-fold to about 200-fold. In some embodiments, the selectivity is about 200-fold to about 500-fold. In some embodiments, the selectivity is about 500-fold to about 1000-fold. In some embodiments, the selectivity is at least about 1000-fold.

[0276] Further Embodiments of Formula I In some embodiments, the compound of Formula I has Formula Ia: [ka] During the ceremony: E is the E3 ubiquitin ligase binding moiety; L is N or CR 5 and; M is N or CR 6 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 6; where R 2 , R 3 , R 7 , and R 8 one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 alkyl)2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0277] In certain embodiments of compounds of Formula Ia, E is an E3 ubiquitin ligase binding moiety; L is N or CR 5 and; M is N or CR 6 and; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 5; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0278] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n-AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 6; where R 2 , R 3 , R 7 , and R 8one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0279] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond or a substituted or unsubstituted C 1-12 alkylene, where one or more carbons are optionally C(O), O, S, SO, NH, or optionally halogen, OH, or C 1-6 NC, which may be substituted by alkyl 1-6 may be replaced by alkyl; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n (C=O)NR A , -A-(CH2) n -(C=O)NR A , -(CH2) n -A-(C=O)NR A, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 5; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0280] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 6; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0281] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl), aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally halogen, SO, NH, or optionally halogen or C 3-8 C, which may be substituted by cycloalkyl 1-6 optionally substituted with alkyl; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n-AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 5; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0282] In some embodiments of the compound of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 6; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0283] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2)n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, a leaving group, a protecting group, an aryl, a heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is 1 to 5; where R 2 , R 3 , R 7 , and R 8 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0284] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each of which is hydrogen; n is 0 to 12; and q is 1 to 6; where R 3 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 It may be replaced by alkyl.

[0285] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8is hydrogen; n is 0 to 12; and q is 1 to 5; where R 3 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 It may be replaced by alkyl.

[0286] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each of which is hydrogen; n is 0 to 12; and q is 1 to 6.

[0287] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 each of which is hydrogen; n is 0 to 12; and q is 1 to 5.

[0288] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -AO-(CH2) n -(C=O)NR A -or-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 6.

[0289] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -A-(CH2) n -NR A - and; A is substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 6.

[0290] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -A-(CH2) n -NR A - and; A is substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 5.

[0291] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2) n -(C=O)NR A - and; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 6.

[0292] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -(CH2)n -(C=O)NR A - and; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 5.

[0293] In certain embodiments of compounds of Formula Ia, L is CR 5 and; M is N; X is a bond; R 9 is hydrogen; R 3 But -AO-(CH2) n -(C=O)NR A - and; Each R 2 , R 7 , and R 8 is hydrogen; n is 0 to 12; and q is 1 to 6.

[0294] In some embodiments, the compound of Formula I has Formula Ib: [ka] During the ceremony: E is the E3 ubiquitin ligase binding moiety; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NRA -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6; where R 3 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 may be replaced by alkyl, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0295] In certain embodiments of compounds of Formula Ib, E is an E3 ubiquitin ligase binding moiety; R 3 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n-AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 3 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 It may be replaced by alkyl.

[0296] In certain embodiments of compounds of Formula Ib, R 3 But -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6.

[0297] In certain embodiments of compounds of Formula Ib, R 3 But -A-(CH2) n -NR A -, -(CH2) n -A-NR A - or -(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5.

[0298] In certain embodiments of compounds of Formula Ib, R 3 But -AO-(CH2) n -(C=O)NR A -or-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6.

[0299] In certain embodiments of compounds of Formula Ib, R 3 But -A-(CH2) n -NR A - and; A is substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6.

[0300] In certain embodiments of compounds of Formula Ib, R 3 But -A-(CH2) n -NR A - and; A is substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5.

[0301] In certain embodiments of compounds of Formula Ib, R 3 But -A-(CH2) n -NR A - and; A is substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6.

[0302] In certain embodiments of compounds of Formula Ib, R 3 But -(CH2) n -(C=O)NR A - and; n is 0 to 12; and q is 1 to 5.

[0303] In some embodiments, the compound of formula Ib has formula Ib-1: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 6, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0304] In some embodiments of a compound of Formula Ib-1, E is an E3 ubiquitin ligase binding moiety; and q is 1-5.

[0305] In some embodiments, the compound of formula Ib has formula Ib-2: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 6, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0306] In some embodiments of a compound of Formula Ib-2, E is an E3 ubiquitin ligase binding moiety; and q is 1-5.

[0307] In some embodiments, the compound of formula Ib has formula Ib-3: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 4, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0308] In some embodiments, the compound of formula Ib has formula Ib-4: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 6, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0309] In some embodiments, the compound of formula Ib has formula Ib-5: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 4, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0310] In some embodiments, the compound of formula I has formula Ic: [ka] During the ceremony: E is the E3 ubiquitin ligase binding moiety; X 3 is CR 15 or N; X 4 is CR 15 or N; X 5 is CR 15 or N; R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2)n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6; where R 14 and R 15 one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 alkyl)2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0311] In certain embodiments of Formula Ic, E is an E3 ubiquitin ligase binding moiety; X 3 But, CR 15 or N; X 4 But, CR 15 or N; X 5 But, CR 15 or N; R 15each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R14 and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0312] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NR A (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2)n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6; where R 14 and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0313] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 each occurrence independently represents hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)Oalkyl, -NRA (C=O)Oaryl, -NR A (C=O) alkyl, -NR A (C=O)aryl, -(C=O)Oalkyl, -(C=O)Oaryl, -(C=O)alkyl, -(C=O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 14 and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0314] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6; where R 14 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 It may be replaced by alkyl.

[0315] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 14 and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, or NC 1-6 It may be replaced by alkyl.

[0316] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -A-(CH2) n -(C=O)NR A -or-(CH2) n -A-(C=O)NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 14 one or more carbons of which may optionally be C(O), O, S, SO2, NH or NC 1-6 It may be replaced by alkyl.

[0317] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -A-(CH2) n -(C=O)NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5.

[0318] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -A-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heterocyclylene; n is 0 to 12; and q is 1 to 5.

[0319] In certain embodiments of the compound of Formula Ic, X 3 But, CR 15 and; X 4 But, CR 15 and; X 5 is N; R 15 Each occurrence of is hydrogen; R 14 But -AO-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6.

[0320] In some embodiments, the compound of Formula I has Formula Id: [ka] During the ceremony: E is the E3 ubiquitin ligase binding moiety; R 14 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -AO-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -AS-(CH2) n -(C=O)NR A -, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -A-NR A -(CH2) n -(C=O)NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 6; where R 14 or R 15 one or more carbons may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 alkyl)2, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0321] In certain embodiments of the compound of Formula Id, E is an E3 ubiquitin ligase binding moiety; R 14 But -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -AO-, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -AS-, -(CH2) n -NR A -, -A-(CH2) n -NR A -, -(CH2) n -A-NR A -, -(CH2) n -(C=O)NR A -, -A-(CH2) n -(C=O)NR A -, -(CH2) n -A-(C=O)NR A -, -(CH2) n -S(O)2NR A -, -A-(CH2) n -S(O)2NR A - or -(CH2) n -AS(O)2NRA - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 14 and R 15 one or more carbons of which may optionally be C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C 1-6 It may be replaced by alkyl).

[0322] In certain embodiments of the compound of Formula Id, R 14 is -A-(CH2) n -(C=O)NR A -or-(CH2) n -A-(C=O)NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5; where R 14 one or more carbons of which may optionally be C(O), O, S, SO2, NH or NC 1-6 It may be replaced by alkyl.

[0323] In certain embodiments of the compound of Formula Id, R 14 But -A-(CH2) n -(C=O)NR A - and; A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is 0 to 12; and q is 1 to 5.

[0324] In certain embodiments of the compound of Formula Id, R 14 But -A-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heterocyclylene; n is 0 to 12; and q is 1 to 5.

[0325] In certain embodiments of formula Id, R 14 But -AO-(CH2) n -(C=O)NR A - and; A is substituted or unsubstituted heteroarylene; N is 0 to 12; and q is 1 to 6.

[0326] In some embodiments, the compound of formula Id has formula Id-1: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 6, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0327] In some embodiments of Formula IdI, E is an E3 ubiquitin ligase binding moiety; and q is 1-5.

[0328] In some embodiments, the compound of formula I has formula Ie: [ka] During the ceremony, E is the E3 ubiquitin ligase binding moiety; R 20are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 is -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A - or -(CH2) n -S(O)2NR A - and; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; n is 0 to 12; and q is 1 to 5; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0329] In certain embodiments of compounds of Formula Ie, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 But -(CH2) n -O-, -(CH2) n -S-, -(CH2) n -NR A -, -(CH2) n -(C=O)NR A- or -(CH2) n -S(O)2NR A - and; n is 0 to 12; and q is 1 to 5.

[0330] In certain embodiments of compounds of Formula Ie, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 But -(CH2) n -NR A -or-(CH2) n -(C=O)NR A - and; n is 0 to 12; and q is 1 to 5.

[0331] In certain embodiments of compounds of Formula Ie, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; R 22 But -(CH2) n -NR A -or-(CH2) n -(C=O)NR A - and; n is 0 to 12; and q is 1 to 5.

[0332] In certain embodiments of compounds of Formula Ie, R 20is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; R 22 But -(CH2) n -NR A -or-(CH2) n -(C=O)NR A - and; n is 0 to 12; and q is 1 to 5.

[0333] In certain embodiments of compounds of Formula Ie, R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted heteroarylene; R 22 But -(CH2) n -NR A - and; n is 0 to 12; and q is 1 to 5.

[0334] In certain embodiments of compounds of Formula Ie, R 20 is alkoxy substituted by one or more halogen or hydroxy groups; G is unsubstituted heteroarylene; R 22 But -(CH2) n -NR A - and; n is 0 to 12; and q is 1 to 5.

[0335] In some embodiments, the compound of formula Ie has formula Ie-1: [ka] In the formula, R 20 is alkoxy substituted with one or more halogen or hydroxy groups; E is an E3 ubiquitin ligase binding moiety; and q is 1 to 5, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0336] In some embodiments, the compound of formula Ie has formula Ie-2: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 5, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0337] In some embodiments, the compound of formula Ie has formula Ie-3: [ka] where E is an E3 ubiquitin ligase binding moiety; and q is 1 to 5.

[0338] In some embodiments, the compound of formula I has the formula If: [ka] During the ceremony: E is the E3 ubiquitin ligase binding moiety; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 are halogens, -OH, -COOH, -SO3H, -NO2, -SH, -NRx R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 is an unsubstituted alkylene, an alkylene substituted with one or more halogen or hydroxy groups, an unsubstituted alkoxylene, or an alkoxylene substituted with one or more halogen or hydroxy groups; R x and R y is independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5. or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0339] In certain embodiments of the compound of formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24 is an unsubstituted alkylene, an alkylene substituted with one or more halogen or hydroxy groups, an unsubstituted alkoxylene, or an alkoxylene substituted with one or more halogen or hydroxy groups; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0340] In certain embodiments of the compound of formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24is a substituted or unsubstituted alkylene, or a substituted or unsubstituted alkoxylene; R x and R y is independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0341] In certain embodiments of the compound of formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24 is a substituted or unsubstituted alkoxylene; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0342] In certain embodiments of the compound of formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24 is an alkoxylene substituted by one or more halogen or hydroxy groups; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0343] In certain embodiments of the compound of formula If, G is substituted or unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24 is an alkoxylene substituted by one or more halogen or hydroxy groups; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0344] In certain embodiments of the compound of formula If, G is unsubstituted heteroarylene; R 23 But, -NR x R y and; R 24 is an alkoxylene substituted by one or more halogen or hydroxy groups; R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5.

[0345] In some embodiments, the compound of formula If has formula If-1: [ka] where E is an E3 ubiquitin ligase binding moiety; G is unsubstituted heteroarylene; and R 23 is -NR x R y and;R x and R y are independently hydrogen or substituted or unsubstituted alkyl; and q is 1 to 5, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0346] In some embodiments, the compound of formula If has formula If-2: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 5, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0347] In some embodiments, the compound of formula If has formula If-3: [ka] wherein E is an E3 ubiquitin ligase binding moiety; and q is 1 to 5, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0348] In some embodiments, the compound of formula I has formula Ig: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 6; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0349] In some embodiments, the compound of formula I has formula Ih: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 6; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0350] In some embodiments, the compound of formula I has formula II: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 6; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0351] In some embodiments, the compound of formula I has formula Ij: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 4; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0352] In some embodiments, the compound of formula I has formula Ik: [ka] During the ceremony: T is a tau protein-binding moiety; and and q is 1 to 4, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0353] In some embodiments, the compound of formula I has formula II: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 4; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0354] In some embodiments, the compound of formula I has the formula Im: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 6; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0355] In some embodiments, the compound of formula I has the formula In: [ka] During the ceremony: T is a tau protein-binding moiety; and q is 1 to 4; or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

[0356] In certain embodiments, the compound of Formula I is a compound of Table 1 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0357] In certain embodiments, the compound of Formula I is a compound of Table 2 or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. [Table 2-1] [Table 2-2]

[0358] In some embodiments, the compound of Formula I contains a radionuclide. In some embodiments, the compound of Formula I is substituted with a radionuclide. In some embodiments, the compound of Formula I is enriched with a radionuclide. In some embodiments, the compound of Formula I is useful as an imaging agent (e.g., for use in positron emission tomography). For example, a radionuclide such as a halogen atom can be easily introduced into the compound using a number of different methods well known in the art. Consequently, a radiolabeled compound of Formula I can be prepared using standard methods known in the art for preparing such radioactive compounds with specific substituents, where the compound is 11 C. 13 N, 15 O. 18 F, 123 I, 124 I, 125 I, 131 I, and 77Br may be incorporated by certain radionuclides selected from the group consisting of:

[0359] In some embodiments, the compounds of Formula I bind to tau protein with a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d Combine with.

[0360] In certain embodiments, a compound of Formula I selectively binds to tau protein over other proteins. In some embodiments, a compound of Formula I selectively binds to tau protein over amyloid beta. In certain embodiments, the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is about 1000-fold.

[0361] In certain embodiments, a compound of Formula I inhibits an E3 ubiquitin ligase with a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d Combine with.

[0362] In some embodiments, the compound of Formula I inhibits cereblon with a K of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. d Combine with.

[0363] In certain embodiments, a compound of Formula I selectively binds to an E3 ubiquitin ligase compared to another protein. In some embodiments, a compound of Formula I selectively binds to cereblon over another protein. In some embodiments, a compound of Formula I selectively binds to cereblon over another E3 ubiquitin ligase. In some embodiments, the selectivity is between about 2-fold and about 5-fold. In some embodiments, the selectivity is between about 5-fold and about 10-fold. In some embodiments, the selectivity is between about 10-fold and about 20-fold. In some embodiments, the selectivity is between about 20-fold and about 50-fold. In some embodiments, the selectivity is between about 50-fold and about 100-fold. In some embodiments, the selectivity is between about 100-fold and about 200-fold. In some embodiments, the selectivity is between about 200-fold and about 500-fold. In some embodiments, the selectivity is between about 500-fold and about 1000-fold. In some embodiments, the selectivity is at least about 1000-fold.

[0364] In some embodiments, the compound of formula I is at or below 100,000 nM, 50,000 nM, 20,000 nM, 10,000 nM, 5,000 nM, 3,500 nM, 2,500 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM , 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less, promotes degradation of 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, 80% or less, 85% or less, 90% or less, 95% or less, 99% or less, or 100% or less of tau protein at a concentration of 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

[0365] In some embodiments, the compound of Formula I is administered at a concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less At a concentration of 0.05 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less, the rate of degradation of tau protein is increased by 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, 80% or less, 85% or less, 90% or less, 95% or less, 99% or less, or 100% or less.

[0366] Pharmaceutical Compositions, Kits and Administration The present disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0367] In some embodiments, the compound of Formula I is provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to treat a neurological disorder in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a neurological disorder in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a neurodegenerative disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a neurodegenerative disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a tauopathy in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a tauopathy in a subject in need thereof. In some embodiments, the effective amount is an amount effective to inhibit the development of a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof.

[0368] In some embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In some embodiments, the subject described herein is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal such as a dog or cat. In some embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal (e.g., transgenic mouse and transgenic pig). In some embodiments, the subject is a fish or reptile.

[0369] In some embodiments, an effective amount is an amount effective to promote degradation of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of tau protein. In some embodiments, an effective amount is an amount effective to inhibit the activity of tau protein and / or promote degradation of MALT1 in a range between a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0370] The present disclosure provides a pharmaceutical composition comprising a compound that interacts with tau protein and / or E3 ubiquitin ligase (e.g., cereblon) for use in treating a neurological disorder in a subject in need thereof. In some embodiments, the composition is for use in treating a neurodegenerative disease. In some embodiments, the composition is for use in treating a tauopathy. In some embodiments, the composition is for use in treating primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Litiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the composition is for use in treating Alzheimer's disease.

[0371] The compounds or compositions as described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents to improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability and ability to cross the blood-brain barrier, improve safety, reduce drug resistance, reduce and / or regulate metabolism, inhibit excretion, and / or regulate distribution in a subject or cell. It will also be understood that the treatments used may achieve the desired effect for the same disorder, and / or they may achieve different effects. In some embodiments, the pharmaceutical compositions described herein, comprising the compounds described herein and additional pharmaceutical agents, exhibit a synergistic effect that is absent in pharmaceutical compositions that contain one of the compounds and additional pharmaceutical agents but not both.

[0372] The compound or composition can be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In some embodiments, the additional pharmaceutical agents are pharmaceutical agents useful for treating and / or preventing diseases (e.g., neurological disorders, neurodegenerative diseases, and / or tauopathies). Each additional pharmaceutical agent can be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents can also be administered together with each other and / or with the compounds or compositions described herein in a single dose or separately in different doses.The specific combination used in the regimen will take into consideration the compatibility of the compounds described herein with the additional pharmaceutical agents, and / or the desired therapeutic and / or preventive effect to be achieved.Generally, it is expected that the additional pharmaceutical agents in the combination will be used at a level that does not exceed the level that they are used individually.In some embodiments, the level that is used in the combination will be lower than that used individually.

[0373] In some embodiments, the compound or pharmaceutical composition is a solid. In some embodiments, the compound or pharmaceutical composition is a powder. In some embodiments, the compound or pharmaceutical composition may be dissolved in a liquid to form a solution. In some embodiments, the compound or pharmaceutical composition may be dissolved in water to form an aqueous solution. In some embodiments, the pharmaceutical composition is a liquid for parenteral injection. In some embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., oral ingestion). In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for intravenous injection. In some embodiments, the pharmaceutical composition is a liquid (e.g., an aqueous solution) for subcutaneous injection.

[0374] After formulation in the desired dosage with suitable pharmaceutically acceptable excipients, the pharmaceutical compositions of the present invention can be administered to humans or other animals orally, parenterally, intracisternally, intraperitoneally, topically, bucally, etc., depending on the disease or condition being treated.

[0375] In some embodiments, pharmaceutical compositions comprising a compound of Formula I are administered orally or parenterally over one or more days (depending on the mode of administration), at a dosage level of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg in one or more doses. In some embodiments, to achieve the desired therapeutic and / or prophylactic effect, the effective amount per dose varies from about 0.001 mg to about 200 mg, about 0.001 mg to about 100 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, preferably about 0.1 mg to about 40 mg, preferably about 0.5 mg to about 30 mg, about 0.01 mg to about 10 mg, or about 0.1 mg to about 10 mg per kg of subject body weight per day, one or more times per day. In certain embodiments, the compounds described herein may be at a dosage level sufficient to deliver about 0.001 mg to about 200 mg, about 0.001 mg to about 100 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 50 mg, preferably about 0.1 mg to about 40 mg, preferably about 0.5 mg to about 30 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, and more preferably about 1 mg to about 25 mg per kg of subject body weight per day, one or more times per day, to achieve the desired therapeutic and / or prophylactic effect. The desired dosage can be delivered three times a day, twice a day, once a day, every two days, every three days, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). In some embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes nonspecific effects.

[0376] In some embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In some embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.

[0377] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such methods include combining a composition containing a compound of Formula I with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into the desired single or multiple dosage units.

[0378] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses.As used herein, " unit dose " is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of active ingredient that would be administered to a subject, and / or a convenient fraction of such dosage, such as half or one-third of such dosage.

[0379] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention may vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is to be administered. For example, the composition may contain between 0.1% and 100% (w / w) of the active ingredient.

[0380] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the compositions.

[0381] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0382] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0383] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethyl alcohol), and the like. Examples of the cellulose derivatives include sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose, and sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 1), polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 1), ... 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij30), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0384] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0385] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0386] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0387] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malate and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0388] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0389] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0390] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0391] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0392] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0393] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0394] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0395] Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl acetate carbonate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and perfumes. In certain embodiments for parenteral administration, the agents of the present invention are mixed with a solubilizing agent such as CREMOPHOR EL®, (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0396] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol.Among acceptable vehicles and solvents, water, Ringer's solution (USP), and isotonic sodium chloride solution can be used.In addition, sterile fixed oils are conventionally used as solvents or suspending media.For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, can be used.In addition, fatty acids such as oleic acid are used in injectable preparations.

[0397] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0398] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is present in at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0399] Solid compositions of a similar type can also be used as fillers in soft or hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft or hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0400] The active agent may be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active agent may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Such solid dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids (such as magnesium stearate and microcrystalline cellulose). In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0401] Formulations suitable for topical administration include liquid or semi-liquid preparations, such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes; or solutions or suspensions, such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier, such as a lotion, cream, ointment, or soap. Useful carriers can form a film or layer on the skin to localize administration and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to tissue surfaces. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions may be advantageously used. Alternatively, tissue-coating solutions, such as pectin-containing formulations, may be used. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of an agent to the body. Such dosage forms can be made by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the agent across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the agent in a polymer matrix or gel.

[0402] In addition, carriers for topical formulations may be in the form of hydroalcoholic systems (e.g., quids and gels), anhydrous oil- or silicone-based systems, or emulsion systems, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. Emulsions can cover a wide range of consistencies, including thin lotions (which may also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like. Emulsions may also include microemulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous-based mousse systems.

[0403] Also encompassed by the present disclosure are kits (e.g., medical packs). The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form.

[0404] Thus, in one aspect, provided is a kit comprising a first container containing a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a disease (e.g., a neurological disorder, a neurodegenerative disease, a tauopathy) in a subject in need thereof. In certain embodiments, the kit is useful for preventing a disease (e.g., a neurological disorder, a neurodegenerative disease, a tauopathy) in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of developing a disease (e.g., a neurological disorder, a neurodegenerative disease, a tauopathy) in a subject in need thereof. In certain embodiments, the kit is useful for promoting the degradation of tau protein in a subject or cell. In certain embodiments, the kit is useful for imaging and / or detecting a neurological disorder in any human tissue (e.g., through the use of a radiolabeled compound of Formula I). ​​In certain embodiments, the kit is useful for promoting the degradation of tau protein in a subject or cell. In certain embodiments, the kit is useful for imaging and / or detecting a neurological disorder in the central nervous system (e.g., through the use of a radiolabeled compound of Formula I). In some embodiments, the kit is useful for promoting the degradation of tau protein in a subject or cell. In some embodiments, the kit is useful for imaging and / or detecting neurological disorders in the central nervous system (e.g., through the use of a radiolabeled compound represented by Formula I). ​​In some embodiments, the kit is useful for imaging and / or detecting pathological aggregation of tau protein in any human tissue (e.g., through the use of a radiolabeled compound represented by Formula I). ​​In some embodiments, the kit is useful for imaging and / or detecting pathological aggregation of tau protein in the central nervous system (e.g., through the use of a radiolabeled compound represented by Formula I). ​​In some embodiments, the kit is useful for imaging and / or detecting pathological aggregation of tau protein in the brain (e.g., through the use of a radiolabeled compound represented by Formula I).

[0405] In some embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information as required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions provide for treating a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In some embodiments, the kit and instructions provide for preventing a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In some embodiments, the kit and instructions provide for reducing the risk of developing a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In some embodiments, the kit and instructions provide for promoting the degradation of tau protein in a subject or cell. In some embodiments, the kit and instructions provide for diagnosing a neurological disorder in the central nervous system (e.g., through the use of a radiolabeled compound of Formula I). In some embodiments, the kits and instructions provide for imaging and / or detecting neurological disorders in the central nervous system (e.g., through the use of a radiolabeled compound of Formula I). ​​In some embodiments, the kits and instructions provide for imaging and / or detecting pathological aggregation of tau protein in the central nervous system (e.g., through the use of a radiolabeled compound of Formula I). ​​The kits described herein may also include, as separate compositions, one or more additional pharmaceutical agents described herein.

[0406] Treatment method The primary neuropathological finding in postmortem examinations of Alzheimer's disease (AD) confirms the presence of AD through the detection of intracellular neurofibrillary tangles (NFTs). NFTs are derived from aggregated, hyperphosphorylated tau protein filaments. The presence and severity of NFTs generally, but not always, correlates with the severity of dementia and cognitive impairment, and it has become clear that the pathological process of AD begins before the onset of dementia and the clinical symptoms of late-stage NFTs. Therefore, reduction and / or detachment of abnormal tau species that precede NFTs or NFTs themselves through tau proteolysis is an attractive approach for the treatment of AD and other tauopathies.

[0407] Immunomodulatory agents, including thalidomide and lenalidomide, bind to cereblon. Consequently, the use of bifunctional compounds that bind to tau protein and E3 ubiquitin ligases (e.g., cereblon) provides a strategy for treating diseases associated with tau protein aggregation, also known as tauopathies.

[0408] The present disclosure provides methods for treating neurological disorders. In some embodiments, the application provides methods for treating neurodegenerative diseases. In some embodiments, the application provides methods for treating tauopathies. In some embodiments, the application provides methods for treating primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-linked parkinsonism, Litiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the application provides methods for treating Alzheimer's disease.

[0409] The present disclosure provides methods for preventing neurological disorders. In some embodiments, the present application provides methods for preventing neurodegenerative diseases. In some embodiments, the present application provides methods for preventing tauopathies. In some embodiments, the present application provides methods for preventing primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-linked parkinsonism, Litiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the present application provides methods for preventing Alzheimer's disease.

[0410] In some embodiments, the present application provides a method for promoting the degradation of tau protein (e.g., in a cell). In some embodiments, the present application provides a method for promoting the degradation of tau protein in a subject in need thereof. In some embodiments, the present application provides a method for binding an E3 ubiquitin ligase and promoting the degradation of tau protein. In some embodiments, the target of the E3 ubiquitin ligase is cereblon.

[0411] In some embodiments, the method includes administering to a subject in need thereof (e.g., a subject with a neurodegenerative disease) a compound that interacts with tau protein, such as a modulator of tau protein, a compound that is a binder of tau protein, a compound that modifies tau protein, or a compound that promotes the degradation of tau protein. The compound may also be an inhibitor of E3 ubiquitin ligase, a modulator of E3 ubiquitin ligase, a binder of E3 ubiquitin ligase, a compound that modifies E3 ubiquitin ligase, or a compound that interferes with the interaction of E3 ubiquitin ligase with another protein. In some embodiments, the method includes administering to a subject in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof.

[0412] The present disclosure also provides a compound of Formula I, or its pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition, for use in treating neurological disorders.In some embodiments, the neurological disorder is a neurodegenerative disease.In some embodiments, the neurodegenerative disease is a tauopathy. In some embodiments, the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Ritiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the tauopathy is Alzheimer's disease.

[0413] The present disclosure also provides the use of a compound of Formula I, or its pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug or composition, in the manufacture of a medicament for treating neurological disorders.In some embodiments, the neurological disorder is a neurodegenerative disease.In some embodiments, the neurodegenerative disease is a tauopathy. In some embodiments, the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Ritiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the tauopathy is Alzheimer's disease.

[0414] In some embodiments, the methods of the present disclosure include administering to a subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0415] In some embodiments, the subject being treated is an animal. The animal may be of either sex and at any stage of development. In some embodiments, the subject is a mammal. In some embodiments, the subject being treated is a human. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal.

[0416] Certain methods described herein may include administering one or more additional pharmaceutical agents in combination with the compounds described herein.The additional pharmaceutical agents can be administered at the same time as the compound of formula I or at different times from the compound of formula I.For example, the compound of formula I and any additional pharmaceutical agents can be administered on the same or different administration schedules.All or part of the dose of the compound of formula I can be administered before all or part of the dose of the additional pharmaceutical agent, after all or part of the dose of the additional pharmaceutical agent, or within the administration schedule of the additional pharmaceutical agent, or a combination thereof.The timing of administration of the compound of formula I and the additional pharmaceutical agent can be different for different additional pharmaceutical agents.

[0417] In some embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of a neurological disorder. In some embodiments, the additional pharmaceutical agent is useful in the treatment of a neurodegenerative disease. In some embodiments, the additional pharmaceutical agent is useful in the treatment of a tauopathy. In some embodiments, the additional pharmaceutical agent is useful in the treatment of primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-associated parkinsonism, Litiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the additional pharmaceutical agent is useful in the treatment of non-Hodgkin's lymphoma. In some embodiments, the additional pharmaceutical agent is useful in the treatment of Alzheimer's disease.

[0418] In another aspect, the disclosure provides a method of promoting the degradation of tau protein, the method comprising administering to a subject a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, or composition.

[0419] In another embodiment, the disclosure provides a method for binding E3 ubiquitin ligase and promoting degradation of tau protein, the method comprising administering to a subject a compound of Formula I, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In one embodiment, the E3 ubiquitin ligase is cereblon.

[0420] Diagnostic methods The pathological development of tauopathies often begins before the onset of clinical symptoms, and therefore in vivo imaging of abnormal and / or aggregated tau protein may be useful for the early and accurate diagnosis of neurological diseases. In particular, the pathological process of AD begins before the onset of clinical symptoms of dementia, and in vivo imaging of abnormal tau and NFTs may be useful for the early and accurate diagnosis of AD. Because the formation of neuritis pathology correlates with the clinical severity of dementia, quantitative assessment of tau pathology may also be useful for tracking and predicting the severity of dementia. The compounds of the present disclosure recognize pathological forms of tau, including forms containing hyperphosphorylated tau protein as a component, as well as other abnormal high molecular weight (chemical) species formed from tau and other post-translational modifications, and thus the compounds can be used as probes for detecting abnormal tau associated with neurodegeneration. Thus, imaging techniques may be useful in assessing the efficacy of novel treatments that prevent or reduce the pathological formation of neurofibrillary pathologies.

[0421] In certain aspects, the present disclosure relates to radiolabeled compounds of Formula I as imaging agents. These imaging agents are useful because they contain a tau protein-binding moiety that interacts with and binds to tau protein, providing the ability to image aggregated tau protein in vivo. Because compounds of Formula I lead to the degradation of tau protein upon regular administration, the progress of the therapeutic effect of compounds of Formula I may be monitored through the use of radiolabeled forms of the compounds or other known imaging agents for tau protein.

[0422] In some embodiments, imaging is achieved by employing a fluorescent or nuclear imaging technique selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT), for monitoring or visualizing the distribution of a radiolabeled or tagged compound within the central nervous system or a portion thereof (e.g., the brain).

[0423] PET and SPECT are sensitive techniques and require small amounts of radiolabeled compounds or tracers. The labeled compounds are transported, accumulated, and transformed in vivo in exactly the same way as the corresponding non-radioactive compounds. The tracers, or probes, 11 C. 13 N, 15 O. 18 F, 64 Cu and 124 by radionuclides useful for PET imaging, such as I, or 99 Tc, 77 Br, 61 Cu, 153 Gd, 123 I, 125 I, 131 I and 32 It can be radiolabeled with a radionuclide useful for SPECT imaging, such as P.

[0424] PET creates images based on the distribution of molecular imaging tracers carrying positron-emitting isotopes in a patient's tissues. PET methods have the potential to detect cellular-level dysfunction in the tissue or organ being investigated. PET has been used in clinical oncology, such as for imaging tumors and metastases, and for diagnosing certain brain diseases and mapping brain and heart function. Similarly, SPECT can be used to complement any gamma-ray imaging study where a true 3D display would be useful, such as imaging tumors, infections (white blood cells), the thyroid, or bone.

[0425] The present disclosure also provides a method for detecting a neurological disorder, the method comprising contacting a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I, with tissue of the central nervous system. In some embodiments, the neurological disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a tauopathy. In some embodiments, the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-linked parkinsonism, Litiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the tauopathy is Alzheimer's disease.

[0426] The present disclosure provides a method for detecting pathological aggregation of tau protein in tissue of the central nervous system (e.g., the brain), the method comprising contacting tissue of the central nervous system with a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the contacting comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject and allowing the compound to distribute into the central nervous system.

[0427] The present disclosure also provides a method for imaging tau protein in a subject, the method comprising administering to the subject a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I. In some embodiments, the method comprises imaging pathological aggregation of tau protein in the central nervous system (e.g., the brain).

[0428] The present disclosure also provides a method for diagnosing a neurological disorder in a subject, comprising contacting tissue of the central nervous system with a compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by Formula I. In some embodiments, the neurological disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a tauopathy. In some embodiments, the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Ritiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease. In some embodiments, the tauopathy is Alzheimer's disease.

[0429] In some embodiments, the central nervous system tissue is brain tissue. In some embodiments, the compound is contacted with the tissue in vivo. In other embodiments, the compound is contacted with the tissue in vitro. In some embodiments, the compound contacts the tissue after administration of the compound to a subject and allows the compound to distribute into the central nervous system. [Example]

[0430] example In order that the invention described herein may be more fully understood, the following examples are set forth: The examples described in this application are presented to illustrate, but should not be construed in any way as limiting the scope of, the compounds, pharmaceutical compositions and methods provided herein.

[0431] Compounds of Formula I can be prepared using the synthetic schemes and procedures described in detail below. Preparation of synthetic intermediates [ka]

[0432] 3-(4-(4-Nitropyridin-3-yl)phenyl)propan-1-ol (C): A solution of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-1-ol (A) (1.65 g, 6.29 mmol), 3-bromo-4-nitropyridine (B) (1.16 g, 5.72 mmol), NaCO (1.52 g, 14.3 mmol), and Pd(PPh) (330 mg, 0.286 mmol) in 1,4-dioxane (40 mL) and HO (10 mL) was stirred at 110 °C for 16 h before being quenched with NHCl (sat. aq., 100 mL). The resulting mixture was extracted with CH2Cl2 (3 x 80 mL), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified...

Claims

1. Formula I: 【Chemistry 1】 During the ceremony: T is a tau protein-binding moiety; E is an E3 ubiquitin ligase binding moiety; L is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted heteroalkylene, a bond, -O-, -N(R Ａ )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR Ａ --, --NR Ａ C(=O)-, -NR Ａ C(=O)R Ａ -, -C(=O)R Ａ --, --NR Ａ C(=O)O-, -NR Ａ C(=O)N(R Ａ )-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R Ａ ) -, -S(O) ２ N.R. Ａ --, --NR Ａ S (O) ２ - or any combination thereof; and R Ａ Each occurrence of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, when attached to a nitrogen atom, a nitrogen protecting group, or two R Ａ the groups are linked to form a substituted or unsubstituted heterocyclic ring, or a pharma- ceutically acceptable salt thereof.

2. T is a compound of formula T-I: 【Chemistry 2】 During the ceremony: L is N or CR ５ and M is N or CR ６ and P is N or CR ７ and Q is N or CR ８ and X is a bond or a substituted or unsubstituted C １－１２ alkylene, where one or more carbons are optionally selected from C(O), O, S, SO ２ , NH, or optionally halogen, OH, or C １－６ NC, which may be substituted by alkyl １－６ may be replaced by alkyl; R ９ is hydrogen, -N ３ , alkynyl, OH, halogen, NH ２ , N(C １－６ Alkyl) ２ , aryl, heteroaryl, or a protecting group, where aryl and heteroaryl are halogen, optionally SO ２ , N.H. ２ or optionally halogen or C ３－８ C, which may be substituted by cycloalkyl １－６ may be substituted with alkyl; R ３ は、-(CH ２ ) ｎ -O-、-A-(CH ２ ) ｎ -O-、-(EH ２ ) ｎ -A-O-、-A-O-(CH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -S-、-A-(CH ２ ) ｎ -S-、-(EH ２ ) ｎ -A-S-、-A-S-(CH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -NR Ａ -、-A-(EH ２ ) ｎ -NR Ａ -、-(E ２ ) ｎ -A-NR Ａ -、-(E ２ ) ｎ -(C=O)NR Ａ -、-A-(EH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -A-(C=O)NR Ａ -、-A-NR Ａ -(H) ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -S(O) ２ NR Ａ -、-A-(EH ２ ) ｎ -S(O) ２ NR Ａ -、or-(CH ２ ) ｎ -A-S(O) ２ NR Ａ - A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R １ , R ２ , and R ４ ~R ８ Each of the is independently hydrogen, OH, halogen, NH ２ , C.H. ３ , S.O. ２ , NO ２ , leaving group, protecting group, aryl, heteroaryl, NHR １２ , N(R １２ ) ２ C ３－８ Cycloalkyl, N(R １２ ) ２ Heterocyclyl, or -(CH ２ ) ｎ -R １２ and R １２ is hydrogen, -CH ３ , aryl, or heteroaryl; and n is 0 to 12; Here, R １－８ One or more carbons may optionally be C(O), O, S, SO ２ , NH, NH-C １－６ Alkyl, NC １－６ Alkyl, NH ２ , or N(C １－６ Alkyl) ２ may be replaced by, 2. The compound according to claim 1, wherein:

3. T is of formula T-I-a: 【Chemistry 3】 3. The compound according to claim 2, wherein:

4. T is of formula T-I-b: 【Chemistry 4】 4. The compound according to claim 2 or 3, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

5. R ３ But -(CH ２ ) ｎ -NR Ａ -, -(CH ２ ) ｎ -(C=O)NR Ａ -, -(CH ２ ) ｎ -S (O) ２ N.R. Ａ -, -A-(CH ２ ) ｎ -NR Ａ -, -(CH ２ ) ｎ -A-NR Ａ -, or -A-O-(CH ２ ) ｎ -(C=O)NR Ａ The compound according to any one of claims 2 to 4, wherein R is -, or a pharma- ceutically acceptable salt thereof.

6. R ３ But -(CH ２ ) ｎ -(C=O)NR Ａ -, -A-(CH ２ ) ｎ -NR Ａ -, or -A-O-(CH ２ ) ｎ -(C=O)NR Ａ - is; and 6. The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt thereof, wherein A is unsubstituted heteroarylene.

7. T is of the formula: 【Chemistry 5】 The compound according to any one of claims 1 to 6, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

8. T is of the formula: 【Chemistry 6】 The compound according to any one of claims 1 to 7, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

9. T is of the formula: 【Chemistry 7】 The compound according to any one of claims 1 to 8, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

10. T is of the formula: 【Chemistry 8】 The compound according to any one of claims 1 to 8, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

11. T is represented by formula T-II: 【Chemistry 9】 During the ceremony: X １ is CH, N, NH, O, or S; X ２ is CH, C, or N; X ３ is CR １５ or N; X ４ is CR １５ or N; X ５ is CR １５ or N; R １３ and R １５ Each occurrence of is independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR Ａ (C=O)Oalkyl, -NR Ａ (C=O)Oaryl, -NR Ａ (C=O)alkyl, -NR Ａ (C═O)aryl, -(C═O)Oalkyl, -(C═O)Oaryl, -(C═O)alkyl, -(C═O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R １４ は、-(CH ２ ) ｎ -O-、-A-(CH ２ ) ｎ -O-、-(EH ２ ) ｎ -A-O-、-A-O-(CH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -S-、-A-(CH ２ ) ｎ -S-、-(EH ２ ) ｎ -A-S-、-A-S-(CH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -NR Ａ -、-A-(EH ２ ) ｎ -NR Ａ -、-(E ２ ) ｎ -A-NR Ａ -、-A-NR Ａ -(H) ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -(C=O)NR Ａ -、-A-(EH ２ ) ｎ -(C=O)NR Ａ -、-(E ２ ) ｎ -A-(C=O)NR Ａ -、-(E ２ ) ｎ -S(O) ２ NR Ａ -、-A-(EH ２ ) ｎ -S(O) ２ NR Ａ -、or-(CH ２ ) ｎ -A-S(O) ２ NR Ａ - A is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and n is 0 to 12; Here, R １３ , R １４ , and R １５ One or more carbons may optionally be C(O), O, S, SO ２ , N.H., N.C. １－６ Alkyl, NH-C １－６ Alkyl, NH ２ , or N(C １－６ Alkyl) ２ may be replaced by, 2. The compound according to claim 1, wherein:

12. T is represented by formula T-II-a: 【Chemistry 10】 12. The compound according to claim 11, wherein:

13. T is represented by formula T-II-b: 【Chemistry 11】 13. The compound of claim 11 or 12, represented by: or a pharma- ceutically acceptable salt thereof.

14. R １４ But -A-(CH ２ ) ｎ -NR Ａ -, -A-(CH ２ ) ｎ -(C=O)NR Ａ -, or -A-(CH ２ ) ｎ -S (O) ２ N.R. Ａ - is; and 14. The compound according to any one of claims 11 to 13, or a pharma- ceutically acceptable salt thereof, wherein A is unsubstituted heterocyclylene.

15. T is of the formula: 【Chemistry 12】 The compound according to any one of claims 1 and 11 to 14, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

16. T is of formula T-III or T-IV: 【Chemistry 13】 During the ceremony: R ２０ and R ２１ are independently halogen, —OH, —COOH, —SO ３ H, -NO ２ , -SH, -NR ｘ R ｙ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R ２２ is -(CH ２ ) ｎ -O-, -(CH ２ ) ｎ -S-, -(CH ２ ) ｎ -NR Ａ -, -(CH ２ ) ｎ -(C=O)NR Ａ - or - (CH ２ ) ｎ -S (O) ２ N.R. Ａ - and R ２３ is halogen, -OH, -COOH, -SO ３ H, -NO ２ , -SH, -NR ｘ R ｙ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R ２４ is an unsubstituted alkylene, an alkylene substituted with one or more halogen or hydroxy groups, an unsubstituted alkoxylene, or an alkoxylene substituted with one or more halogen or hydroxy groups; R ｘ and R ｙ are independently hydrogen or substituted or unsubstituted alkyl; n is 0 to 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2; 2. The compound according to claim 1, wherein:

17. T is represented by formula T-III: 【Chemistry 14】 17. The compound according to claim 1 or 16, wherein:

18. T is represented by formula T-III-a: 【Chemistry 15】 18. The compound according to any one of claims 1, 16 and 17, wherein the compound is represented by the formula: or a pharma- ceutically acceptable salt thereof.

19. R ２０ is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R ２２ But -(CH ２ ) ｎ -NR Ａ - or - (CH ２ ) ｎ -(C=O)NR Ａ 19. The compound according to any one of claims 16 to 18, wherein:

20. T is of the formula: 【Chemistry 16】 20. The compound according to any one of claims 1 and 16 to 19, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

21. T is a compound of formula T-IV: 【Chemistry 17】 17. The compound according to claim 16, wherein:

22. T is of formula T-IV-a: 【Chemistry 18】 22. The compound according to claim 16 or 21, wherein:

23. R ２４ is an unsubstituted alkylene, an alkylene substituted with one or more halogen or hydroxy groups, an unsubstituted alkoxylene, or an alkoxylene substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R ２３ is N.R. ｘ R ｙ 23. The compound of any one of claims 16, 21 and 22, wherein:

24. T is of the formula: 【Chemistry 19】 The compound according to any one of claims 1, 16 and 21 to 23, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

25. T is of the formula: 【Chemistry 20】 2. The compound according to claim 1, wherein:

26. T is of the formula: 【Chemistry 21】 【Chemical 22】 2. The compound according to claim 1, wherein:

27. T is of the formula: 【Chemistry 23】 【Chemistry 24】 2. The compound according to claim 1, wherein:

28. 28. The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene.

29. L, 【Chemistry 25】 and q is 1 to 12; u is 1 to 12; p is 1 to 10; and 29. The compound according to any one of claims 1 to 28, wherein s is 1 to 10, or a pharma- ceutically acceptable salt thereof.

30. L, 【Chemistry 26】 and q is 1 to 5; p is 2 to 5; and 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein s is 1 to 5.

31. L is unsubstituted C ３ -C １２ alkylene, or 【Chemical 27】 29. The compound according to any one of claims 1 to 28, wherein q is 1 to 12, or a pharma- ceutically acceptable salt thereof.

32. 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein E is a cereblon E3 ubiquitin ligase binding moiety or a VHL E3 ubiquitin ligase binding moiety.

33. E is of formula E-II or E-III: 【Chemistry 28】 It is expressed as During the ceremony: Y is -(CH ２ ), -(CH ｋ ), -O-, -O(CH ２ ), -NR ｋ ), -(CH ２ ), -NR ｋ ), -(CH Ｂ ), -NR ２ ), -(CH ｋ ), -(CH ２ ), -NR ｋ ), -(CH Ｂ ), -(CH ２ ), -(C=O)NR ｋ ), -O(CH Ｂ ), -(C=O)NR ２ ), -O(CH ｋ ), -(C=O)NR Ｂ ), -O(CH ２ ), -NR ｋ ), -NR Ｂ ), -NR Ｂ ), -NR ２ ), -O-, -NR ｋ ), -NR Ｂ ), -NR ２ ), -NR ｋ ), -NR Ｂ ), -(C=O)-, or -(CH ２ ), -NR ｋ ), -NR Ｂ ), -(C=O)-; X Ａ is C(O) or C(R ３Ａ ) ２ and X １ -X ２ is C(R ３Ａ )=N or C(R ３Ａ ) ２ -C(R ３Ａ ) ２ and Each R Ｂ are independently hydrogen or substituted or unsubstituted alkyl; Each R １Ａ are independently halogen, OH, C １ -C ６ Alkyl, or C １ -C ６ is alkoxy; Each R ３Ａ are independently H or C １ -C ３ is alkyl; Each R ３′ is independently １ -C ３ is alkyl; Each R ４Ａ are independently H or C １ -C ３ alkyl; or two R ４Ａ are, together with the carbon atom to which they are attached, C(O), C ３ -C ６ forming a carbocyclic or 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O; R ５Ａ is H, deuterium, C １ -C ３ alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2.

34. E is of formula E-II-a: 【Chemical 29】 34. The compound of claim 33, wherein:

35. E: 【Chemistry 30】 The compound according to any one of claims 1 to 32, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

36. E is of the formula: 【Chemistry 31】 The compound according to any one of claims 1 to 34, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

37. E is of the formula: 【Chemistry 32】 The compound according to any one of claims 1 to 32, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

38. E is of the formula: 【Chemical Formula 33】 The compound according to any one of claims 1 to 32, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

39. E is of the formula: 【Chemical 34】 The compound according to any one of claims 1 to 37, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

40. The compound has formula I-a: 【Chemistry 35】 40. The compound according to any one of claims 2, 3, 5, 6, and 28 to 39, wherein q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

41. The compound has formula I-b: 【Chemical 36】 41. The compound according to any one of claims 2 to 6 and 28 to 40, wherein q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

42. The compound has formula I-c: 【Chemical 37】 40. The compound according to any one of claims 11, 12, 14 and 28 to 39, wherein q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

43. The compound has formula I-d: 【Chemical 38】 43. The compound according to any one of claims 11 to 14, 28 to 39 and 42, wherein q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

44. The compound has the formula I-e: 【Chemical Formula 39】 40. The compound according to any one of claims 16 to 19 and 28 to 39, wherein q is 1 to 5, or a pharma- ceutically acceptable salt thereof.

45. The compound has the formula If: 【Chemistry 40】 40. The compound according to any one of claims 16, 21 to 23 and 28 to 39, wherein q is 1 to 5, or a pharma- ceutically acceptable salt thereof.

46. The compound has formula I-g: 【Chemistry 41】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

47. The compound has formula I-h: 【Chemistry 42】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

48. The compound has formula I-I: 【Chemistry 43】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

49. The compound has formula I-j: 【Chemistry 44】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 4, or a pharma- ceutically acceptable salt thereof.

50. The compound has the formula I-k: 【Chemistry 45】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 4, or a pharma- ceutically acceptable salt thereof.

51. The compound has formula I-l: 【Chemistry 46】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 4, or a pharma- ceutically acceptable salt thereof.

52. The compound has the formula Im: 【Chemistry 47】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 6, or a pharma- ceutically acceptable salt thereof.

53. The compound has the formula In: 【Chemistry 48】 33. The compound of any one of claims 1 to 32, wherein T is a tau protein binding moiety, and q is 1 to 4, or a pharma- ceutically acceptable salt thereof.

54. The compound is 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 2. The compound of claim 1, wherein:

55. The compound is 【Chemistry 53】 【Chemical 54】 2. The compound of claim 1, wherein:

56. 56. A radiolabeled compound comprising the compound of any one of claims 1 to 55, or a pharma- ceutically acceptable salt thereof, enriched with a radionuclide.

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

58. 57. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

59. 59. The method of claim 58, wherein the neurological disorder is a neurodegenerative disease.

60. 60. The method of claim 59, wherein the neurodegenerative disease is a tauopathy.

61. 61. The method of claim 60, wherein the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease.

62. 58. A method of promoting degradation of tau protein in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 56 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

63. 58. A method for detecting a neurological disorder, the method comprising contacting a tissue with a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

64. 57. A method for detecting pathological aggregation of tau protein, the method comprising contacting a tissue with a compound according to any one of claims 1 to 56 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

65. 58. A method of diagnosing a neurological disorder in a subject, the method comprising contacting a tissue with a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

66. 66. The method of any one of claims 63 to 65, wherein the tissue is a tissue of the central nervous system.

67. 67. The method of claim 66, wherein the central nervous system tissue is brain tissue.

68. 58. A compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, for use in the treatment of a neurological disorder in a subject in need thereof.

69. 69. The compound or pharmaceutical composition of claim 68, wherein the neurological disorder is a neurodegenerative disease.

70. 70. The compound or pharmaceutical composition of claim 69, wherein the neurological disorder is a tauopathy.

71. 71. The compound or pharmaceutical composition of claim 70, wherein the tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritiko-Bodic disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease.

72. A compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, for use in promoting degradation of tau protein in a subject in need thereof.

73. 58. A kit comprising a compound according to any one of claims 1 to 56, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57; and instructions for administering the compound, the pharma- ceutically acceptable salt thereof, or the pharmaceutical composition to a subject.

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