Tau protein degradation compounds

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, U.S.SN 62 / 531,773, filed on 12 July 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Field of Invention The present invention generally relates to a bifunctional compound that binds to tau protein and promotes its degradation via the recruitment of E3 ubiquitin ligase, and to the use of said compound in the treatment of neurological diseases (e.g., Alzheimer's disease).

[0003] Background of the present invention Alzheimer's disease (AD) is characterized by the progressive loss of memory and other mental functions. Nearly 35 million people worldwide suffer from AD. While the exact mechanisms of AD are not fully understood, the deposition of two characteristic proteins, senile plaques and neurofibrillary tangles (NFTs), is defined as the causative event of AD. Senile plaques consist of extracellular aggregations of amyloid-beta peptide (Aβ), while NFTs consist of highly phosphorylated tau protein. Targeting tau protein has become a strategy for treating AD because tau accumulation begins before widespread neuronal loss. Therefore, tau is not only a drug target but also a biomarker for the early diagnosis of AD by measuring tau loading in the brain. Positron emission tomography (PET) is a molecular imaging technique that provides a non-invasive diagnostic method for detecting tau aggregation. Thus, several tau radioactive tracers have been developed and tested in humans.

[0004] Recently, a novel therapeutic strategy to reduce and / or eliminate proteins associated with a certain pathological condition, PROTAC (protein degradation-targeted chimera; see, for example, U.S. Patent Application 2015, USSN 14 / 792,414, filed July 6, 2015), has been developed by creating a bifunctional compound in which the target protein is grafted onto an E3 ubiquitin ligase, which subsequently induces proteasome-mediated degradation of the target protein. E3 ubiquitin ligases, in combination with E2 ubiquitin-coupled enzymes, are proteins that facilitate the binding of ubiquitin to lysine on target proteins via isopeptide bonds (e.g., amide bonds not present on the protein's backbone). Ubiquitination of such proteins generally results in the degradation of proteasome-target proteins.

[0005] Currently, there are no clinically approved compounds targeting tau for the treatment of Alzheimer's disease (AD), and the overall clinical failure rate is even higher for AD compared to other diseases. Consequently, the need for identifying drugs that can effectively treat neurological disorders such as AD remains. In particular, drugs that exploit cellular mechanisms involved in protein homeostasis (e.g., ubiquitination, proteasomal degradation) may find specific applications as therapeutic agents. [Overview of the project]

[0006] PROTACs rely on strategies that involve gradual addition of target proteins to E3 ubiquitin ligases and subsequent induction of proteasome-mediated degradation of the target proteins. This disclosure describes the conjugation of a tau-binding moiety to an E3 ubiquitin ligase-binding moiety (e.g., lenalidomide, thalidomide) and provides compounds that can induce ubiquitination of tau proteins and promote their degradation in cells. Therefore, this 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 from the recognition that a single bifunctional compound can promote the degradation of tau protein by targeting both tau protein or any post-translational modified form of tau and gradual addition of an E3 ubiquitin ligase (e.g., cereblon) to ubiquitinate the tau protein and mark the tau protein for proteasomal degradation, thus providing novel compounds, compositions and methods for the treatment of neurological disorders (e.g., tauopathies such as AD). Thus, this disclosure represents a significant advance in the treatment of neurological disorders, specifically tauopathies.

[0007] In one aspect, the following is provided: Formula I: [ka] It is represented as, During the ceremony: T is the tau protein binding site; E is the E3 ubiquitin ligase binding site; 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, 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)2NR A -,-NR A S(O)2- or a combination thereof; and R A each occurrence of which 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 carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or when attached to a nitrogen protecting group, a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring, a compound or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or a prodrug thereof.

Problems to be Solved by the Invention

[0008] In one embodiment, T is of formula T-I:

Chemical Formula

[0009] In one embodiment 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 combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C 1-6 alkyl)2, aryl, heteroaryl, or a protecting group, where aryl and heteroaryl may be substituted with halogen, optionally, SO2, NH2, or, optionally, halogen or C 3-8 alkyl substituted cycloalkyl; 1-6 may also be substituted with; R 3 is -(CH2) n -O-, -A-(CH2) n -O-, -(CH2) n -A-O-, -A-O-(CH2) n -(C=O)NR A -, -(CH2) n -S-, -A-(CH2) n -S-, -(CH2) n -A-S-, -A-S-(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​​​​​​​​​​​​2 , and R 4 ~R 8 Each of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 but is hydrogen, -CH3, aryl, or heteroaryl; and n is between 0 and 12; Here, R 1-8 One or more carbon atoms are arbitrarily C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2. [Effects of the Invention]

[0010] In one aspect, T is given by equation T-II: [ka] It is represented as, During the ceremony: X 1 is CH, N, NH, O, or S; X 2 is CH, C, or N; X 3 CR 15 or N; X 4 CR 15 or N; X 5 CR 15 or N; R 13 and R 15Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 between 0 and 12; Here, R 13 , R 14 , and R 15 One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0011] In one aspect of equation T-II: X 1 However, it is CH, N, O, or S; X 2 However, it is CH, C, or N; X 3 However, CR 15 or N; X 4 However, CR 15 or N; X 5 However, CR 15 or N; R 13 and R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 However, -(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; and n is between 0 and 12; Here, R 13 , R 14 , and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0012] In one embodiment, T is given by formula T-III or T-IV: [ka] It is represented as, During the ceremony: R 20 and R 21 These are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, and -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 These are halogen, -OH, -COOH, -SO3H, -NO2, -SH, -NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 This includes unsubstituted alkylenes, alkylenes substituted with one or more halogens or hydroxyl groups, unsubstituted alkoxylenes, or alkoxylenes substituted with one or more halogens or hydroxyl groups; R x and R y These are independently hydrogen, or substituted or unsubstituted alkyl groups; n is between 0 and 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0013] In one embodiment, E is a cereblon E3 ubiquitin ligase binding site or a VHL E3 ubiquitin ligase binding site.

[0014] In one embodiment, E is the cereblon E3 ubiquitin ligase binding site.

[0015] The compounds represented by formula I as an example are not limited to these: [ka] [ka] [ka] [ka] [ka] ; or including pharmaceutically acceptable salts thereof.

[0016] In another aspect, what is offered is a radiolabeled compound comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.

[0017] In another aspect, what is 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, the provided method is a method for treating a neurological disorder in a subject requiring it, the method comprising administering a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I. In one embodiment, the neurological disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is a tauopathy (e.g., Alzheimer's disease).

[0019] In another aspect, the present invention provides a method for promoting the degradation of tau protein in a subject requiring such action, the method comprising administering to the subject a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I.

[0020] In another aspect, the present invention provides a method for detecting neurological disorders, the method comprising contacting a tissue with a compound represented by formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound represented by formula I.

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

[0022] In another aspect, the present invention provides a method for diagnosing a neurological disorder in a subject, the method comprising contacting the subject with a compound represented by formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound represented by formula I.

[0023] In another respect, what is offered is a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, for use in treating neurological disorders in subjects requiring it; and / or in promoting the degradation of tau protein.

[0024] In another aspect, what is provided is a kit comprising a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I. In one embodiment, the kit further includes instructions for administration (e.g., administration to humans) and / or use.

[0025] Details of specific embodiments of the present invention are described in the embodiments for carrying out the invention described below. Other features, problems and advantages of the present invention are evident from the definitions, examples, drawings and claims. [Brief explanation of the drawing]

[0026] Simple description of the drawing [Figure 1A]Figure 1A shows a series of Western blot stains illustrating the effect of the example compound 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 highly phosphorylated tau from the Western blot in Figure 1A. These graphs demonstrate a significant tau-reducing effect of the example compound, but not of lenalidomide, a compound that binds only to CRBN.

[0027] [Figure 2A] Figure 2A shows a series of Western blot stains illustrating the effect of the example compounds on tau protein levels in a 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 highly phosphorylated tau from the Western blot in Figure 2A. These graphs demonstrate a significant tau-reducing effect of the example compound, but not of lenalidomide, a compound that binds only to CRBN.

[0028] [Figure 3] Figure 3 shows a series of Western blot stains illustrating the effect of the well-known tau-binding compound, T807, on tau protein levels in non-mutant human neurons (control) and human tau A152T neurons. The graph on the right shows the quantification of the blots. No significant tau reduction effect of T807 was observed in any of the cell lines.

[0029] [Figure 4A] Figure 4A shows a series of Western blot stains after 24 hours of treatment, illustrating the effects of the exemplary compounds on the levels of E3 ubiquitin ligase cereblon (CRBN), von Hippel-Lindau disease tumor suppressor (VHL), and the C-terminus (CHIP) of HSC70 interacting proteins in human tau A152T and tau P301L neurons. [Figure 4B-C]Figure 4B is a series of bar graphs quantifying CRBN from the Western blot in Figure 4A; CRBN levels in tau A152T neurons are on the left (medium gray bars), and CRBN levels in tau P301L 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 tau A152T neurons are on the left (medium gray bars), and Tau5 levels in tau P301L 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 in tau A152T neurons is on the left (medium gray bars) and VHL levels in tau P301L neurons are on the right (black bars).

[0030] [Figure 5A] Figure 5A shows a series of Western blot stains illustrating the effects of the exemplary compound on tau protein levels in human non-mutant (control), human tau A152T, and human tau P301L neurons at 6 weeks of differentiation. [Figure 5B] Figure 5B is a series of bar graphs quantifying total tau, highly phosphorylated tau (upper graph), and CRBN (lower graph) from the Western blot in Figure 5A. [Figure 5C] Figure 5C quantifies total tau, hyperphosphorylated tau (upper graph), and CRBN (lower graph) from the mean of three Western blot experiments, as shown in Figure 5A.

[0031] [Figure 6A] Figure 6A shows a series of Western blot stains illustrating the effects of the example compounds on 6-week differentiated human tau A152T neurons. [Figure 6B] Figure 6B is a series of bar graphs quantifying total tau, highly phosphorylated tau, and CRBN from the Western blot in Figure 6A.

[0032] [Figure 7] Figure 7 is a bar graph quantifying the results of a neuronal viability assay for the ability of exemplary compounds to provide protection from toxic stimuli associated with neurodegeneration, in this case β-amyloid (1-42), as a functional readout of the peptide effectively degraded by tau (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 due to β-amyloid (1-42) exposure is due to tau. Left, schematic diagram of the experimental design; right, graph of viability.

[0033] [Figure 8A-B] Figure 8A shows a series of Western blot stains illustrating the effects of the exemplary compound and T-807 on tau protein levels in a human tau A152T neuronal model after 24 hours of treatment. The control is a non-mutant neuron (8330-8-RC1). Figure 8B shows a series of graphs quantifying total tau and hyperphosphorylated tau from the Western blots in Figure 8A.

[0034] [Figure 9A-B] Figure 9A shows a series of Western blot stains illustrating 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-mutant neuron (CTR2-L17-RC2). Figure 9B shows a series of graphs quantifying total tau and hyperphosphorylated tau from the Western blots in Figure 9A.

[0035] [Figure 10]Figure 10 is a series of bar graphs quantifying total tau and highly phosphorylated tau from Western blots in Figures 8A and 9A.

[0036] definition Chemical definition Specific functional groups and chemical terminology are defined in more detail below. Chemical elements are identified according to the CAS version of the periodic table on the inside cover of the Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are generally defined as described therein. In addition, general laws of organic chemistry, as well as specific functional parts 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 chiral 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 in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers). Isomers may 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 may be prepared by asymmetric synthesis. See, for example, 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., Univ. of Notre Dame Press, Notre Dame, IN 1972). In addition, the present invention encompasses compounds as individual isomers with substantially no other isomers, and instead as mixtures of various isomers.

[0038] During the ceremony, [ka] This is a single bond in which the stereochemistry of the part directly bonded to it is not specified. [ka] It does not exist or is a single bond, and [ka] or [ka] It is either a single bond or a double bond.

[0039] Unless otherwise specified, the structures described herein include compounds that differ in the presence of one or more isotopically enriched atoms. For example, hydrogen substitution with deuterium or tritium, 18 F 19 Substitution of F, or 13 C or 14 By C 12 Compounds having the structure of the present invention except for the substitution of C are within the scope of this disclosure. Such compounds may be useful, for example, as analytical tools or probes in biological assays.

[0040] When a range of values ​​is enumerated, it is intended to cover each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to 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 The intention is to cover all alkyl groups.

[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 a radical of a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 Alkyl). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C"). 1-9 Alkyl). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C"). 1-8 Alkyl). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C"). 1-7 Alkyl). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C"). 1-6 Alkyl). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C"). 1-5 Alkyl). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C"). 1-4 Alkyl). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C"). 1-3 Alkyl). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C"). 1-2 Alkyl). In some embodiments, an alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has two to six carbon atoms ("C1 alkyl"). 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), etc. Unless otherwise specified, each alkyl group is independently either unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) ("substituted alkyl"). In some embodiments, the alkyl group is unsubstituted C 1-10 Alkyl (unsubstituted C) 1-6Alkyl groups include, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (I-Pr)), and 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 one embodiment, the alkyl group is substituted C 1-10 Alkyl (substituted C) 1-6 Examples include alkyl groups, such as -CF3 and Bn.

[0043] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently substituted with halogens, such as fluoro, bromo, chloro, or iodine. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C"). 1-8 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 6 carbon atoms ("C"). 1-6 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 4 carbon atoms ("C"). 1-4 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 3 carbon atoms ("C"). 1-3 ("Haloalkyl"). In some embodiments, the haloalkyl portion has 1 to 2 carbon atoms ("C"). 1-2 Haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, etc.

[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 main chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions (one or more). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the main chain ("heteroC").1-20 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms in its main chain ("hetero C"). 1-9 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms in its main chain ("hetero C"). 1-18 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms in its main chain ("hetero C"). 1-16 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms in the parent chain ("hetero C"). 1-14 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC"). 1-12 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC"). 1-10 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms in the parent chain ("heteroC"). 1-8 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms in its main chain ("hetero C"). 1-6 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in its main chain ("hetero C"). 1-4 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in its main chain ("hetero C"). 1-3 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom in its main chain ("heteroC"). 1-2(Alkyl). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group as defined herein is a partially unsaturated group, such as a carbonyl group, having one or more heteroatoms and at least one unsaturated carbon in the parent chain. For example, a heteroalkyl group may contain amide or ester functional groups in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each heteroalkyl group is independently either unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC1 alkyl group. 1-20 It is alkyl. In one embodiment, the heteroalkyl group is a substituted heteroC 1-20 It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0045] The term "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 bonds). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2-3 carbon atoms ("C"). 2-3"Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., in 2-butenyl) or terminal (e.g., 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), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 This includes alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise specified, each alkenyl group is independently either unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In some embodiments, the alkenyl group is an unsubstituted C 2-10 It is an alkenyl. In one embodiment, the alkenyl group is a substituted C 2-10 It is an alkenyl. In the alkenyl group, the stereochemistry of the C=C double bond is not specified (for example, -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 main chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions (one or more). In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the main chain ("hetero C 2-10This refers to an "alkenyl" group. In some embodiments, a heteroalkenyl group has 2-9 carbon atoms, at least one double bond, and one or more heteroatoms within its main chain ("hetero C"). 2-9 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in its main chain ("hetero C"). 2-8 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in its main chain ("hetero C"). 2-7 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in its main chain ("hetero C"). 2-6 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2-5 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2-4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2~4 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2-3 carbon atoms, at least one double bond, and one heteroatom inside the main chain ("hetero C"). 2-3 ("Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2-6 (Alkenyl). Unless otherwise specified, each heteroalkenyl group is independently either unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl group is an unsubstituted hetero C 2-10 It is an alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is Alkenil.

[0047] The term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkynyl"). In some embodiments, the alkynyl group has 2-3 carbon atoms ("C"). 2- 3-alkynyl). In some embodiments, the alkynyl group has two carbon atoms ("C2-alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2-4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2-6 An example of an alkenyl group is the aforementioned C 2-4 This includes alkynyl groups as well as pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyls include heptynyl (C7), octinyl (C8), etc. Unless otherwise specified, each alkynyl group is independently either unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In some embodiments, the alkynyl group is an unsubstituted C 2-10 It is an alkynyl group. In one embodiment, the alkynyl group is a substituted C 2-10 It is alkinyl.

[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 main chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions (one or more). In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the main chain ("heteroC"). 2-10 This refers to an "alkynyl" group. In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms within its main chain ("hetero C 2-9 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in its main chain ("heteroC"). 23-8 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in its main chain ("hetero C"). 2-7 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms inside the main chain ("hetero C"). 2-6 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2-5 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2-4 ("Alkynyl"). In some embodiments, a heteroalkynyl group has 2-3 carbon atoms, at least one triple bond, and one heteroatom inside the main chain ("hetero C"). 2-3("Alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in its main chain ("hetero C"). 2-6 (Alkynyl). Unless otherwise specified, each heteroalkynyl group is independently either unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2-10 It is an alkynyl group. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkinyl.

[0049] The term "carbocyrill" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring-forming carbon atoms and zero heteroatoms in a non-aromatic ring system ("C 3-14 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 10 ring-forming carbon atoms ("C"). 3-10 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 8 ring-forming carbon atoms (C 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 7 ring-forming carbon atoms ("C"). 3-7 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring-forming carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 4 to 6 ring-forming carbon atoms ("C"). 4-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5-6 ring-forming carbon atoms ("C"). 5-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring-forming carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6The carbocyclyl group includes, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 The carbocyclyl group is, without limitation, the above C 3-6 This includes carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 The carbocyclyl group is, without limitation, the above C 3-8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 This includes, for example, ) and so on. As the above examples show, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including condensed, bridging, or spirocyclic systems such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring as defined above is condensed with one or more aryl or heteroaryl groups, and the bond site is on the carbocyclyl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the carbocyclic system. Unless otherwise specified, each carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C 3-14 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-14It is carbocyclyl.

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

[0051] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having a ring-forming carbon atom and 1 to 4 ring-forming heteroatoms ("3-14-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heterocyclyl group containing one or more nitrogen atoms, the bond site can be carbon or nitrogen atom, as long as the valence allows. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., condensed, bridging, or spirocyclic systems such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. A heterocyclyl polycyclic system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, with the bond site located on either the heterocyclyl or carbocyclyl ring, or a ring system in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, with the bond site located on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members of 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 member heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 member heterocyclyl.

[0052] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclil has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclil has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] A three-membered heterocyclyl group containing one exemplary heteroatom includes, without limitation, azilidinyl, oxyranyl, and thiiranyl. A four-membered heterocyclyl group containing one exemplary heteroatom includes, without limitation, azetidinyl, oxetanyl, and thietanyl. A five-membered heterocyclyl group containing one exemplary heteroatom includes, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. A five-membered heterocyclyl group containing two exemplary heteroatoms includes, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. A five-membered heterocyclyl group containing three exemplary heteroatoms includes, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. An exemplary six-membered heterocyclyl group containing one heteroatom includes, without limitation, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. An exemplary six-membered heterocyclyl group containing two heteroatoms includes, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanil. An exemplary six-membered heterocyclyl group containing three heteroatoms includes, without limitation, triazinyl. An exemplary seven-membered heterocyclyl group containing one heteroatom includes, without limitation, azepanyl, oxepanyl, and thiepanyl. An exemplary eight-membered heterocyclyl group containing one heteroatom includes, without limitation, azokanyl, oxecanyl, and thiokanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthaliumidyl, naphthaliumidyl, chromanyl, clomenyl, and 1H-benzo[e][1,4]diazepinyl This includes 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-fl[3,2-b]pyrrolyl, 6,7-dihydro-5H-fl[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofl[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofl[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthilidinyl, and others.

[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 π electrons shared in an array of rings) that has 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; phenyl is an example). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, 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 includes ring systems in which an aryl ring is fused with one or more carbocyrillic or heterocyclyl groups, as defined above, and the radical or attachment site lies on the aryl ring. In such examples, the number of carbon atoms is specified through the number of carbon atoms in the aryl ring system. Unless otherwise specified, each aryl group is independently either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is unsubstituted C 6-14 It is aryl. In one embodiment, the aryl group is a substituted C 6-14 It is Ariel.

[0055] "Aralkyl" is a sub-concept of "alkyl," referring to an alkyl group that has a bond point on the alkyl portion and is substituted with an aryl group.

[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 a ring-forming carbon atom and 1-4 ring-forming heteroatoms provided within the aromatic ring system ("5-14 membered heteroaryl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl polycyclic system may contain one or more heteroatoms in one or both rings. "Heteroaryl" encompasses a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyrill or heterocyclyl groups, and the bond site lies on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members of the heteroaryl ring system. "Hyperaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site lies on an aryl or heteroaryl ring, in which case the number of ring members specifies 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), the bond site may lie on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0057] In some embodiments, the heteroaryl group is a 5-10 member aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 membered ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 member aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 member aromatic ring system having a ring carbon atom provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl group 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] An exemplary 5-membered heteroaryl group containing one heteroatom includes, without limitation, pyrrolyl, furanyl, and thiophenyl. An exemplary 5-membered heteroaryl group containing two heteroatoms includes, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. An exemplary 5-membered heteroaryl group containing three heteroatoms includes, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. An exemplary 5-membered heteroaryl group containing four heteroatoms includes, without limitation, tetrazolyl. An exemplary 6-membered heteroaryl group containing one heteroatom includes, without limitation, pyridinyl. An exemplary 6-membered heteroaryl group containing two heteroatoms includes, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. An exemplary 6-membered heteroaryl group containing three or four heteroatoms includes, without limitation, triazinyl and tetradinyl, respectively. Exemplary seven-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, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthylidinyl, putrelidinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridine, dibenzofuranil, carbazolyl, acridinil, phenothiazinil, phenoxadinil, and phenadinil.

[0059] "Heteroaralkyl" is a sub-concept of "alkyl," referring to an alkyl group that has a bond point on the alkyl portion and is substituted with a heteroaryl group.

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

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

[0062] The term "saturated" refers to a portion that does not contain double or triple bonds, i.e., a portion that contains only single bonds.

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

[0064] Unless otherwise specified, groups are optionally substituted. The term “optionally substituted” means either substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” means a group that can be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). Typically, the term “substituted” means that at least one hydrogen present on a group is substituted with a suitable substituent, for example, a substituent that, upon substitution, results in a stable compound, such as one that does not spontaneously undergo conversion by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions within the group, and 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 by all suitable substituents of an organic compound and any substituent that results in the formation of a stable compound as described herein. The present invention intends for any and all such combinations to reach a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any of the preferred 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, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -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 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 2-10Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 This includes aryls and 5-14 member heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Substituted by the base; where X - is the counterion; Alternatively, the two geminal hydrogens on a carbon atom form the group =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 It can be replaced by; R aa Each of them is independent, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 2-10 Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups link together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R bb Each of these is independently hydrogen, -OH, and -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 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 2-10 Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups link together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; here X - is the counterion; R cc Each of them independently consists of hydrogen and C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C2-10 Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups link together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R dd Each of these is independently 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 Alkenil, C 2-6 Alkinyl, HeteroC 1-6 Alkyl, hetero C 2-6 Alkenyl, HeteroC 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 member heterocyclyl, C 6-10 Selected from aryls, 5-10 membered heteroaryls (where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg (Substituted with) or two Geminal R dd Substituents can be linked to form =O or =S; where X - is the counterion; R ee Each of them is independent, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, HeteroC 1-6 Alkyl, hetero C2-6 Alkenyl, HeteroC 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with the base; R ff Each of them independently consists of hydrogen and C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, HeteroC 1-6 Alkyl, hetero C 2-6 Alkenyl, HeteroC 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 member heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups link together to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base; and R gg Each of these is independently 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 Alkenil, C 2-6 Alkinyl, HeteroC 1-6 Alkyl, hetero C 2-6 Alkenyl, HeteroC 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 It is an aryl, a 3-10 member heterocyclyl, or a 5-10 member heteroaryl; or two geminal R gg Substituents can be linked to form =O or =S; where X - It is a counterion.

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

[0067] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is substituted 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 encompasses a base selected from 2, where X - , R aa , R bb , and R cc This is defined herein.

[0068] The term "amino" refers to the -NH2 group. By extension, the term "substituted amino" refers to a monosubstituted, disubstituted, or trisubstituted amino acid. In certain aspects, "substituted amino" is a monosubstituted or disubstituted amino group.

[0069] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly bonded to the parent molecule is substituted with one hydrogen atom 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 encompasses a group selected from 2, in the formula R aa , Rbb and R cc This is as defined herein, and -NH(R bb ) Base R bb It is not hydrogen.

[0070] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly bonded to the parent molecule is replaced by two groups other than hydrogen, i.e., -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 encompasses a group selected from 2, in the formula R aa , R bb and R cc This is as defined herein, except that nitrogen atoms directly bonded to the parent molecule are not substituted with hydrogen.

[0071] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly bonded to the parent molecule is substituted with three groups, i.e., -N(R bb )3 and -N(R bb )3 + X - It includes a base selected from, in the formula, R bb and X - This is defined herein.

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

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

[0074] The term "acyl" is -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 ) refers to a group having the general formula 2, where 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, aliphatic oxy, heteroaliphatic oxy, alkyl oxy, heteroalkyl oxy, aryl oxy, heteroaryl oxy, aliphatic thio, heteroaliphatic thio, alkyl thio, heteroalkyl thio, aryl thio, heteroaryl thio, mono or dialiphatic amino, mono or diheteroaliphatic amino, mono or dialkylamino, mono or diheteroalkylamino, mono or diarylamino, or mono or diheteroarylamino, or two R X1The groups combine to form a 5-6 membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. The substituents on the acyl group include, without limitation, any of the substituents described herein that provide a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, imino, oxo, isocyano, thiooxo, cyano, amino, azide, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thiooxy, heteroaliphatic thiooxy, alkyl thiooxy, heteroalkyl thiooxy, aryl thiooxy, heteroaryl thiooxy, acyloxy, etc. Each of these may be further substituted or unsubstituted).

[0075] The term "carbonyl" refers to a group in which the carbon directly bonded to the parent molecule undergoes sp hybridization and is substituted with an oxygen, nitrogen, or sulfur atom, such as a ketone (e.g., -C(=O)R). aa ), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g., -CO2R) 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 imide (for example, -C(=NR bb )R aa -C(=NR bb )OR aa ), -C(=NR bb )N(R bb )2) refers to a group selected from, where R aa and R bbThis is defined herein.

[0076] The term "silyl" refers to the base-SI(R aa ) pointing to 3, here, R aa This is defined herein.

[0077] The term "oxo" refers to an oxygen group (=O), while the term "thiooxo" refers to an sulfur group (=S).

[0078] Nitrogen atoms can be substituted or unsubstituted, to the extent their valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary substituents on nitrogen atoms 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 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 2-10 Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C6-14 aryl and 5-14 member heteroaryls, or two R atoms attached to the N atom cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base, where R aa , R bb , R cc , and R dd This is as defined herein.

[0079] In certain embodiments, substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen protecting groups are, 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 Alkenil, C 2-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 2-10 Alkenyl, HeteroC 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C6-14 Encompassing aryl and 5-14 membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd Substituted with the base, in the formula, R aa , R bb , R cc and R dd The nitrogen protecting group is as defined herein. The nitrogen protecting group is well known in the art and is incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd This edition includes details described in John Wiley & Sons, 1999.

[0080] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)R aa ) includes, but is not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolineamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazofenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0081] Nitrogen protecting groups such as carbamate groups (for example, -C(=O)OR aa) are not limited to these, but include methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfo)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluorenyl methyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-tri 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-dicyclohexylcarboxamide)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, A Lukyldithiocarbamate, benzylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, [2-(1,3-Dithianyl)methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chloro Monylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -Methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,It contains 6-trimethylbenzylcarbamate.

[0082] Nitrogen protecting groups such as sulfonamide groups (for example, -S(=O)2R aa These 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), and 2,4,6-trimethylbenzenesulfonamide. This includes dimethoxy-4-methylbenzenesulfonamide (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, and N-1,1,4,4-tetramethyl Disilyl azacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3) -yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosberylamine, 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-cyclohexyllideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboronic acid derivative, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain 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"). The oxygen protecting group is, 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 encompasses X - , R aa , R bb and R cc This is defined herein. Oxygen protecting groups are well known in the art and are incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd This includes details described in the edition, John Wiley & Sons, 1999.

[0085] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (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, and 2-methoxyethoxymethyl. 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 1,4-4-methoxypiperidine-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 Roethyl, 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-dibenzosberyl, 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(benzoyl) Xyphenyl)methyl, 3-(imidazole-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, benzoisothiazolyl 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 (lebriate), 4,4-(ethylenedithio)pentanoate (lebrinoyl dithioacetal), pivalic acid, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitic 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)benzoic acid This includes fragrant acids, 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'-tetramethylphosphodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinthioyl, alkyl 2,4-dinitrophenylsulfenic acid, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts). In one embodiment, the oxygen protecting group is silyl. In one embodiment, 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, 2,2These are 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 one aspect, a protecting group present on a 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 is given, and here 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), which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0087] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electrical neutrality. The anionic counterion may be monovalent (i.e., encompassing one formal negative charge). The anionic counterion can be polyvalent such as divalent or trivalent (i.e., encompassing more than one formal negative charge). Exemplary counterions are halide ions (e.g., F - 、Cl - 、Br - 、I - ), NO3 - 、ClO4 - 、OH - 、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) - ) includes. An example of a potentially polyvalent counterion is CO3 2- HPO4 2- , PO4 3- B4O7 2- SO4 2- , S2O3 2- This includes carboxylate anions (e.g., tartarate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimerate, suberate, azelate, sebaset, salicylate, phthalate, aspartate, glutamate, etc.) and carboranes.

[0088] The term "leaving group" is given its usual meaning in the field of synthetic organic chemistry and refers to an atom or group that can be replaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry, 6th edition (501-502). Examples of suitable leaving groups, but not limited to these, include halogens (e.g., F, Cl, Br, or I (iodine)), alkoxycarbonyloxys, aryloxycarbonyloxys, alkanesulfonyloxys, arenesulfonyloxys, alkylcarbonyloxys (e.g., acetoxy), arylcarbonyloxys, aryloxys, methoxys, N,O-dimethylhydroxylaminos, pixyls, and haloforms. In some cases, the leaving group is a sulfonic acid 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 include water, ammonia, alcohol, ether moiety, thioether moiety, zinc halide, magnesium moiety, diazonium salt, and copper moiety. Further exemplary leaving groups, though not limited to these, include halos (e.g., chloro, bromo, iodine) 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, here R aa , R bb , and R cc Examples include (as defined herein).

[0089] The use of the phrase "at least one" as used in this invention refers to the cases of 1, 2, 3, 4 or more, but also includes cases of ranges, such as 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4, including the ends.

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

[0091] Those 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 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, within the bounds of reasonable medical knowledge, is suitable for use in contact with human and lower animal tissues, is free from excessive toxicity, irritation, allergic reactions, etc., and has 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 organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipine, 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-hydroxyethanesulfonate. This includes lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 Alkyl)4 -This includes salts. Typical 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, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acids, and aryl sulfonic acids).

[0095] The term "solvate" refers to a compound or a salt thereof that has been bonded to a solvent, usually by a solvosis reaction. This physical bond may include hydrogen bonds. 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. Preferred solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In some examples, a solvate may be isolated when, for example, one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution phases and isolateable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0096] The term "hydrate" refers to a compound that has been bound to water. Typically, the number of water molecules contained in the hydrate of a compound is in a constant ratio to the number of compound molecules in the hydrate. Thus, the 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, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H₂O)), and polyhydrate (x is a number greater than 1, for example, dihydrate (R·2H₂O) and hexahydrate (R·6H₂O)).

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

[0098] Compounds that have the same molecular formula but differ in the nature or order of their atomic bonding, or in the arrangement of those atoms in space, are also understood to be called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers."

[0099] Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are incompatible mirror images of each other are called "enantiomers." A pair of enantiomers is possible when a compound has a chiral center (for example, it is bonded to four different groups). Enantiomers can be characterized by the absolute configuration of their chiral center, described by Cahn and Prelog's R and S order rules, or by the way the molecule rotates its plane of polarization, and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0100] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, 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 dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0101] The term “prodrug” refers to a compound having a cleavable group and which, by solvolysis or under physiological conditions, becomes a compound described herein, which is pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and N-alkylmorpholine esters. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but in their acid-sensitive forms they often provide advantages of solubility, tissue compatibility, or delayed release to mammals (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to experts in the art, such as esters prepared by the reaction of a hydrophilic acid with a suitable alcohol, or amides prepared by the reaction of a hydrophilic compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from a pendant acidic group on the compounds described herein are certain prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds described herein include C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and C7-C 12 Substituting aryls, and C7~C 12 Aryl alkyl esters may also be preferred.

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

[0103] The “subjects” to which the administration is intended refers to humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, minors) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) or non-human animals. In some embodiments, non-human animals are mammals (e.g., primates (e.g., crab-eating macaques or rhesus macaques), commercially relevant mammals (e.g., cattle, pigs, horses, sheep, goats, cats, or dogs), or birds (e.g., commercially relevant birds such as chickens, ducks, geese, or turkeys). In some embodiments, non-human animals are fish, reptiles, or amphibians. Non-human animals may be male or female at any stage of development. Non-human animals may be transgenic animals or genetically modified animals. The term “patient” refers to a human subject requiring treatment for a disease. Subjects may also be plants. 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, e.g., maize, corn, wheat, rice, oats, barley, rye, or foxtail millet. In some embodiments, the plant is a leguminous plant, e.g., a bean plant, e.g., a soybean plant. In some embodiments, the plant is a tree or shrub.

[0104] The term “biological specimen” refers to any specimen that includes tissue specimens (such as tissue sections and tissue needle biopsies); cell specimens (e.g., cytological smears (such as Pap or blood smears) or specimens of cells obtained by microdissection); specimens of the whole organism (e.g., specimens of yeast or bacteria); or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological specimens include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any material containing biomolecules derived from the first biological specimen.

[0105] The term “tissue” means any living tissue (including groups of cells, parts of the body, or organs) of an object, including blood vessels and / or lymphatic vessels, or a portion thereof, to which the compounds, particles, and / or compositions of the present invention are to be delivered. Tissue may be abnormal or unhealthy tissue that may need to be treated. Tissue may also be normal or healthy tissue that is at higher-than-normal risk of becoming abnormal or unhealthy, which may need to be prevented. In one embodiment, tissue is the central nervous system. In one embodiment, tissue is the brain.

[0106] The terms “administer,” “give,” or “give” refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing the compounds or compositions described herein into, on, or in a subject.

[0107] The terms “treatment,” “to treat,” and “to treat” refer to stopping, alleviating, delaying the onset of, or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the 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 subsided, for example, to delay or prevent recurrence.

[0108] The terms “condition,” “disease,” and “disability” are used interchangeably.

[0109] In this specification, the “effective dose” of a compound refers to an amount sufficient to induce a desired biological response. The effective dose of a compound described herein may 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 dose is a therapeutic dose. In some embodiments, the effective dose is a prophylactic dose. In some embodiments, the effective dose is the amount of the compound described herein in a single dose. In some embodiments, the effective dose is the combined amount of the compounds described herein in multiple doses.

[0110] In this specification, “therapeutic dose” of a compound means an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. The therapeutic dose of a compound means the amount of a therapeutic agent, either alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of a condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids a condition, or its symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent. In some embodiments, the therapeutic dose is sufficient to promote the binding and / or degradation of tau protein. In some embodiments, the therapeutic dose is sufficient to treat a neurological disorder (e.g., AD). In some embodiments, the therapeutic dose is sufficient to promote the binding and / or degradation of tau protein and to treat cancer (e.g., DLBCL).

[0111] In this specification, “preventive effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a condition or one or more signs or symptoms associated with a condition. The preventive effective dose of a compound means the amount of a therapeutic agent, either alone or in combination with other agents, that provides a preventive benefit in the prevention of a condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In some embodiments, the preventive effective dose is sufficient to promote the binding and / or degradation of tau protein. In some embodiments, the preventive effective dose is sufficient to treat a neurological disorder (e.g., AD). In some embodiments, the preventive effective dose is sufficient to promote the binding and / or degradation of tau protein and to 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 classification of proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and, though less common, are also expressed at extremely low levels in CNS astrocytes and oligodendrocytes. In humans, tau protein is named MAPT (microtubule-associated protein tau) and is the product of alternative splicing from a single gene located on chromosome 17. The tau protein described herein encompasses all post-translational modified forms of the protein.

[0114] The term "tauopathy" refers to a classification of neurodegenerative diseases associated with the pathological aggregation of tau proteins in neurofibrillary or glial tangles in the human brain. First-class tauopathy, that is, conditions in which neurofibrillary tangles (NFTs) are primarily observed, includes, but is 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, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, and argyrophilic granule disease.

[0115] The terms “biologic,” “biologic drug,” and “biological product” refer to a broad range of products, including vaccines, blood and blood components, allergenic agents, somatic cells, gene therapies, tissues, nucleic acids, and proteins. Biologics may contain sugars, proteins, or nucleic acids, or complex combinations thereof, or they may be living organisms such as cells and tissues. Biologics may be isolated from diverse natural sources (e.g., humans, animals, microorganisms), or they may be produced by biotechnology methods 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., through chemical synthesis). Typically, these are small molecule organic compounds (i.e., they contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocyclic rings). 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 less, 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 less than or equal to about 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutic 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 form complexes 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. Examples of small molecules include, but are not limited to, radionuclides and imaging agents. In some embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate government agency or regulatory authority.For example, drugs approved for use in humans are listed by the FDA under 21 C. FR § 330.5, 331-361, and 440-460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C. FR § 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 possesses therapeutic properties that produce a desired (usually beneficial) effect. For example, a therapeutic agent can treat, induce remission of, and / or prevent a disease. Therapeutic agents disclosed herein may be biologics or small molecule therapeutic agents.

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

[0119] Detailed description of a certain aspect Provided herein are bifunctional compounds that bind to tau protein and mobilize specific E3 ligases (e.g., cereblon) to promote the degradation of tau protein. In one aspect, this disclosure provides compounds of formula I, and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, radiolabeled derivatives, prodrugs, and pharmaceutical compositions. The compounds are useful for the treatment and / or prevention of diseases associated with tau protein aggregation (e.g., tauopathy (e.g., AD)) in subjects requiring it.

[0120] compound The compounds described herein interact with tau protein and E3 ubiquitin ligases (e.g., cereblon). As described herein, the therapeutic effect may result from the degradation, regulation, binding, or modification of tau protein by the compounds described herein. Although we do not wish to be bound by any particular theory, the therapeutic effect may result from the regulation, targeting, binding, or modification of E3 ubiquitin ligases (e.g., cereblon) by the compounds described herein. The therapeutic effect may result from the recruitment of E3 ubiquitin ligases (e.g., cereblon) by the compounds through inhibition, targeting, binding, or modification of E3 ubiquitin ligases, such as ubiquitinating tau protein and labeling it for proteasome degradation. The compounds may be provided as pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs for use in any composition, kit, or method described herein.

[0121] In one aspect, the compound of formula I is disclosed: [ka] T is the tau protein binding site; E is the E3 ubiquitin ligase binding site: 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, 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)2NR A -, -NR A S(O)2-, or a combination thereof; and R A In each case, independently, a hydrogen atom, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a nitrogen protecting group if bonded to a nitrogen atom, or two R A The groups can be linked together to form substituted or unsubstituted heterocyclic rings.

[0122] Group T In one embodiment, T is the binding site of any tau protein. In one embodiment, T is any tau protein derived from the tau protein binding compounds described in U.S. Patent Application No. 13 / 447,095 filed May 22, 2012; U.S. Patent Application No. 13 / 035,405 filed February 25, 2011; U.S. Patent Application No. 13 / 881,872 filed October 28, 2011; U.S. Patent Application No. 09 / 378,662 filed August 20, 1999; and U.S. Patent Application No. 14 / 346,914 filed March 24, 2014, each of which is incorporated herein by reference.

[0123] In one aspect, T is given by formula TI: [ka] It is represented 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 combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 This is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; 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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; and n is between 0 and 12; Here R 1-8 One or more carbon atoms can be any of C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0124] In one embodiment, formula TI: It is represented 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 combination, or substitution, or non-substitution of C. 1-12It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 but is hydrogen, -CH3, aryl, or heteroaryl; and n is between 0 and 12; Here R 1~8 One or more carbon atoms are arbitrarily C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0125] In one embodiment, L is N or CR 5 And; M is N or CR 6 And; P is CR 7 Q is CR 8 In one aspect, L is CR 5 And; M is N or CR 6 And; P is CR 7 Q is CR 8 In one aspect, L is CR 5 M is N; P is CR 7 Q is CR 8 That is the case.

[0126] In one aspect, X is a combination.

[0127] In one embodiment, R 9 It is hydrogen.

[0128] In one embodiment, 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 one embodiment, 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 one embodiment, 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 one embodiment, 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 one embodiment, 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 heteroarylene. In one embodiment, 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 heteroarylene. In one embodiment, R 3 is -A-(CH2) n -NR A -,-(CH2) n -A-NR A -, or -(CH2) n -(C=O)NR A- and A is a substituted or unsubstituted heteroarylene. In one embodiment, 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 a substituted or unsubstituted heteroarylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A -, or -AO-(CH2) n -(C=O)NR A -In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -or -A-(CH2) n -NR A -In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -In one embodiment, R 3 is -A-(CH2) n -NR A -In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A -In one embodiment, 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 an unsubstituted heteroarylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -or -A-(CH2)n -NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -In one embodiment, R 3 is -A-(CH2) n -NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -A-(CH2) n -NR A - and A is unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene.

[0129] In one embodiment, R 1 , R 2 , and R 4 Each of these is independently hydrogen, OH, halogen, NH2, CH3, SO2, NO2, aryl, heteroaryl, NHR 12 , N(R 12 )2C3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and R 12は、 It is hydrogen, -CH3, aryl, or heteroaryl. In one embodiment, R 1 , R 2 , and R 4 Each of them is independently a hydrogen atom.

[0130] In one aspect, T is given by equation TIa: [ka] It is represented as, During the ceremony: L is N or CR 5 and; M is N or CR 6 and; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 This is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; 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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; and n is between 0 and 12; Here, R 2 , R 3 , R 7 , and R8 One or more carbon atoms can be any of C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0131] In one embodiment of formula TIa: L is N or CR 5 and; M is N or CR 6 and; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 but is hydrogen, -CH3, aryl, or heteroaryl; and n is between 0 and 12; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are arbitrarily C(O), O, S, SO2, NH, NH-C 1-6 Alkyl, NC 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0132] In one aspect, T is given by formula TIb: [ka] It is represented 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 - is

[0133] In one embodiment of formula TIb, R 3 However, -(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 - is

[0134] In one embodiment of formula TIb, R 3 However, -(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 - is

[0135] In one embodiment of formula TIb, R 3 However, -(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 one embodiment, R 3 is, -(CH2) n -(C=O)NR A -, -A-(CH2) n -NR A -, or -AO-(CH2) n -(C=O)NR A-In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -or -A-(CH2) n -NR A -In one embodiment, R 3 is, -(CH2) n -(C=O)NR A - or -AO-(CH2) n -(C=O)NR A -In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -In one embodiment, R 3 is -A-(CH2) n -NR A -In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A -In one embodiment, 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 an unsubstituted heteroarylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NR A -or -A-(CH2) n -NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -A-(CH2) n -NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -A-(CH2) n -NR A - and A is an unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 3 is, -(CH2) n -(C=O)NRA - or -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 3 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene.

[0136] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0137] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0138] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0139] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0140] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0141] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0142] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0143] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0144] In one aspect, T is given by the formula: [ka] . It is represented as follows.

[0145] In one aspect, T is given by equation T-II: [ka] It is represented as, During the ceremony: X 1 teeth 、 It is CH, N, NH, O, or S; X 2 teeth 、 It is 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 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 between 0 and 12; Here, R 13 , R 14 , and R 15 One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0146] In one aspect of equation T-II: X 1 However, it is CH, N, O, or S; X 2 However, it is CH, C, or N; X 3 However, CR 15 or N; X 4 However, CR 15 or N; X 5 However, CR 15 or N; R 13 and R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 However, -(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; and n is between 0 and 12; Here, R 13 , R 14 , and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

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

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

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

[0150] In one embodiment, 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 one embodiment, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A -In one embodiment, 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 an unsubstituted heterocycline. In one embodiment, R 14 is -A-(CH2) n -(C=O)NR A -In one embodiment, R 14 is -A-(CH2) n -(C=O)NR A - and A is an unsubstituted heterocycline. In one embodiment, R14 is -A-(CH2) n -(C=O)NR A - and A is an unsubstituted piperidine or piperidine. In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A -In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene.

[0151] In one aspect, T is given by equation T-II-a: [ka] It is represented as, During the ceremony: X 3 CR 15 or N; X 4 CR 15 or N; X 5 CR 15 or N; R 13 and R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 between 0 and 12; Here, R 13 , R 14 , and R 15One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0152] In one aspect of equation T-II-a: X 3 However, CR 15 or N; X 4 However, CR 15 or N; X 5 However, CR 15 or N; R 13 and R 15 Each occurrence is, 、 Independently, hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 However, -(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 a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and n is between 0 and 12; Here, R 13 , R 14 , and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0153] In one aspect, T is given by equation T-II-b: [ka] It is represented 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 - is

[0154] In one embodiment 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 - is

[0155] In one embodiment, 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 one embodiment, R 14 is -A-(CH2) n -NR A -, -A-(CH2) n -(C=O)NR A -, or -A-(CH2) n -S(O)2NR A -In one embodiment, 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 an unsubstituted heterocycline. In one embodiment, R 14 is -A-(CH2) n -(C=O)NR A -In one embodiment, R 14 is -A-(CH2) n -(C=O)NR A - and A is an unsubstituted heterocycline. In one embodiment, R 14 is -A-(CH2) n -(C=O)NR A - and A is an unsubstituted piperidine or piperidine. In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A -In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted heteroarylene. In one embodiment, R14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene, pyrimidinylene, or pyridadinylene. In one embodiment, R 14 is -AO-(CH2) n -(C=O)NR A - and A is an unsubstituted pyridinylene.

[0156] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0157] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0158] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0159] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0160] In one embodiment, T is given by formula T-III or T-IV: [ka] It is represented as, During the ceremony: R 20 and R 21 These are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, and -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 These are halogen, -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 These are independently hydrogen, or substituted or unsubstituted alkyl groups; n is between 0 and 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0161] In one aspect, T is given by equation T-III: [ka] It is represented as, During the ceremony: R 20 and R 21 These are independently halogen, -OH, -COOH, -SO3H, -NO2, -SH, and -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 These are independently hydrogen, or substituted or unsubstituted alkyl groups; n is between 0 and 12; t is 0, 1, 2, 3, or 4; and r is 0, 1, or 2.

[0162] In one aspect, T is given by equation T-III-a: [ka] It is represented as, During the ceremony: R 20 These are 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 is independently hydrogen, or a substituted or unsubstituted alkyl; and n is between 0 and 12.

[0163] In one embodiment, R 20 G is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 22 is, -(CH2) n -NR A -or-(CH2) n -(C=O)NR A - is

[0164] In one embodiment, R 20 G is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 22 is, -(CH2) n -NR A - is

[0165] In one embodiment, G is an unsubstituted arylene. In one embodiment, G is an unsubstituted phenylene. In one embodiment, G is an unsubstituted heteroarylene. In one embodiment, G is an unsubstituted pyridinylene, pyrimidinylene, pyridadinylene, pyrazolinylene, pyrazolinylene, imidazoylene, oxazolinylene, or thiazoylene. In one embodiment, G is an unsubstituted pyridinylene or pyrazolinylene. G is an unsubstituted pyridinylene. In one embodiment, G is an unsubstituted phenylene, pyridinylene, or pyrazonylylene.

[0166] In one embodiment, R 20G is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 22 is, -(CH2) n -NR A -or-(CH2) n -(C=O)NR A - is

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

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

[0169] In one embodiment, R 20 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R22 is, -(CH2) n -NR A - is

[0170] In one embodiment, R 20 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 22 is, -(CH2) n -NR A - is

[0171] In one embodiment, R 20 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 22 is, -(CH2) n -NR A - is

[0172] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0173] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0174] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0175] In one aspect, T is given by equation T-IV: [ka] It is represented as, During the ceremony: R 21 These are 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 23 These are halogen, -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 is independently hydrogen, or a substituted or unsubstituted alkyl; and r is 0, 1, or 2.

[0176] In one aspect, T is given by equation T-IV-a: [ka] It is represented as, During the ceremony: G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 These are halogen, -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 These are independently hydrogen, or substituted or unsubstituted alkyl groups.

[0177] In one embodiment, R 24 This includes unsubstituted alkylenes, alkylenes substituted with one or more halogens or hydroxyl groups, unsubstituted alkoxylenes, or alkoxylenes substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 23 , NR x R y That is the case.

[0178] In one embodiment, G is an unsubstituted arylene. In one embodiment, G is an unsubstituted phenylene. In one embodiment, G is an unsubstituted heteroarylene. In one embodiment, G is an unsubstituted pyridinylene, pyrimidinylene, pyridadinylene, pyrazolinylene, imidazoylene, oxazolinylene, or thiazoylene. In one embodiment, G is an unsubstituted pyridinylene or pyrazolinylene. In one embodiment, G is an unsubstituted pyridinylene. In one embodiment, G is an unsubstituted phenylene, pyridinylene, or pyrazolinylene.

[0179] In one embodiment, R 24 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 23 , NR x R y That is the case.

[0180] In one embodiment, R 24 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 23 , NR x R y That is the case.

[0181] In one embodiment, R 24 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 23 , NR x R y That is the case.

[0182] In one embodiment, R 24 teeth, [ka] and; G is an unsubstituted arylene or an unsubstituted heteroarylene; and R 23 , NR x R y That is the case.

[0183] In one aspect, T is given by the formula: [ka] [ka] It is represented as follows.

[0184] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0185] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0186] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0187] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0188] In one aspect, T is given by the formula: [ka] [ka] It is represented as follows.

[0189] In one aspect, T is given by the formula: [ka] It is represented as follows.

[0190] In some respects, the tau bond portion has K atoms with a molecular weight 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 30 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 3 nM, less than 2 nM, or less than 1 nM. dIt then binds to the tau protein.

[0191] In some aspects, the tau-binding moiety selectively binds to tau proteins over other tau proteins. In some aspects, the compound represented by formula I selectively binds to tau proteins over amyloid-beta. In some aspects, the selectivity is between approximately 2 and 5 times. In some aspects, the selectivity is between approximately 5 and 10 times. In some aspects, the selectivity is between approximately 10 and 20 times. In some aspects, the selectivity is between approximately 20 and 50 times. In some aspects, the selectivity is between approximately 50 and 100 times. In some aspects, the selectivity is between approximately 100 and 200 times. In some aspects, the selectivity is between approximately 200 and 500 times. In some aspects, the selectivity is between approximately 500 and 1000 times. In some aspects, the selectivity is at least approximately 1000 times.

[0192] Group L L is the divalent part that connects T and E. In one embodiment, 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)2NR A -, -NR A It is S(O)2-, or a combination thereof.

[0193] In some embodiments, L is any “L” group described in U.S. Patent Application No. 14 / 792,414, filed on 6 July 2015 and incorporated herein by reference. In some embodiments, L is any “linker” group described in U.S. Patent Application No. 14 / 707,930, filed on 8 May 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 one embodiment, L contains up to three atoms, excluding hydrogen atoms. In another embodiment, any carbon atom in L can be substituted.

[0194] In one embodiment, L is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted heteroalkylene.

[0195] In one embodiment, L is a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene. In one embodiment, L is a substituted or unsubstituted C 1-30 It is an alkylene. In one embodiment, L is a substituted or unsubstituted C 1-20 It is an alkylene. In one embodiment, L is a substituted or unsubstituted C 1-10 It is an alkylene. In one embodiment, L is a substituted or unsubstituted C 1-30 It is a heteroalkylene. In one embodiment, L is a substituted or unsubstituted C 1-20 It is a heteroalkylene. In one embodiment, L is a substituted or unsubstituted C 1-10 It is a heteroalkylene.

[0196] In one aspect, L is [ka] and; q is between 1 and 12; u is between 1 and 12; p is between 1 and 10; and s is between 1 and 10.

[0197] In one aspect, L is [ka] and; q is between 1 and 12; p is between 1 and 10; and s is between 1 and 10.

[0198] In one aspect, L is [ka] and; q is between 1 and 5; p is between 2 and 5; and s is between 1 and 5.

[0199] In one aspect, L is [ka] and; And q is between 1 and 12. In one aspect, L is [ka] and; And q is between 1 and 5. In one aspect, L is [ka] and; And q is 2. In one aspect, L is [ka] and; And q is 3. In one aspect, L is [ka] and; And q is 4. In one aspect, L is [ka] and; And q is 5.

[0200] In one aspect, L is [ka] And u is 1 to 12. In one embodiment, L is [ka] And u is 1 to 5.

[0201] In one aspect, L is [ka] p is 1 to 10, and s is 1 to 10. In one embodiment, L is [ka] And; p is 2 to 5; and s is 1 to 5. In one embodiment, L is [ka] p is 3, and s is 2.

[0202] In one aspect, L is unsubstituted C3~C 12 Alkylene, or [ka] Here, q is between 1 and 12. In one aspect, L is unsubstituted C3~C 12 Alkylene, or [ka] Here, q is between 1 and 11. In one embodiment, L is unsubstituted C4~C 12 Alkylene or [ka] Here, q is between 1 and 11. In one embodiment, L is unsubstituted C4~C 10 Alkylene or [ka] Here, q is between 1 and 11. In one embodiment, L is an unsubstituted C5-C7 alkylene or [ka] Here, q is between 1 and 11. In one embodiment, L is an unsubstituted C5-C7 alkylene or [ka] Here, q is between 1 and 6.

[0203] In one aspect, L is [ka] And here q is 1 to 12. In one embodiment, L is [ka] And here q is 1 to 6. In one embodiment, L is [ka] And here q is 1. In one embodiment, L is [ka] And here q is 2. In one embodiment, L is [ka] And here q is 3. In one embodiment, L is [ka] And here q is 4. In one embodiment, L is [ka] And here q is 5. In one embodiment, L is [ka] And here q is 6. In one embodiment, L is [ka] And here q is 7. In one embodiment, L is [ka] And here q is 8. In one embodiment, L is [ka] And here q is 9. In one embodiment, L is [ka] And here q is 10. In one embodiment, L is [ka] And here q is 11. In one embodiment, L is [ka] And here q is 12.

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

[0205] R Abasis In one embodiment, R A Independently, these are hydrogen, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a nitrogen protecting group if bonded to a nitrogen atom, an oxygen protecting group if bonded to an oxygen atom, or a sulfur protecting group if bonded to a sulfur atom, or two R A The groups are linked together to form substituted or unsubstituted heterocyclic rings. In one embodiment, R A These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a nitrogen protecting group if bonded to a nitrogen atom, an oxygen protecting group if bonded to an oxygen atom, or two R A The groups are linked together to form substituted or unsubstituted heterocyclic rings. In one embodiment, R A These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycline, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or two R A The groups are linked together to form substituted or unsubstituted heterocyclic rings. In one embodiment, R A These are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5-6 member heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 member heteroaryl, or two R A The groups are linked together to form substituted or unsubstituted heterocyclic rings. In one embodiment, R A These are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-30Heteroalkyl, substituted or unsubstituted 5-6 member heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 member heteroaryl, or two R A The groups are linked together to form substituted or unsubstituted heterocyclic rings. In one embodiment, R A These are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 1-30 It is heteroalkyl. In one embodiment, R A These are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 1-20 It is heteroalkyl. In one embodiment, R A These are, independently, hydrogen, or substituted or unsubstituted C 1-6 It is alkyl. In one embodiment, R A It is, independently, hydrogen.

[0206] E group E is the E3 ubiquitin ligase binding portion. E includes all portions that bind to or can bind to any E3 ubiquitin ligase. For example, in one embodiment, E can bind to an E3 ubiquitin ligase such as cereblon or von Hippel-Lindau tumor suppressor protein (VHL). In one embodiment, E can bind to multiple different E3 ubiquitin ligases. In one embodiment, E binds to cereblon. In one embodiment, 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 the testes, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovaries, small intestine, peripheral blood leukocytes, colon, brain, and retina. CRBN is located in the cytoplasm, nucleus, and periphery membrane (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), karin-4A (CUL4A), and karin-1 regulator (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism not yet fully understood, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, controls numerous developmental processes, including limb and auditory vesicle formation.

[0209] In some embodiments, E is a modifier, binder, inhibitor, or ligand of cereblon. In some embodiments, E is a modifier 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 modifier, binder, inhibitor, or ligand of cereblon disclosed in U.S. Patent Application No. 6, July 6, 2015, USSN 14 / 792,414, U.S. Patent Application No. 8, May 8, 2015, USSN 14 / 707,930, and International Patent Application No. 13, August 13, 2013, PCT / US2013 / 054663, each of which is incorporated herein by reference. In some embodiments, E is a modifier, binder, inhibitor, or ligand of a variant of cereblon. In one embodiment, E is a modifier, binder, inhibitor, or ligand for 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-oxoquinazoline-3(4H)-yl)piperidine-2,6-dione, or an analog or derivative thereof.

[0211] In one embodiment, E is given by the formula EI: [ka] It is represented 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 These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3′ These are independently C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 either 1 or 2.

[0212] In one embodiment 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 However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0213] In one embodiment, Y is -(CH2) 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 one embodiment, Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, or -(CH2) k -NR B (C=O)-. In one embodiment, Y is -(CH2) k -NR B -,-(CH2) k -O-, or -NR B (C=O)-(CH2) k -O-. In one embodiment, Y is -(CH2) k It is -NH-. In one embodiment, Y is -NH-. In one embodiment, Y is -(CH2) k It is -O-. In one embodiment, Y is -O-. In one embodiment, Y is -NH(C=O)-(CH2)-O-. In one embodiment, Y is -NH-, -O-, or -NH(C=O)-(CH2)-O-.

[0214] In one embodiment, E is given by formula E-II or E-III: [ka] It is represented 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 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3′ These are independently C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 either 1 or 2.

[0215] In one embodiment 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 However, C(O) or C(R 3A )2; X 1 -X 2 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0216] In one embodiment, E is given by equation E-II: [ka] It is represented 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 C(R 3A ) = N or C(R 3A )2-C(R 3A)2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3′ These are independently C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 either 1 or 2.

[0217] In one embodiment of equation 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 However, C(O) or C(R 3A )2; X 1 -X 2 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0218] In one embodiment of equation 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 However, C(O) or C(R 3A )2; X 1 -X 2 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0219] In one embodiment of equation E-II: Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, or -(CH2) k -NR B (C=O)-; X A However, C(O) or C(R 3A )2; X 1 -X 2 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0220] In one aspect, E is given by equation E-II-a: [ka] It is represented 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 BThese are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 one embodiment 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 However, C(O) or C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4AHowever, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 one embodiment, E is given by equation E-II-b: [ka] It is represented 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 These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or 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 one embodiment 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 However, C(O) or C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A but is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0224] In one aspect, E is given by equation E-II-c: [ka] It is represented 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 BThese are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or 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 one embodiment 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 However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A but is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0226] In one aspect, E is given by equation E-II-d: [ka] It is represented 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 These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or 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 one embodiment 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 However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A but is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0228] In one embodiment, E is given by equation E-II-e: [ka] It is represented as, During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; Each R 3A These are independently H or C1-C3 alkyl groups; R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0229] In one embodiment, E is given by equation E-II-e-1: [ka] It is represented as, During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; Each R 3A These are independently H or C1-C3 alkyl groups; R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0230] In one embodiment, E is given by equation E-II-e-1: [ka] It is represented as, During the ceremony: X A is C(O) or C(R 3A )2; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; Each R 3A These are independently H or C1-C3 alkyl; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0231] In one aspect, E is given by equation E-II-f: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0232] In one aspect, E is given by equation E-II-f-1: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0233] In one aspect, E is given by equation E-II-f-2: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0234] In one aspect, E is given by equation E-II-g: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0235] In one embodiment, E is given by equation E-II-g-1: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0236] In one aspect, E is given by equation E-II-g-2: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0237] In one embodiment, E is given by equation E-III: [ka] It is represented 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 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3′ These are independently C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 either 1 or 2.

[0238] In one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 3′ However, they are independently C1-C3 alkyl groups; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 either 1 or 2.

[0239] In one embodiment, Y is -(CH2) 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 one embodiment, Y is -(CH2) k -NR B -, -O(CH2) k -(C=O)NR B -, or -(CH2) k -NR B (C=O)-. In one embodiment, Y is -(CH2) k -NR B -,-(CH2) k -O-, or -NR B (C=O)-(CH2) k -O-. In one embodiment, Y is -(CH2) k It is -NH-. In one embodiment, Y is -NH-. In one embodiment, Y is -(CH2) k It is -O-. In one embodiment, Y is -O-. In one embodiment, Y is -NH(C=O)-(CH2)-O-. In one embodiment, Y is -NH-, -O-, or -NH(C=O)-(CH2)-O-.

[0240] In one embodiment, E is given by equation E-III-a: [ka] It is represented 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 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 1A These are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A These are 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 one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 1A However, they are independently halogens, OH groups, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A However, it 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 one embodiment, E is given by equation E-III-b: [ka] It is represented 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 C(R 3A) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or 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 one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A but is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0246] In one embodiment, E is given by equation E-III-c: [ka] It is represented 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 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A Together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or 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 one embodiment 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 However, C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B However, independently, they are hydrogen, or substituted or unsubstituted alkyl groups; Each R 3A However, they are independently H or C1-C3 alkyl; Each R 4A However, independently, they are H or C1-C3 alkyl; or two R 4A However, together with the carbon atoms to which they are attached, they form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O; R 5A but is H, deuterium, C1-C3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.

[0248] In one aspect, E is given by equation E-III-d: [ka] It is represented as, During the ceremony: X 1 -X 2 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3AThese are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0249] In one aspect, E is given by equation E-III-d-1: [ka] It is represented as, During the ceremony: X 1 -X 2 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0250] In one aspect, E is given by equation E-III-d-2: [ka] It is represented as, During the ceremony: X 1 -X 2 C(R 3A ) = N or C(R 3A )2-C(R 3A )2; Each R B These are independently hydrogen, or a substituted or unsubstituted alkyl group; Each R 3A These are independently H or C1-C3 alkyl groups; Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0251] In one embodiment, E is given by equation E-III-e: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0252] In one embodiment, E is given by equation E-III-e-1: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

[0253] In one embodiment, E is given by equation E-III-e-2: [ka] It is represented as, During the ceremony: Each R 4A These are independently H or C1-C3 alkyl; or two R 4A They form 4-, 5-, or 6-membered heterocycles containing one or two heteroatoms selected from C(O), C3-C6 carbocyclic compounds, or N and O, together with the carbon atoms to which they are attached; and R 5A These are H, deuterium, C1-C3 alkyl, F, or Cl.

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

[0255] In one manner, E is [ka] That is the case.

[0256] In one manner, E is [ka] That is the case.

[0257] In one manner, E is [ka] That is the case.

[0258] In one manner, E is [ka] That is the case.

[0259] In one manner, E is [ka] That is the case.

[0260] In one manner, E is [ka] That is the case.

[0261] In one manner, E is [ka] That is the case.

[0262] Von Hippel-Lindau disease tumor suppressor (VHL) is a 3-ubiquitin ligase. VHL contains a substrate-recognizing subunit / E3 ubiquitin ligase complex VCB, which includes a complex containing elongin B and C, as well as karin-2 and Rbx1. The main substrates of VHL are hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as angiogenic growth factor VEGF and erythropoietin, a cytokine that induces erythrocytes, in response to hypoxic 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.) The second VHL gene product arises from internal translation initiation from methionine at codon 54, producing a 160-amino acid protein ("pVHL19"). VHL has two main structural domains: an N-terminal domain (β-domain) consisting mainly of β-sheets, and a smaller C-terminal domain (α-domain) between amino acids 155 and 192, consisting mainly of α-helices. The α-domain consists of three α-helices, which combine with a fourth α-helice provided by elongin C. The β-domain is located on the opposite side of the α-domain and can freely contact other proteins.

[0264] In some embodiments, E is a modifier, binder, inhibitor, or ligand of VHL. In some embodiments, E is a modifier 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 modifier, binder, inhibitor, or ligand of a variant of VHL. In some embodiments, E is a modifier, binder, inhibitor, or ligand of an isoform of VHL. In some embodiments, E is a modifier, binder, inhibitor, or ligand of the gene product of VHL (e.g., pVHL19).

[0265] In one embodiment, E comprises a peptide backbone structure. In one embodiment, E is a structure of formula: [ka] It belongs to; In the formula, R 5 is a heteroaryl ring, and R 6 is hydrogen or C 1-4 It is alkyl. In one embodiment, R 5 is a five-membered heteroaryl ring containing at least one nitrogen atom. In one embodiment, R 5 This is a substituted or unsubstituted oxazolinyl, or a substituted or unsubstituted thiazolinyl.

[0266] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0267] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0268] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0269] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0270] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0271] In one embodiment, E is given by the formula: [ka] It is represented as follows.

[0272] In some respects, the E3 ligase binding site contains K100,000, 50,000, 20,000, 10,000, 5,000, 2,500, 1,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 3, 20, 10, 5, 4, 3, 2, or 1. d Then, it binds to E3 ubiquitin ligase.

[0273] In some respects, the E3 ligase binding site contains K100,000, 50,000, 20,000, 10,000, 5,000, 2,500, 1,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 3, 20, 10, 5, 4, 3, 2, or 1. d Then, it binds to Cereblon.

[0274] In some respects, the E3 ligase binding site contains K100,000, 50,000, 20,000, 10,000, 5,000, 2,500, 1,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 3, 20, 10, 5, 4, 3, 2, or 1. d Then, combine them into VHL.

[0275] In some embodiments, the E3 ligase-binding moiety selectively binds to E3 ubiquitin ligase compared to another protein. In some embodiments, the E3 ligase-binding moiety selectively binds to cereblon compared to another protein. In some embodiments, the E3 ligase-binding moiety selectively binds to cereblon compared to another E3 ubiquitin ligase. In some embodiments, the E3 ligase-binding moiety selectively binds to VHL compared to another protein. In some embodiments, the E3 ligase-binding moiety selectively binds to VHL compared to another E3 ubiquitin ligase. In some embodiments, the selectivity is approximately 2 to 5 times. In some embodiments, the selectivity is approximately 5 to 10 times. In some embodiments, the selectivity is approximately 10 to 20 times. In some embodiments, the selectivity is approximately 20 to 50 times. In some embodiments, the selectivity is approximately 50 to 100 times. In some embodiments, the selectivity is approximately 100 to 200 times. In one aspect, the selectivity is approximately 200 to 500 times. In another aspect, the selectivity is approximately 500 to 1000 times. In another aspect, the selectivity is at least approximately 1000 times.

[0276] Further aspects of Equation I In one aspect, the compound represented by formula I is: [ka] During the ceremony: E is the E3 ubiquitin ligase binding site; L is N or CR 5 and; M is N or CR 6 and; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9This is hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; 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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 is hydrogen, -CH3, aryl, or heteroaryl; n is 0 to 12; and q is between 1 and 6; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 Can be replaced by alkyl)2, The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0277] In one embodiment of the compound represented by formula Ia, E is the E3 ubiquitin ligase binding site; L is N or CR 5 and; M is N or CR 6 and; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C)1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 5; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0278] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 6; Here, R 2 , R 3 , R 7 , and R 8One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0279] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination, or substitution, or non-substitution of C. 1-12 It is an alkylene, where one or more carbon atoms are optionally C(O), O, S, SO2, NH, or optionally a halogen, OH, or C 1-6 NC that can be substituted with alkyl 1-6 It may be replaced by an alkyl group; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 5; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0280] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 6; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0281] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, hydrogen, -N3, alkynyl, OH, halogen, NH2, N(C) 1-6 Alkyl)2, aryl, heteroaryl, or protecting group, where the aryl and heteroaryl are optionally halogens, SO2, NH2, or optionally halogens or C 3-8 C can be substituted with cycloalkyl groups. 1-6 Substitution with alkyl groups is also acceptable; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 5; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0282] In one embodiment, the compound represented by formula Ia L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(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 these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 6; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0283] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(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 of these independently represents hydrogen, OH, halogen, NH2, CH3, SO2, NO2, leaving group, protecting group, aryl, heteroaryl, NHR 12 , N(R 12 )2C 3-8 Cycloalkyl, N(R 12 )2 heterocyclyl, or -(CH2) n -R 12 and; R 12 However, it is hydrogen, -CH3, aryl, or heteroaryl; n is between 0 and 12; and q is between 1 and 5; Here, R 2 , R 3 , R 7 , and R 8 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0284] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(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 them is hydrogen; n is between 0 and 12; and q is between 1 and 6; Here, R 3 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0285] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(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 8However, it is hydrogen; n is between 0 and 12; and q is between 1 and 5; Here, R 3 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0286] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -A-(CH2) n -NR A -,-(CH2) n -A-NR A -, or -(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 Each of them is hydrogen; n is between 0 and 12; and q is between 1 and 6.

[0287] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -A-(CH2) n -NR A -,-(CH2) n -A-NR A -, or -(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 2 , R 7 , and R 8 Each of them is hydrogen; n is between 0 and 12; and q is between 1 and 5.

[0288] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -AO-(CH2) n -(C=O)NR A -or-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 6.

[0289] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -A-(CH2) n -NR A -and; A is a substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 6.

[0290] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -A-(CH2) n -NR A -and; A is a substituted or unsubstituted heteroarylene; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 5.

[0291] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(CH2) n -(C=O)NR A -and; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 6.

[0292] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -(CH2)n -(C=O)NR A -and; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 5.

[0293] In one embodiment of the compound represented by formula Ia, L, CR 5 and; M is N is; X is a combination; R 9 However, it is hydrogen; R 3 However, -AO-(CH2) n -(C=O)NR A -and; Each R 2 , R 7 , and R 8 However, it is hydrogen; n is between 0 and 12; and q is between 1 and 6.

[0294] In one aspect, the compound represented by formula I is: [ka] During the ceremony: E is the E3 ubiquitin ligase binding site; 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 between 1 and 6; Here, R 3 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 Can be replaced by alkyl groups. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0295] In one embodiment of the compound represented by formula Ib, E is the E3 ubiquitin ligase binding site; R 3 However, -(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 between 0 and 12; and q is between 1 and 5; Here, R 3 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0296] In one embodiment of the compound represented by formula Ib, R 3 However, -A-(CH2) n -NR A -,-(CH2) n -A-NR A -, or -(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 6.

[0297] In one embodiment of the compound represented by formula Ib, R 3 However, -A-(CH2) n -NR A -,-(CH2) n -A-NR A -, or -(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 5.

[0298] In one embodiment of the compound represented by formula Ib, R 3 However, -AO-(CH2) n -(C=O)NR A -or-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 6.

[0299] In one embodiment of the compound represented by formula Ib, R 3 However, -A-(CH2) n -NR A -and; A is a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 6.

[0300] In one embodiment of the compound represented by formula Ib, R 3 However, -A-(CH2) n -NR A -and; A is a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 5.

[0301] In one embodiment of the compound represented by formula Ib, R 3 However, -A-(CH2) n -NR A -and; A is a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 6.

[0302] In one embodiment of the compound represented by formula Ib, R 3 However, -(CH2) n -(C=O)NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0303] In one aspect, the compound represented by formula Ib is formula Ib-1: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 6, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0304] In one embodiment of the compound represented by formula Ib-1, E is the E3 ubiquitin ligase binding site; and q is 1 to 5.

[0305] In one aspect, the compound represented by formula Ib is formula Ib-2: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 6, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0306] In one embodiment of the compound represented by formula Ib-2, E is the E3 ubiquitin ligase binding site; and q is 1 to 5.

[0307] In one aspect, the compound represented by formula Ib is formula Ib-3: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 4, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0308] In one aspect, the compound represented by formula Ib is formula Ib-4: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 6, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0309] In one aspect, the compound represented by formula Ib is formula Ib-5: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 4, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0310] In one embodiment, the compound represented by formula I is: [ka] During the ceremony: E is the E3 ubiquitin ligase binding site; X 3 CR 15 or N; X 4 CR 15 or N; X 5 CR 15 or N; R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 between 1 and 6; Here, R 14 and R 15 One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 Can be replaced by alkyl)2, The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotope-enriched derivatives, or prodrugs.

[0311] In one form of equation Ic, E is the E3 ubiquitin ligase binding site; X 3 However, CR 15 or N; X 4 However, CR 15 or N; X 5 However, CR 15 or N; R 15Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 However, -(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 between 0 and 12; and q is between 1 and 5; Here, R14 and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0312] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NR A (C=O)O aryl, -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 However, -(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 between 0 and 12; and q is between 1 and 6; Here, R 14 and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0313] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each occurrence is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, -NR A (C=O)O alkyl, -NRA (C=O)O aryl, -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 However, -(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 between 0 and 12; and q is between 1 and 5; Here, R 14 and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0314] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -(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 between 0 and 12; and q is between 1 and 6; Here, R 14 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0315] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -(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 between 0 and 12; and q is between 1 and 5; Here, R 14 and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0316] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -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 between 0 and 12; and q is between 1 and 5; Here, R 14 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0317] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -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 between 0 and 12; and q is between 1 and 5.

[0318] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -A-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heterocycline; n is between 0 and 12; and q is between 1 and 5.

[0319] In one embodiment of the compound represented by formula Ic, X 3 However, CR 15 and; X 4 However, CR 15 and; X 5 However, N is; R 15 Each appearance is hydrogen; R 14 However, -AO-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heteroarylene; n is between 0 and 12; and q is between 1 and 6.

[0320] In one aspect, the compound represented by formula I is: [ka] During the ceremony: E is the E3 ubiquitin ligase binding site; 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 between 1 and 6; Here, R 14 or R 15 One or more carbon atoms can be any of the following: C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 Can be replaced by alkyl)2, The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0321] In one embodiment of the compound represented by formula Id, E is the E3 ubiquitin ligase binding site; R 14 However, -(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 between 0 and 12; and q is between 1 and 5; Here R 14 and R 15 One or more carbon atoms are optionally C(O), O, S, SO2, NH, NC 1-6 Alkyl, NH-C 1-6 Alkyl, NH2, or N(C) 1-6 It can be replaced by alkyl)2.

[0322] In one embodiment of the compound represented by 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 between 1 and 5; Here, R 14 One or more carbon atoms are optionally C(O), O, S, SO2, NH, or NC. 1-6 It can be replaced by alkyl groups.

[0323] In one embodiment of the compound represented by formula Id, R 14 However, -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 between 1 and 5.

[0324] In one embodiment of the compound represented by formula Id, R 14 However, -A-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heterocycline. n is 0 to 12; and q is between 1 and 5.

[0325] In a certain form represented by formula Id, R 14 However, -AO-(CH2) n -(C=O)NR A -and; A is a substituted or unsubstituted heteroarylene; N is between 0 and 12; and q is between 1 and 6.

[0326] In one aspect, a compound represented by formula Id is: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 6, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0327] In one embodiment of formula IdI, E is the E3 ubiquitin ligase binding site; and q is 1 to 5.

[0328] In one aspect, the compound represented by formula I is: [ka] During the ceremony, E is the E3 ubiquitin ligase binding site; R 20These are 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 These are independently hydrogen, or substituted or unsubstituted alkyl groups; n is 0 to 12; and q is between 1 and 5. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0329] In one embodiment of the compound represented by formula Ie, R 20 However, it is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 However, -(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 between 0 and 12; and q is between 1 and 5.

[0330] In one embodiment of the compound represented by formula Ie, R 20 However, it is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 22 However, -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0331] In one embodiment of the compound represented by formula Ie, R 20 However, it is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; R 22 However, -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0332] In one embodiment of the compound represented by formula Ie, R 20However, it is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted arylene or an unsubstituted heteroarylene; R 22 However, -(CH2) n -NR A -or-(CH2) n -(C=O)NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0333] In one embodiment of the compound represented by formula Ie, R 20 However, it is an unsubstituted alkyl, an alkyl substituted with one or more halogens or hydroxyl groups, an unsubstituted alkoxy, or an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted heteroarylene; R 22 However, -(CH2) n -NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0334] In one embodiment of the compound represented by formula Ie, R 20 However, it is an alkoxy substituted with one or more halogens or hydroxyl groups; G is an unsubstituted heteroarylene; R 22 However, -(CH2) n -NR A -and; n is between 0 and 12; and q is between 1 and 5.

[0335] In one embodiment, the compound represented by formula Ie is formula Ie-1: [ka] In the formula, R 20 The compound represented by is an alkoxy substituted with one or more halogen or hydroxyl groups; E is an E3 ubiquitin ligase binding site; and q is 1 to 5; or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

[0336] In one embodiment, the compound represented by formula Ie is formula Ie-2: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 5, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0337] In one embodiment, the compound represented by formula Ie is formula Ie-3: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 5.

[0338] In one aspect, the compound represented by formula I is, if: [ka] During the ceremony: E is the E3 ubiquitin ligase binding site; G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 These are halogen, -OH, -COOH, -SO3H, -NO2, -SH, -NRx R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 24 This includes unsubstituted alkylenes, alkylenes substituted with one or more halogens or hydroxyl groups, unsubstituted alkoxylenes, or alkoxylenes substituted with one or more halogens or hydroxyl groups; R x and R y is independently hydrogen, or a substituted or unsubstituted alkyl group; and q is 1 to 5. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0339] In one embodiment of the compound represented by formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24 However, these are unsubstituted alkylenes, alkylenes substituted with one or more halogens or hydroxyl groups, unsubstituted alkoxylenes, or alkoxylenes substituted with one or more halogens or hydroxyl groups; R x and R y These are independently hydrogen, or substituted or unsubstituted alkyl; and q is between 1 and 5.

[0340] In one embodiment of the compound represented by formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24However, these are substituted or unsubstituted alkylenes, or substituted or unsubstituted alkoxylenes; R x and R y However, these are independently hydrogen, or substituted or unsubstituted alkyl groups; and q is between 1 and 5.

[0341] In one embodiment of the compound represented by formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24 However, these are substituted or unsubstituted alkoxylenes; R x and R y However, these are independently hydrogen, or substituted or unsubstituted alkyl; and q is between 1 and 5.

[0342] In one embodiment of the compound represented by formula If, G is a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24 However, it is an alkoxylene substituted with one or more halogens or hydroxyl groups; R x and R y However, these are independently hydrogen, or substituted or unsubstituted alkyl; and q is between 1 and 5.

[0343] In one embodiment of the compound represented by formula If, G is a substituted or unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24 However, it is an alkoxylene substituted with one or more halogens or hydroxyl groups; R x and R y However, these are independently hydrogen, or substituted or unsubstituted alkyl; and q is between 1 and 5.

[0344] In one embodiment of the compound represented by formula If, G is an unsubstituted heteroarylene; R 23 However, -NR x R y and; R 24 However, it is an alkoxylene substituted with one or more halogens or hydroxyl groups; R x and R y However, these are independently hydrogen, or substituted or unsubstituted alkyl; and q is between 1 and 5.

[0345] In one aspect, a compound represented by formula If is given by formula If-1: [ka] Here, E is the E3 ubiquitin ligase binding site; G is the unsubstituted heteroarylene; R 23 -NR x R y And; R x and R y is independently hydrogen, or a substituted or unsubstituted alkyl group; and q is 1 to 5; the compound represented by is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug thereof.

[0346] In one aspect, the compound represented by formula If is: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 5, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0347] In one aspect, the compound represented by formula If is formula If-3: [ka] Here, E is the E3 ubiquitin ligase binding site; and q is 1 to 5, and the compound represented by this compound is a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0348] In one aspect, the compound represented by formula I is formula Ig: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 6. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0349] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 6. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0350] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 6. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0351] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 4. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0352] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is 1 to 4, and is a compound represented by or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug.

[0353] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 4. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0354] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 6. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0355] In one aspect, the compound represented by formula I is: [ka] During the ceremony: T is the tau protein binding site; and q is between 1 and 4. The compound represented by or its pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically concentrated derivatives, or prodrugs.

[0356] In one embodiment, the compound represented by formula I is a compound of Table 1 or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0357] In one embodiment, the compound represented by formula I is a compound of Table 2 or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug. [Table 2-1] [Table 2-2]

[0358] In one embodiment, the compound represented by formula I contains a radionuclide. In one embodiment, the compound represented by formula I is substituted with a radionuclide. In one embodiment, the compound represented by formula I is enriched with a radionuclide. In one embodiment, the compound represented by formula I is useful as a contrast agent (for example, for use in positron emission tomography). For example, radionuclides such as halogen atoms may be readily introduced into the compound using a variety of methods well known in the art. Consequently, the radiolabeled compound represented by formula I may be prepared using standard methods known in the art to prepare such radioactive compounds having specific substituents, wherein the compound is 11 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I, and 77It may also be incorporated by specific radionuclides selected from the group consisting of Br.

[0359] In some aspects, the compound represented by formula I contains tau protein with K at concentrations 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 They are joined together.

[0360] In some aspects, the compound represented by formula I binds to tau protein more selectively than another protein. In some aspects, the compound represented by formula I binds to tau protein more selectively than amyloid-beta. In some aspects, the selectivity is between approximately 2 and 5 times. In some aspects, the selectivity is between approximately 5 and 10 times. In some aspects, the selectivity is between approximately 10 and 20 times. In some aspects, the selectivity is between approximately 20 and 50 times. In some aspects, the selectivity is between approximately 50 and 100 times. In some aspects, the selectivity is between approximately 100 and 200 times. In some aspects, the selectivity is between approximately 200 and 500 times. In some aspects, the selectivity is between approximately 500 and 1000 times. In some aspects, the selectivity is approximately 1000 times.

[0361] In some aspects, the compound represented by formula I is an E3 ubiquitin ligase with K at concentrations 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 30 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 They are joined together.

[0362] In some aspects, the compound represented by formula I contains cereblon with K at concentrations 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 They are joined together.

[0363] In one aspect, the compound represented by formula I selectively binds to E3 ubiquitin ligase compared to another protein. In some aspects, the compound represented by formula I selectively binds to cereblon rather than another protein. In some aspects, the compound represented by formula I selectively binds to cereblon rather than another E3 ubiquitin ligase. In one aspect, the selectivity is between approximately 2 and 5 times. In one aspect, the selectivity is between approximately 5 and 10 times. In one aspect, the selectivity is between approximately 10 and 20 times. In one aspect, the selectivity is between approximately 20 and 50 times. In one aspect, the selectivity is between approximately 50 and 100 times. In one aspect, the selectivity is between approximately 100 and 200 times. In one aspect, the selectivity is between approximately 200 and 500 times. In one aspect, the selectivity is between approximately 500 and 1000 times. In one embodiment, the selectivity is at least about 1000 times.

[0364] In one aspect, the compound of formula I has concentrations 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, and 50 nM or less. At concentrations 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, it promotes the 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.

[0365] In one aspect, the compound represented by formula I has a methylnaturation 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, and 50 nM. The following concentrations 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 increase the rate of tau protein degradation 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 administrations This disclosure provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug, and optionally a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical compositions described herein comprise a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0367] In one embodiment, the compound of formula I is provided in an effective amount in a pharmaceutical composition. In one embodiment, the effective amount is a therapeutic effective amount. In one embodiment, the effective amount is a preventive effective amount. In one embodiment, the effective amount is an effective amount for treating a neurological disorder in a subject that needs it. In one embodiment, the effective amount is an effective amount for preventing a neurological disorder in a subject that needs it. In one embodiment, the effective amount is an effective amount for treating a neurodegenerative disease in a subject that needs it. In one embodiment, the effective amount is an effective amount for preventing a neurodegenerative disease in a subject that needs it. In one embodiment, the effective amount is an effective amount for treating tauopathy in a subject that needs it. In one embodiment, the effective amount is an effective amount for preventing tauopathy in a subject that needs it. In one embodiment, the effective amount is an effective amount for inhibiting the development of a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject that needs it.

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

[0369] In one embodiment, the effective amount is an amount effective in promoting the 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 the tau protein. In one embodiment, the effective amount is an amount effective in inhibiting the activity of the tau protein and / or promoting the degradation of MALT1, within the range (including both ends) between the percentages described in this paragraph and other percentages described in this paragraph.

[0370] This disclosure provides pharmaceutical compositions comprising compounds that interact with tau protein and / or E3 ubiquitin ligase (e.g., cereblon) for use in treating neurological disorders in subjects where such treatment is required. In one embodiment, the composition is for use in treating neurodegenerative diseases. In another embodiment, the composition is for use in treating tauopathy. In one embodiment, the composition is for use in treating primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. In another embodiment, the composition is for use in treating Alzheimer's disease.

[0371] Compounds or compositions as described herein may be administered in combination with one or more further pharmaceuticals (e.g., therapeutically and / or prophylactically active agents). Compounds or compositions may be administered in combination with further pharmaceuticals that improve their activity (e.g., potency and / or efficacy) in treating a disease in a subject that needs it, in preventing a disease in a subject that needs it, and / or reducing the risk of developing a disease in a subject that needs it), improve bioavailability and ability to cross the blood-brain barrier, improve safety, reduce drug resistance, reduce and / or regulate metabolism, inhibit elimination, and / or regulate distribution in a subject or cell. It will also be understood that the treatment used may achieve the desired effect for the same disorder, and / or it may achieve a different effect. In some embodiments, a pharmaceutical composition described herein, comprising a compound and a further pharmaceutical, exhibits a synergistic effect that is absent in a pharmaceutical composition containing one or both of the compound and / or the further pharmaceutical, but not both.

[0372] A compound or composition may be administered prior to or following one or more further pharmaceuticals, for example, as a combination therapy. Pharmaceuticals may include therapeutic activators. Pharmaceuticals may also include prophylactic activators. Pharmaceuticals may 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, further pharmaceuticals are pharmaceuticals useful for treating and / or preventing diseases (e.g., neurological disorders, neurodegenerative diseases, and / or tauopathies). Each further pharmaceutical may be administered in a dose and / or time schedule determined for that pharmaceutical. Further pharmaceuticals may 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 combinations used in a regimen will take into account the compatibility of the compounds described herein with the further pharmaceuticals, and / or the desired therapeutic and / or preventive effects to be achieved. Generally, the further pharmaceuticals in a combination are expected to be used at levels not exceeding those used individually. In some embodiments, the levels used in a combination will be lower than those used individually.

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

[0374] After being formulated in the desired dosage with appropriate pharmaceutically acceptable excipients, the pharmaceutical composition of the present invention can be administered to humans or other animals orally, parenterally, intracisorally, intraperitoneally, topically, buccally, etc., depending on the disease or condition being treated.

[0375] In one embodiment, a pharmaceutical composition comprising a compound of formula I is administered orally or parenterally over a day or several days (depending on the mode of administration) at dose levels of each pharmaceutical composition sufficient to deliver about 0.001 mg / kg to about 200 mg / kg in one or more doses. In one embodiment, to obtain the desired therapeutic and / or preventive effect, the effective dose per dose varies at least once daily, per kg of body weight per day, from about 0.001 mg to about 200 mg, from about 0.001 mg to about 100 mg, from about 0.01 mg to about 100 mg, from about 0.01 mg to about 50 mg, preferably from about 0.1 mg to about 40 mg, preferably from about 0.5 mg to about 30 mg, from about 0.01 mg to about 10 mg, and from about 0.1 mg to about 10 mg. In one embodiment, the compounds described herein may be at dose levels sufficient to deliver approximately 0.001 mg to approximately 200 mg, approximately 0.001 mg to approximately 100 mg, approximately 0.01 mg to approximately 100 mg, approximately 0.01 mg to approximately 50 mg, preferably approximately 0.1 mg to approximately 40 mg, preferably approximately 0.5 mg to approximately 30 mg, approximately 0.01 mg to approximately 10 mg, approximately 0.1 mg to approximately 10 mg, and more preferably approximately 1 mg to approximately 25 mg per kg of body weight per day, once or more daily, in order to obtain the desired therapeutic and / or preventive effect. The desired dose 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 one embodiment, the desired dose can be delivered using multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more doses). In one embodiment, the compositions described herein are administered at a dose lower than the dose at which the agent produces a nonspecific effect.

[0376] In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.001 mg to approximately 1000 mg per unit dose. In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.01 mg to approximately 200 mg per unit dose. In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.01 mg to approximately 100 mg per unit dose. In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.01 mg to approximately 50 mg per unit dose. In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.01 mg to approximately 10 mg per unit dose. In one embodiment, the pharmaceutical composition is administered in doses of approximately 0.1 mg to approximately 10 mg per unit dose.

[0377] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include the steps of combining a composition comprising a compound of formula I with a carrier and / or one or more other minor components, and then, if necessary and / or desirable, forming and / or packaging the product into desired single or multiple dose units.

[0378] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as single unit doses and / or as multiple single unit doses. As used herein, “unit dose” refers to a specific amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that will be administered to a subject, and / or a convenient fraction of such dose, such as half or one-third of such dose.

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

[0380] pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical composition include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavorings, and perfumering agents may also be present in the composition.

[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 gum, pectin, gelatin, egg yolk, casein, lanolin, tallow, cholesterol, wax, and lecithin), colloidal clay (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) Polyethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, 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, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 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)) Includes 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, sodium doxate, 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 rubbers (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucus, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), aluminum magnesium silicate (Veegum), and larch alabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, waxes, water, alcohols, and / or mixtures thereof.

[0385] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In one embodiment, the preservative is an antioxidant. In another embodiment, 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., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, 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, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury 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, tocopherol 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 buffers 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 oil, 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, blackcurrant seed, borage, cadet, chamomile, canola, caraway, carnauba, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, and more. This includes, but is not limited to, mon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ. 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 activator, the liquid dosage form may also contain, for example, inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl ethyl 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 fragrances. In one embodiment for parenteral administration, the agent of the present invention is mixed with a solubilizer such as CREMOPHOR EL® (polyethoxylated castor oil), alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and combinations thereof.

[0396] In preparations for injection, for example, sterile aqueous or oily suspensions for injection may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile preparations for injection may be sterile solutions, suspensions, or emulsions for injection in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer solution (USP), and isotonic sodium chloride solution. In addition, sterile fixatives have traditionally been employed as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic mono- or diglycerides, may be employed. Furthermore, fatty acids such as oleic acid are used in preparations for injection.

[0397] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that 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 activator is at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or expanders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, a silicate, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate. h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, are mixed with the agent. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0399] Similar types of solid compositions can also be used as fillers in soft or rigid filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifying agents and may have a composition that releases the active ingredient only at specific sites in the intestinal tract, or preferentially therein, in an optionally delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft or rigid filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0400] The activator may be in a microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared with coatings and casings, such as enteric coatings, controlled-release coatings, and other coatings known in the pharmaceutical field. In such solid dosage forms, the activator may be miscible with at least one inert diluent, such as sucrose, lactose, or starch. Such solid dosage forms may also, in common practice, contain additional substances other than the inert diluent, e.g., 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 buffers. They may optionally contain opacifiers and may consist of compositions that release only the active ingredient(s) or, preferentially, in a delayed manner in a portion of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0401] Suitable formulations 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 limit 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 the tissue surface. For example, hydroxypropylcellulose 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 intended to be within the scope of the present invention. In addition, this disclosure intends to provide transdermal patches, which have the further advantage of providing controlled delivery of the drug to the body. Such a dosage form can be prepared by dissolving or dispersing the drug in a suitable medium. Absorption enhancers can also be used to increase the flow of the drug across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the drug in a polymer matrix or gel.

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

[0403] Furthermore, this disclosure encompasses kits (e.g., medical packs). The kits provided may include the pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes, and / or dispenser packages, or other suitable containers). In some embodiments, the kits provided may optionally further include a second container containing pharmaceutical excipients for dilution or suspension of the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first container and the second container are combined to form a single unit dosage form.

[0404] Accordingly, in one aspect, what is provided is a kit comprising a first container containing a compound or pharmaceutical composition described herein. In one aspect, the kit is useful for treating a disease (e.g., neurological disorder, neurodegenerative disease, tauopathy) in a subject that needs it. In one aspect, the kit is useful for preventing a disease (e.g., neurological disorder, neurodegenerative disease, tauopathy) in a subject that needs it. In one aspect, the kit is useful for reducing the risk of developing a disease (e.g., neurological disorder, neurodegenerative disease, tauopathy) in a subject that needs it. In one aspect, the kit is useful for promoting the degradation of tau protein in a subject or cell. In one aspect, the kit is useful for imaging and / or detecting any neurological disorder in human tissue (e.g., through the use of a radiolabeled compound represented by formula I). ​​In one aspect, the kit is useful for promoting the degradation of tau protein in a subject or cell. In one aspect, the kit is useful for imaging and / or detecting neurological disorder in the central nervous system (e.g., through the use of a radiolabeled compound represented by formula I). In one embodiment, the kit is useful for promoting the degradation of tau protein in a target or cell. In one embodiment, 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 one embodiment, 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 one embodiment, 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 one embodiment, 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 required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescription information. In some embodiments, the kit and instructions provide treatment for a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject that needs it. In some embodiments, the kit and instructions provide prevention for a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject that needs it. In some embodiments, the kit and instructions provide mitigation of the risk of developing a disease (e.g., neurological disorder, neurodegenerative disease, or tauopathy) in a subject that needs it. In some embodiments, the kit and instructions provide acceleration of tau protein degradation in a subject or cell. In some embodiments, the kit and instructions provide diagnosis of neurological disorders in the central nervous system (e.g., through the use of a radiolabeled compound represented by formula I). In one embodiment, the kit and instructions provide imaging and / or detection of neurological disorders within the central nervous system (e.g., through the use of a radiolabeled compound represented by formula I). ​​In another embodiment, the kit and instructions provide imaging and / or detection of pathological aggregation of tau protein within the central nervous system (e.g., through the use of a radiolabeled compound represented by formula I). ​​The kits described herein may include, as separate compositions, one or more additional pharmaceuticals described herein.

[0406] Treatment method The primary neuropathological finding in postmortem examination of Alzheimer's disease (AD) is the detection of intracellular neurofibrillary tangles (NFTs) to confirm the presence of AD. NFTs originate from aggregated, hyperphosphorylated tau protein filaments. The presence and severity of NFTs are generally, but not always, correlated with the severity of dementia and cognitive impairment, and it has been shown that the pathological process of AD begins before the clinical symptoms of dementia and late-stage NFTs. Therefore, reduction and / or elimination of the abnormal tau species preceding NFTs or NFTs themselves, by tau proteolysis, is an attractive method for treating 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 ligase (cereblon, for example) provides a strategy for treating diseases associated with tau protein aggregation, also known as tauopathy.

[0408] This disclosure provides methods for treating neurological disorders. In some aspects, this application provides methods for treating neurodegenerative diseases. In some aspects, this application provides methods for treating tauopathy. In some aspects, this application provides methods for treating primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritiko-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. In some aspects, this application provides methods for treating Alzheimer's disease.

[0409] This disclosure provides methods for preventing neurological disorders. In one aspect, this application provides methods for preventing neurodegenerative diseases. In one aspect, this application provides methods for preventing tauopathy. In one aspect, this application provides methods for preventing primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. In one aspect, this application provides methods for preventing Alzheimer's disease.

[0410] In one embodiment, the present application provides a method for promoting the degradation of tau protein (for example, in cells). In one embodiment, the present application provides a method for promoting the degradation of tau protein in an object that requires it. In one embodiment, the present application provides a method for binding an E3 ubiquitin ligase and promoting the degradation of tau protein. In one embodiment, the target of the E3 ubiquitin ligase is cereblon.

[0411] In one embodiment, the method comprises administering to a subject in need thereof a compound that interacts with tau protein, such as a tau protein modifier, a tau protein binder, a tau protein modifying compound, or a compound that promotes the degradation of tau protein. The compound may also be an E3 ubiquitin ligase inhibitor, an E3 ubiquitin ligase modifier, an E3 ubiquitin ligase binder, an E3 ubiquitin ligase modifying compound, or a compound that interferes with the interaction between E3 ubiquitin ligase and another protein. In one embodiment, the method comprises administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug or composition thereof. In some embodiments, the method involves administering a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug, or composition thereof, to a subject requiring it.

[0412] This disclosure also provides compounds of formula I, or pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotope-enriched derivatives, or prodrugs or compositions thereof, for use in the treatment of neurological disorders. In one embodiment, the neurological disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is a tauopathy. In some embodiments, tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. In some embodiments, tauopathy is Alzheimer's disease.

[0413] This disclosure also provides the use of compounds of formula I, or pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotope-enriched derivatives, or prodrugs or compositions thereof, in the manufacture of pharmaceuticals for the treatment of neurological disorders. In one embodiment, the neurological disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is a tauopathy. In some embodiments, tauopathy is primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. In some embodiments, tauopathy is Alzheimer's disease.

[0414] In some embodiments, the methods of the present disclosure involve administering to a subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotope-enriched derivative, or prodrug or composition thereof. In some embodiments, the effective amount is a therapeutic effective amount. In some embodiments, the effective amount is a prophylactic effective amount.

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

[0416] Certain methods described herein may include administering one or more additional pharmaceuticals in combination with the compound described herein. The additional pharmaceuticals may be administered at the same time as the compound of formula I, or at a different time. For example, the compound of formula I and any additional pharmaceuticals may be on the same or different administration schedules. All or some doses of the compound of formula I may be administered before, after, or within the administration schedule of the additional pharmaceuticals, or a combination thereof. The timing of administration of the compound of formula I and the additional pharmaceuticals may differ for different additional pharmaceuticals.

[0417] In one embodiment, the additional pharmaceuticals include agents useful in the treatment of neurological disorders. In one embodiment, the additional pharmaceuticals are useful in the treatment of neurodegenerative diseases. In one embodiment, the additional pharmaceuticals are useful in the treatment of tauopathy. In one embodiment, the additional pharmaceuticals are useful in the treatment of primary age-related tauopathy (PART) / neurofibrillary tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chro...

Claims

1. Formula I: 【Chemistry 1】 During the ceremony: T is the tau protein binding site; Here, T is the formula 【Chemistry 2】 It is represented by; E is the ubiquitin ligase binding site, where E is group L, M, or N: Group L: 【Transformation 3】 or Group M: 【Chemistry 4】 or Group N: 【Transformation 5】 It is expressed as an expression selected from; 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)-, -NRC(=O)-, -NRC(=O)R Ａ Ａ Ａ Ａ Ａ Ａ Ａ ２ Ａ Ａ ２ ), -OC(=O)-, -OC(=O)O-, -OC(=O)N(R Ａ ), -S(O)NR ２ [[ID=​​​​​​ R Ａ Each appearance is, independently, a nitrogen protecting group when attached to hydrogen, a substituted or unsubstituted acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or two R atoms. Ａ The elements, when linked together, form a ring in a substituted or non-substituted heterocyclic formula. A compound represented by , or a pharmaceutically acceptable salt thereof.

2. L is a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene, or a substituted or unsubstituted heteroalkylene. Arbitrarily, L is from group J or group K: Group J: 【Transformation 6】 During the ceremony: q is between 1 and 12; u is between 1 and 12; p is between 1 and 10; and s is between 1 and 10; Furthermore, L may be, 【Transformation 7】 During the ceremony: q is between 1 and 5; p is 2 to 5; and s is between 1 and 5; or Group K: unsubstituted C ３ -C １２ Alkylene, or 【Transformation 8】 During the ceremony: q is between 1 and 12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

3. The compound belongs to group O, P, Q, R, S, or T: Group O: Formula Ig: 【Chemistry 9】 In the formula, T is as claimed in claim 1; and q is 1 to 6; or Group P: Formula Ih: 【Chemistry 10】 In the formula, T is as claimed in claim 1; and q is 1 to 6; or Group Q: Formula Ii: 【Chemistry 11】 In the formula, T is as claimed in claim 1; and q is 1 to 6; or Group R: Formula I-j: 【Chemistry 12】 In the formula, T is as claimed in claim 1; and q is 1 to 4; or Group S: Formula Ik: 【Chemistry 13】 In the formula, T is as claimed in claim 1; and q is 1 to 4; or Group T: Formula I-l: 【Chemistry 14】 In the formula, T is as claimed in claim 1; and q is 1 to 4; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

4. A radiolabeled compound comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein methods A, B, C and D: Method A: A method for promoting the degradation of tau protein in a subject requiring such degradation, wherein the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the subject; or Method B: A method for detecting neurological disorders, wherein the method comprises contacting a compound or a pharmaceutically acceptable salt thereof with a tissue; or Method C: A method for detecting pathological aggregation of tau protein, wherein the method comprises contacting a compound or a pharmaceutically acceptable salt thereof with a tissue; or Method D: A method for diagnosing neurological disorders in a subject, wherein the method comprises bringing a compound or a pharmaceutically acceptable salt thereof into contact with the tissue of the subject; Here, "tissue" can optionally refer to the tissue of the central nervous system, such as brain tissue. A compound or a pharmaceutically acceptable salt thereof for use in a method selected from the above.

7. The pharmaceutical composition according to claim 5, wherein methods A, B, C and D: Method A: A method for promoting the degradation of tau protein in a subject that requires it, wherein the method comprises administering a pharmaceutical composition to the subject; or Method B: A method for detecting neurological disorders, wherein the method comprises bringing a pharmaceutical composition into contact with a tissue; or Method C: A method for detecting pathological aggregation of tau protein, wherein the method comprises contacting a pharmaceutical composition with a tissue; or Method D: A method for diagnosing neurological disorders in a subject, wherein the method comprises bringing a pharmaceutical composition into contact with the tissue of the subject; Here, "tissue" can optionally refer to the tissue of the central nervous system, such as brain tissue. The pharmaceutical composition for use in a method selected from the following.

8. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, for use in a subject requiring the treatment of neurological disorders, Here, we arbitrarily define neurological disorders as neurodegenerative diseases. Furthermore, optionally, hereby, the neurodegenerative disease is tauopathy, and the tauopathy is primary age-related tauopathy (PART) / neurofibrillar tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. The aforementioned compound or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition according to claim 5, for use in a person requiring treatment for neurological disorders, Here, we arbitrarily define neurological disorders as neurodegenerative diseases. Furthermore, optionally, hereby, the neurodegenerative disease is tauopathy, and the tauopathy is primary age-related tauopathy (PART) / neurofibrillar tangle-dominant senile dementia, chronic traumatic encephalopathy, boxer's dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and chromosome 17-related parkinsonism, Ritico-Bodik disease, ganglioglioma, gangliocytoma, meningeal hemangioma, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, lead brain injury, tuberous sclerosis, Haller-Holden-Spats disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic granule disease. The aforementioned pharmaceutical composition.

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