US20210154184A1 - Compounds for tau protein degradation - Google Patents

Compounds for tau protein degradation Download PDF

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US20210154184A1
US20210154184A1 US16/630,294 US201816630294A US2021154184A1 US 20210154184 A1 US20210154184 A1 US 20210154184A1 US 201816630294 A US201816630294 A US 201816630294A US 2021154184 A1 US2021154184 A1 US 2021154184A1
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substituted
unsubstituted
compound
alkyl
pharmaceutically acceptable
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Nathanael S. Gray
Stephen J. Haggarty
Quan CAI
Tinghu Zhang
Maria Catarina Telo Baptista Lima da Silva
Fleur M. Ferguson
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General Hospital Corp
Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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Assigned to DANA-FARBER CANCER INSTITUTE, INC. reassignment DANA-FARBER CANCER INSTITUTE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAI, Quan, FERGUSON, Fleur M., GRAY, NATHANAEL S., ZHANG, TINGHU
Assigned to THE GENERAL HOSPITAL CORPORATION D/B/A MASSACHUSETTS GENERAL HOSPITAL reassignment THE GENERAL HOSPITAL CORPORATION D/B/A MASSACHUSETTS GENERAL HOSPITAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAGGARTY, STEPHEN J., TELO BAPTISTA LIMA DA SILVA, Maria Catarina
Assigned to DANA-FARBER CANCER INSTITUTE, INC. reassignment DANA-FARBER CANCER INSTITUTE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAI, Quan, FERGUSON, Fleur M., GRAY, NATHANAEL S., ZHANG, TINGHU
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates generally to bifunctional compounds that bind tau protein and promote its degradation via recruitment of an E3 ubiquitin ligase, and uses of the compounds in the treatment of neurological diseases (e.g., Alzheimer's disease).
  • neurological diseases e.g., Alzheimer's disease.
  • AD Alzheimer's disease
  • NFT neurofibrillary tangles
  • PROTAC proteolysis targeting chimeras; e.g., see U.S. Patent Application, U.S. Ser. No. 14/792,414, filed Jul. 6, 2015
  • E3 ubiquitin ligases are proteins that, in combination with an E2 ubiquitin-conjugating enzyme, promote the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond (e.g., an amide bond that is not present on the main chain of a protein).
  • the ubiquitination of the protein commonly results in degradation of the target protein by the proteasome.
  • AD Alzheimer's disease
  • PROTAC relies on a strategy of recruiting target protein to an E3 ubiquitin ligase and subsequently inducing proteasome-mediated degradation of the target protein.
  • the present disclosure describes the conjugation of tau binding moieties with an E3 ubiquitin ligase binding moiety (e.g., lenalidomide, thalidomide) to provide compounds that can induce the ubiquitination of tau protein and promote its degradation in cells.
  • E3 ubiquitin ligase binding moiety e.g., lenalidomide, thalidomide
  • the present disclosure stems from the recognition that the aggregation of tau protein, in particular hyperphosphorylated tau protein, causes certain neurological disorders (e.g., tauopathies such as AD), and that by targeting both tau protein, or any post-translationally modified form of tau, and recruiting an E3 ubiquitin ligase (e.g., Cereblon) to ubiquitinate the tau protein and mark it for proteasome degradation, a single bifunctional compound can promote the degradation of tau protein, thus providing new compounds, compostions, and methods for the treatment of neurological disease (e.g., tauopathies such as AD).
  • the present disclosure represents an important advance in the treatment of neurological disease, particularly tauopathies.
  • T is a tau protein binding moiety
  • E is an E3 ubiquitin ligase binding moiety
  • L is 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)—, —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 )—, —C( ⁇ O)—, —C( ⁇ O)O—, —
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • T is of Formula T-I:
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • P is N or CR 7 ;
  • Q is N or CR 8 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n S—, —(CH 2 ) n -A—S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each of R 1 , R 2 , and R 4 -R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 1-8 wherein one or more carbon of R 1-8 is optionally replaced with C(O), O, S, SO 2 , NH, NH—C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • P is N or CR 7 ;
  • Q is N or CR 8 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n S—, —(CH 2 ) n -A-—S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each of R 1 , R 2 , and R 4 -R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 1-8 wherein one or more carbon of R 1-8 is optionally replaced with C(O), O, S, SO 2 , NH, NH—C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • T is of formula T-II:
  • X 1 is CH, N, NH, O, or S;
  • X 2 is CH, C, or N
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • X 1 is CH, N, O, or S
  • X 2 is CH, C, or N
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n A-O—, —(CH 2 ) n S-—-A-(CH 2 ) n S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A-(C ⁇ O)NR A —, —(CH 2 ) n -A-(C ⁇ O)NR A —, —(CH 2 ) n -A-(C ⁇ O)NR A —,
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • T is of formula T-III or T-IV:
  • R 20 and R 21 are independently halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 22 is —(CH 2 ) n —O—, —(CH 2 ) n —S—, —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, or —(CH 2 ) n —S(O) 2 NR A —;
  • R 23 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 24 is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl
  • n 0-12;
  • t 0, 1, 2, 3, or 4;
  • r 0, 1, or 2.
  • E is a cereblon E3 ubiquitin ligase binding moiety or a VHL E3 ubiquitin ligase binding moiety.
  • E is a cereblon E3 ubiquitin ligase binding moiety.
  • Exemplary compounds of Formula I include, but are not limited to:
  • radiolabeled compounds comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.
  • compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a neurological disorder in a subject in need thereof, the method comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, to the subject.
  • the neurological disorder is a neurodegenerative disease.
  • the neurodegenerative disease is a tauopathy (e.g. Alzheimer's disease).
  • a neurological disorder comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, with a tissue.
  • a method of detecting pathological aggregation of tau protein in tissue comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, with a tissue.
  • kits for diagnosing a neurological disorder in a subject comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, with a tissue of the subject.
  • compositions comprising a compound of Formula I, for use in treating a neurological disorder in a subject in need thereof; and/or promoting the degradation of tau protein.
  • kits comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.
  • the kit further comprises instructions for administration (e.g., human administration) and/or use.
  • FIG. 1A is a series of western blot stains showing the effect of exemplary compounds on levels of tau protein in a human tau-A152T neuronal model, after 24 h treatment.
  • FIG. 1B is a series of bar graphs quantifying the total tau and hyperphosphorylated tau from the western blots in FIG. 1A . These figures demonstrate the significant tau lowering effects of the exemplary compounds, but not lenalinomide, a CRBN-only binding compound.
  • FIG. 2A is a series of western blot stains showing the effect of exemplary compounds on levels of tau protein in a human tau-P301L neuronal model, after 24 h treatment.
  • FIG. 2B is a series of bar graphs quantifying the total tau and hyperphosphorylated tau from the western blots in FIG. 2A . These figures demonstrate the significant tau lowering effects of the exemplary compounds, but not lenalinomide, a CRBN-only binding compound.
  • FIG. 3 is a series of western blot stains showing the effect of T807, a known tau-binding compound, on levels of tau protein 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 lowering activity of T807 was observed in either cell line.
  • FIG. 4A is a series of western blot stains showing the effect of exemplary compounds on levels of E3 ubiquitin ligases Cereblon (CRBN), von Hippel-Lindau tumor suppressor (VHL), and C terminus of HSC70-Interacting Protein (CHIP) in human tau-A152T and tau-P301L neurons, after 24 h treatment.
  • FIG. 4B is a series of bar graphs quantifying CRBN from the western blots in FIG. 4A ; CRBN levels in the tau-A152T neurons are on the left (medium grey bars) and CRBN levels in the tau-P301L neurons are on the right (black bars).
  • FIG. 4A is a series of western blot stains showing the effect of exemplary compounds on levels of E3 ubiquitin ligases Cereblon (CRBN), von Hippel-Lindau tumor suppressor (VHL), and C terminus of HSC70-Interacting Protein (CHIP) in human tau-A152T
  • FIG. 4C is a series of bar graphs quantifying total tau from the western blots in FIG. 4A ; Tau5 (total tau) levels in the tau-A152T neurons are on the left (medium grey bars) and Tau5 levels in the tau-P301L neurons are on the right (black bars).
  • FIG. 4D is a series of bar graphs quantifying CHIP from the western blots in FIG. 4A ; CHIP levels in the tau-A152T neurons are on the left (medium grey bars) and CHIP levels in the tau-P301L neurons are on the right (black bars).
  • FIG. 4E is a series of bar graphs quantifying VHL from the western blots in FIG. 4A ; VHL levels in the tau-A152T neurons are on the left (medium grey bars) and VHL levels in the tau-P301L neurons are on the right (black bars).
  • FIG. 5A is a series of western blot stains showing the effect of exemplary compounds on levels of tau protein in human non-mutant (control), human tau-A152T, and human tau-P301L neurons at 6 weeks of differentiation.
  • FIG. 5B is a series of bar graphs quantifying total tau, hyperphosphorylated tau (upper graphs), and CRBN (bottom graphs) from the western blots in FIG. 5A .
  • FIG. 5C is a series of bar graphs quantifying total tau, hyperphosphorylated tau (upper graphs), and CRBN (bottom graphs) from an average of three experiments of the western blots as represented in FIG. 5A .
  • FIG. 6A is a series of western blot stains showing the effect of exemplary compounds in 6-week differentiated human tau-A152T neurons.
  • FIG. 6B is a series of bar graphs quantifying total tau, hyperphosphorylated tau, and CRBN from the western blots in FIG. 6A .
  • FIG. 7 is a bar graph quantifying the results of neuronal cell viability assays for the ability of exemplary compounds to provide protection from toxic stimuli associated with neurodegeneration, here chosen to be ⁇ -amyloid (1-42) peptide, as a functional readout of having effectively degraded tau (at 8 weeks of differentiation).
  • ⁇ -amyloid (1-42) peptide As shown by Silva et al. ( Stem Cell Reports, 2016, 7(3), 325-40; doi: 10.1016/j.stemcr.2016.08.001) reduction of viability due to ⁇ -amyloid (1-42) exposure is dependent on tau.
  • Left schematic of experimental design, right, graph of viability.
  • FIG. 8A is a series of western blot stains showing the effect of exemplary compounds and T-807 on levels of tau protein in a human tau-A152T neuronal model, after 24 h treatment.
  • the control is a non-mutant neuron (8330-8-RC1).
  • FIG. 8B is a series of graphs quantifying the total tau and hyperphosphorylated tau from the western blots in FIG. 8A .
  • FIG. 9A is a series of western blot stains showing the effect of exemplary compounds and T-807 on levels of tau protein in a human tau-P301L neuronal model, after 24 h treatment.
  • the control is a non-mutant neuron (CTR2-L17-RC2).
  • FIG. 9B is a series of graphs quantifying the total tau and hyperphosphorylated tau from the western blots in FIG. 9A .
  • FIG. 10 is a series of bar graphs quantifying the total tau and hyperphosphorylated tau from the western blots in FIGS. 8A and 9A .
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3 - 4 , C 4 - 6 , C 4-5 , and C 5-6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 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”).
  • 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 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., —CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
  • the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g.,
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). Examples of haloalkyl groups include —CHF 2 , —CH 2 F, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CF 2 CF 2 CF 3 , —CCl 3 , —CFCl 2 , —CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-18 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within 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 within the parent chain (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within 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 within the parent chain (“heteroC 1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
  • each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC 1-20 alkyl.
  • the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
  • the heteroalkyl group is a substituted heteroC 1-20 alkyl.
  • the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C 2-10 alkenyl.
  • the alkenyl group is a substituted C 2-10 alkenyl.
  • a C ⁇ C double bond for which the stereochemistry is not specified e.g., —CH ⁇ CHCH 3 or
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 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 within the parent chain (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 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 within the parent chain (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”).
  • an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is an unsubstituted C 2-10 alkynyl.
  • the alkynyl group is a substituted C 2-10 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”).
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 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 within the parent chain (“heteroC 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 within the parent chain (“heteroC 2-4 alkynyl”).
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 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 within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”).
  • a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4-
  • 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 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C 6-14 aryl.
  • the aryl group is a substituted C 6-14 aryl.
  • Alkyl is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • unsaturated or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which may 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).
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X ⁇ , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C( ⁇ O)R aa , —CO 2 H, —CHO, —C(OR cc ) 3 , —CO 2 R aa , —C( ⁇ O)R aa , —OCO 2 R aa , —C( ⁇ O)N(R bb ) 2 , —C( ⁇ O)N(Rbb) 2 , —NR bb C( ⁇
  • each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR 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
  • each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R CC groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —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 , —CO 2 H, —CO 2 R ee , —OC( ⁇ O)R ee , —OCO 2 R ee , —C( ⁇ O)N(R ff ) 2 , —OC( ⁇ O)N(R ff ) 2 , —NR ff C( ⁇ O)R ee , —NR ff CO 2 R ee , —NR
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1 -6 alkyl, —ON(C 1-6 alkyl), —N(C 1-6 alkyl), —N(C 1-6 alkyl) 3 + X ⁇ , —NH(C 1-6 alkyl) 2 + X ⁇ , —NH 2 (C 1-6 alkyl) + X ⁇ , —NH 3 + 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), —CO 2 H, —CO 2 (C 1-6 alkyl), —C( ⁇ O)(C 1-6 alky
  • halo or halogen refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).
  • hydroxyl refers to the group —OH.
  • substituted hydroxyl or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from —OR aa , —ON(R bb ) 2 , —OC( ⁇ O)SR aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —OC( ⁇ O)N(R bb ) 2 , —OC( ⁇ NR bb )R aa , —OC( ⁇ NR bb OR aa , —OC( ⁇ NR bb )N(R bb ) 2 , —OS( ⁇ O)R aa , —OSO 2 R aa , —OSi(R aa ) 3 , —OP(
  • amino refers to the group —NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • the term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from —NH(R bb ), —NHC( ⁇ O)R aa , —NHCO 2 R aa , —NHC( ⁇ O)N(R bb ) 2 , —NHC( ⁇ NR bb )N(R bb ) 2 , —NHSO 2 R aa , —NHP( ⁇ O)(OR cc ) 2 , and —NHP( ⁇ O)(N(R bb ) 2 ) 2 , wherein R aa , R bb and R cc are as defined herein, and wherein R bb of the group —NH(R bb ) is not hydrogen.
  • disubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from —N(R bb ) 2 , —NR bb C( ⁇ O) R aa , —NR bb CO 2 R aa , —NR bb C( ⁇ O)N(R bb ) 2 , —NR bb C( ⁇ NR bb )N(R bb ) 2 , —NR bb SO 2 R aa , —NR bb P( ⁇ O)(OR cc ) 2 , and —NR bb P( ⁇ O)(N(R bb ) 2 ) 2 , wherein R aa , R bb , and R cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from —N(R bb ) 3 and —N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from —SO 2 N(R bb ) 2 , —SO 2 R aa , and —SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • sulfinyl refers to the group —S( ⁇ O)R aa , wherein R aa is as defined herein.
  • acyl refers to a group having the general formula —C( ⁇ O)R X1 , —C( ⁇ O)OR X1 , —C( ⁇ O)—O—C( ⁇ O)R X1 , —C( ⁇ O)SR X1 , —C( ⁇ O)N(R X1 ) 2 , —C( ⁇ S)R X1 , —C( ⁇ S)N(R X1 ) 2 , —C( ⁇ S)O(R X1 ), —C( ⁇ S)S(R X1 ), —C( ⁇ NR X1 )R X1 , —C( ⁇ NR X1 )OR X1 , —C( ⁇ NR x1 )SR X1 , and —C(—NR X1 )N(R X1 ) 2 , wherein R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl;
  • acyl groups include aldehydes (—CHO), carboxylic acids (—CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • carbonyl refers a group wherein the carbon directly attached to the parent molecule is sp 2 hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., —C( ⁇ O)R aa ), carboxylic acids (e.g., —CO 2 H), aldehydes (—CHO), esters (e.g., —CO 2 R aa , —C( ⁇ O)SR aa , —C( ⁇ S)SR aa ), amides (e.g., —C( ⁇ O)N(R bb ) 2 , —C( ⁇ O)NR bb SO 2 R aa , —C( ⁇ S)N(R bb ) 2 ), and imines (e.g., —C( ⁇ NR bb )R aa , —C( ⁇ NR bb )OR aa , —C( ⁇
  • sil refers to the group —Si(R aa ) 3 , wherein R aa is as defined herein.
  • oxo refers to the group ⁇ O
  • thiooxo refers to the group ⁇ S.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR bb )R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • Nitrogen protecting groups include, but are not limited to, —OH, —OR aa , —N(R cc ) 2 , —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , C( ⁇ NR cc )R aa , —C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R cc ) 2 , —C( ⁇ O)SR cc , —C( ⁇
  • Nitrogen 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, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • nitrogen protecting groups such as amide groups (e.g., —C( ⁇ O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitro
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,1 0-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), p-toluenesulfonamide (
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4
  • a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (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).
  • Bn benzyl
  • BOC tert-butyloxycarbonyl
  • Cbz carbobenzyloxy
  • Fmoc 9-flurenylmethyloxycarbony
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen protecting groups include, but are not limited to, —R aa , —N(R bb ) 2 , —C( ⁇ O)SR aa , —C( ⁇ O)R aa , —CO 2 R 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 , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 + X ⁇ , —P(OR cc
  • Oxygen 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, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-meth
  • an oxygen protecting group is silyl.
  • an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetra
  • the substituent 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 , —CO 2 R 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 , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 + X ⁇ , —P(OR c
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
  • a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ), NO 3 ⁇ , ClO 4 ⁇ , OH ⁇ , H 2 PO 4 ⁇ , HCO 3 , HSO 4 ⁇ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 ⁇
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry 6th ed. (501-502).
  • Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, Cl, Br, or I (iodine
  • the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs),p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS( ⁇ O) 2 (CF 2 ) 3 CF 3 (nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf).
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • phosphineoxide e.g., formed during a Mitsunobu reaction
  • an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC( ⁇ O)SR aa , —OC( ⁇ O)R aa , —OCO 2 R aa , —OC( ⁇ O)N(R bb ) 2 , —OC( ⁇ NR bb )R aa , —OC( ⁇ NR bb )OR aa , —OC( ⁇ NR bb )N(R bb ) 2 , —OS( ⁇ O)R aa , —OSO hd 2 R aa , —OP(R cc ) 2 , —OP(R cc ) 3 , —OP( ⁇ O) 2 R aa , —OP( ⁇ O)(R aa ) 2 , —OP( ⁇ O)(OR
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 ⁇ salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R.x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R.2 H 2 O) and hexahydrates (R.6 H 2 O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5 H 2 O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R.2 H 2 O) and hexahydrates (R.6 H 2 O)
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 7-12 substituted aryl, and C 7-12 arylalkyl esters of the compounds described herein may be preferred.
  • composition and “formulation” are used interchangeably.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • the term “patient” refers to a human subject in need of treatment of a disease.
  • the subject may also be a plant.
  • the plant is a land plant.
  • the plant is a non-vascular land plant.
  • the plant is a vascular land plant.
  • the plant is a seed plant.
  • the plant is a cultivated plant.
  • the plant is a dicot.
  • the plant is a monocot.
  • the plant is a flowering plant.
  • the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet.
  • the plant is a legume, e.g., a bean plant, e.g., soybean plant.
  • the plant is a tree or shrub.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • tissue refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered.
  • a tissue may be an abnormal or unhealthy tissue, which may need to be treated.
  • a tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.
  • the tissue is the central nervous system.
  • the tissue is the brain.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • a “therapeutically effective amount” of a compound described herein is 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.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for tau protein binding and/or promoting the degradation of tau protein.
  • a therapeutically effective amount is an amount sufficient for treating a neurological disorder (e.g., AD).
  • a therapeutically effective amount is an amount sufficient for tau protein binding and/or promoting the degradation of protein and treating a neurological disorder (e.g., AD).
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for tau protein binding and/or promoting the degradation of tau protein.
  • a prophylactically effective amount is an amount sufficient for treating a neurological disorder (e.g., AD).
  • a prophylactically effective amount is an amount sufficient for tau protein binding and/or promoting the degradation of tau protein and treating a neurological disorder (e.g., AD).
  • neurological disorder refers to any disorder, disease, or condition of the nervous system.
  • tau protein refers to a class of proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.
  • the tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau) and is located on chromosome 17.
  • MAPT microtubule-associated protein tau
  • Tau protein described herein include all post-translationally modified forms of the protein.
  • tauopathy refers to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain.
  • Primary tauopathies i.e., conditions in which neurofibrillary tangles (NFT) are predominantly observed, include, but are not limited to, primary age-related tauopathy (PART)/neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden
  • biological refers to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins.
  • Biologics may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues.
  • Biologics may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.
  • small molecule or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight.
  • a small molecule is an organic compound (i.e., it contains carbon).
  • the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e g , amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
  • the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
  • the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
  • the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
  • the small molecule may also be complexed with one or more metal atoms and/or metal ions.
  • the small molecule is also referred to as a “small organometallic molecule.”
  • Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents.
  • the small molecule is a drug.
  • the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
  • therapeutic agent refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect.
  • therapeutic agents may treat, ameliorate, and/or prevent disease.
  • therapeutic agents, as disclosed herein, may be biologics or small molecule therapeutics.
  • E3 ubiquitin ligase or “E3 ligase” refers to any protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 protein to the protein substrate.
  • bifunctional compounds that bind tau protein and recruit an E3 ligase (e.g., Cereblon) to promote the degradation of tau protein.
  • E3 ligase e.g., Cereblon
  • the disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof
  • the compounds are useful for the treatment and/or prevention of diseases associated with tau protein aggregation (e.g., tauopathies (e.g., AD)) in a subject in need thereof.
  • tauopathies e.g., AD
  • the compounds described herein interact with tau protein and an E3 ubiquitin ligase (e.g., Cereblon).
  • the therapeutic effect may be a result of degradation, modulation, binding, or modification of tau protein by a compound described herein.
  • the therapeutic effect may be the result of modulation, targeting, binding, or modification of an E3 ubiquitin ligase (e.g., Cereblon) by a compound described herein.
  • the therapeutic effect may be a result of recruitment of an E3 ubiquitin ligase (e.g., Cereblon) by modulation, targeting, binding, or modification of the E3 ubiquitin ligase to ubiquitinate tau protein and mark it for proteasomal degradation, by a compound.
  • E3 ubiquitin ligase e.g., Cereblon
  • a compound may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • T is a tau protein binding moiety
  • E is an E3 ubiquitin ligase binding moiety
  • L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, —O—, —N(R A )—, —S—, —C( ⁇ O)—, —C( ⁇ O)O—, —C( ⁇ O)NR A —, —NR A C( ⁇ O)—, —NR A C( ⁇ O)R A —, —C( ⁇ O)R A —, —NR A C( ⁇ O)O—, —NR A C( ⁇ O)N(R A )—, —OC( ⁇ O)—, —OC( ⁇ O)O—,
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • T is any tau protein binding moiety. In certain embodiments, T is any tau protein binding moiety derived from the tau protein binding compounds described in U.S. Patent Applications, U.S. Ser. No. 13/447,095, filed May 22, 2012; U.S. Ser. No. 13/035,405, filed Feb. 25, 2011; U.S. Ser. No. 13/881,872, filed Oct. 28, 2011; U.S. Ser. No. 09/378,662, filed Aug. 20, 1999; and U.S. Ser. No. 14/346,914, filed Mar. 24, 2014, each of which is incorporated herein by reference.
  • T is of Formula T-I:
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • P is N or CR 7 ;
  • Q is N or CR 8 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl, optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n A—(C
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each of R 1 , R 2 , and R 4 -R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 1-8 wherein one or more carbon of R 1-8 is optionally replaced with C(O), O, S, SO 2 , NH, NH—C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alk Y 1 ) 2 .
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • P is N or CR 7 ;
  • Q is N or CR 8 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl, optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each of R 1 , R 2 , and R 4 -R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 1-8 wherein one or more carbon of R 1-8 is optionally replaced with C(O), O, S, SO 2 , NH, NH-C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • L is N or CR 5 ; M is N or CR 6 ; P is CR 7 ; and Q is CR 8 . In certain embodiments, L is CR 5 ; M is N or CR 6 ; P is CR 7 ; and Q is CR 8 . In certain embodiments, L is CR 5 ; M is N; P is CR 7 ; and Q is CR 8 .
  • X is a bond
  • R 9 is hydrogen
  • R 3 is —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —.
  • R 3 is —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —NR A —, or —(CH 2 ) n -A-NR A —.
  • R 3 is —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or —(CH 2 ) n -A—(C ⁇ O)NR A —; and A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A-(C ⁇ O)NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or —(CH 2 ) n -A—(C ⁇ O)NR A -—; and A is substituted or unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A-(C ⁇ O)NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is substituted or unsubstituted heteroarylene.
  • R 3 is -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, or —(CH 2 ) n —(C ⁇ O)NR A —; and A is substituted or unsubstituted heteroarylene.
  • R 3 is -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is substituted or unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-(CH 2 ) n —NR A —. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is -A-(CH 2 ) n —NR A —.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-(CH 2 ) n —NR A —; and A is unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is -A-(CH 2 ) n —NR A —; and A is unsubstituted heteroarylene. In certain embodiments, R 3 is -A-(CH 2 ) n —NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene.
  • each of R 1 , R 2 , and R 4 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ; and R 12 is hydrogen, —CH 3 , aryl, or heteroaryl.
  • each of R 1 , R 2 , and R 4 are independently hydrogen.
  • T is of Formula T-I-a:
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ).—O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each R 2 , R 7 , and R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 2 , R 3 , R 7 , and R 8 is optionally replaced with C(O), O, S, SO 2 , NH, NH-C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • L is N or CR 5 ;
  • M is N or CR 6 ;
  • X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl optionally substituted with halogen, OH, or C 1-6 alkyl;
  • R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • each R 2 , R 7 , and R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
  • R 12 is hydrogen, —CH 3 , aryl, or heteroaryl
  • n 0-12;
  • R 2 , R 3 , R 7 , and R 8 is optionally replaced with C(O), O, S, SO 2 , NH, NH—C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • T is of Formula T-I-b:
  • R 3 is —(CH 2 ) n —O—, -A4(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n
  • R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A—NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O
  • R 3 is —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —.
  • R 3 is —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —NR A —, or —(CH 2 ) n -A-NR A —.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-(CH 2 ) n —NR A —. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A — or -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is —(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 3 is -A-(CH 2 ) n —NR A —. In certain embodiments, R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —NR A —, or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-(CH 2 ) n —NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-(CH 2 ) n —NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-(CH 2 ) n —NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene.
  • R 3 is —(CH 2 ) n —(C ⁇ O)NR A - or -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In certain embodiments, R 3 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene.
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of Formula T-II:
  • X 1 is CH, N, NH, O, or S;
  • X 2 is CH, C, or N
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —; —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —; —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —; —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • X 1 is CH, N, O, or S
  • X 2 is CH, C, or N
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n -(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • X 1 and X 2 are N.
  • At least one of X 3 , X 4 , or X 5 is N.
  • X 5 is N; and X 3 and X 4 are CH.
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —.
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —.
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —; and A is unsubstituted heterocyclylene.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heterocyclylene.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted piperidinylene or piperazinylene. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene.
  • T is of Formula T-II-a:
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) N -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 )
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH—C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • X 3 is CR 15 or N
  • X 4 is CR 15 or N
  • X 5 is CR 15 or N
  • each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C ⁇ O)Oalkyl, —NR A (C ⁇ O)Oaryl, —NR A (C ⁇ O)alkyl, —NR A (C ⁇ O)aryl, —(C ⁇ O)Oalkyl, —(C ⁇ O)Oaryl, —(C ⁇ O)alkyl, —(C ⁇ O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n -(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O
  • A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • n 0-12;
  • R 13 , R 14 , and R 15 are optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
  • T is of Formula T-II-b:
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n —
  • R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, —(CH 2 ) n —S—, -A-(CH 2 ) n S—, —(CH 2 ) n -A-S—, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR A —, —(CH 2 ) n -A—(C ⁇ O)NR
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, -A-O—(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —.
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —.
  • R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C ⁇ O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —; and A is unsubstituted heterocyclylene.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heterocyclylene.
  • R 14 is -A-(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted piperidinylene or piperazinylene. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted heteroarylene.
  • R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene, pyrimidinylene, or pyridazinylene. In certain embodiments, R 14 is -A-O—(CH 2 ) n —(C ⁇ O)NR A —; and A is unsubstituted pyridinylene.
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of formula T-III or T-IV:
  • each of R 20 and R 21 is independently halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 22 is —(CH 2 ) n —O—, —(CH 2 ) n —S—, —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, or —(CH 2 ) n —S(O) 2 NR A —;
  • R 23 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 24 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkoxylene;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl
  • n 0-12;
  • t 0, 1, 2, 3, or 4;
  • r 0, 1, or 2.
  • T is of formula T-III:
  • R 20 and R 21 are independently halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 22 is —(CH 2 ) n —O—, —(CH 2 ) n —S—, —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O)NR A —, or —(CH 2 ) n —S(O) 2 NR A —;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl
  • n 0-12;
  • t 0, 1, 2, 3, or 4;
  • r 0, 1, or 2.
  • T is of formula T-III-a:
  • R 20 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 22 is —(CH 2 ) n —O—, —(CH 2 ) n —S—, —(CH 2 ) n —NR A —, —(CH 2 ) n —(C ⁇ O) NR A —, or —(CH 2 ) n —S(O) 2 NR A —;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl
  • n 0-12.
  • R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups;
  • G is unsubstituted arylene or unsubstituted heteroarylene; and
  • R 22 is —(CH 2 ) n —NR A - or —(CH 2 ) n —(C ⁇ O)NR A —.
  • R 2 ° is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups;
  • G is unsubstituted arylene or unsubstituted heteroarylene; and
  • R 22 is —(CH 2 ) n —NR A —.
  • G is unsubstituted arylene. In certain embodiments, G is unsubstituted phenylene. In certain embodiments, G is unsubstituted heteroarylene. In certain embodiments, G is unsubstituted pyridinylene, pyrimidinylene, pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or thiazolylene. In certain embodiments, G is unsubstituted pyridinylene or pyrazolinylene. In certain embodiments, G is unsubstituted pyridinylene. In certain embodiments, G is unsubstituted phenylene, pyridinylene, or pyrazolinylene.
  • R 2 ° is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups;
  • G is unsubstituted arylene or unsubstituted heteroarylene; and
  • R 22 is —(CH 2 ) n —NR A - or —(CH 2 ) n —(C ⁇ O)NR A —.
  • R 20 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is —(CH 2 ) n —NR A - or —(CH 2 ) n —(C ⁇ O)NR A —.
  • R 20 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is —(CH 2 ) n —NR A - or —(CH 2 ) n —(C ⁇ O)NR A —.
  • R 20 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is —(CH 2 ) n —NR A —.
  • R 20 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is —(CH 2 ) n —NR A —.
  • R 20 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 is —(CH 2 ) n —NR A —.
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of formula T-IV:
  • R 21 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 23 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 24 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkoxylene;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl
  • r 0, 1, or 2.
  • T is of formula T-IV-a:
  • G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 23 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R 24 is substituted or unsubstituted alkylene, or substituted or unsubstituted alkoxylene;
  • R x and R y are independently hydrogen, or substituted or unsubstituted alkyl.
  • R 24 is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups;
  • G is unsubstituted arylene or unsubstituted heteroarylene; and
  • R 23 is NR x R y .
  • G is unsubstituted arylene. In certain embodiments, G is unsubstituted phenylene. In certain embodiments, G is unsubstituted heteroarylene. In certain embodiments, G is unsubstituted pyridinylene, pyrimidinylene, pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or thiazolylene. In certain embodiments, G is unsubstituted pyridinylene or pyrazolinylene. In certain embodiments, G is unsubstituted pyridinylene. In certain embodiments, G is unsubstituted phenylene, pyridinylene, or pyrazolinylene.
  • R 24 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y .
  • R 24 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y .
  • R 24 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y .
  • R 24 is
  • G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y .
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • T is of the formula:
  • the tau binding moiety binds tau protein with a K d 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.
  • the tau binding moiety selectively binds tau protein over another protein.
  • the compound of Formula I selectively binds tau protein over amyloid ⁇ .
  • the selectivity is between about 2-fold and about 5-fold. In certain embodiments, the selectivity is between about 5-fold and about 10-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.
  • L is a divalent moiety linking T and E.
  • L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, —O—, —N(R A )—, —S—, —C( ⁇ O)—, —C( ⁇ O)O—, —C( ⁇ O)NR A —, —NR A C( ⁇ O)—, —NR A C( ⁇ O)R A —, —C( ⁇ O)R A —, —NR A C( ⁇ O)O—, —NR A C( ⁇ O)N(R A )—, —OC
  • L is any “L” group recited in U.S. Patent Application, U.S. Ser. No. 14/792,414, filed Jul. 6, 2015, which is incorporated herein by reference.
  • L is any “Linker” group recited in U.S. Patent Application, U.S. Ser. No. 14/707,930, filed May 8, 2015, which is incorporated herein by reference.
  • L comprises up to 50 atoms, excluding hydrogen atoms.
  • L comprises up to 40 atoms, excluding hydrogen atoms.
  • L comprises up to 30 atoms, excluding hydrogen atoms.
  • L comprises up to 20 atoms, excluding hydrogen atoms.
  • L comprises up to 15 atoms, excluding hydrogen atoms. In certain embodiments, L comprises up to 12 atoms, excluding hydrogen atoms. In certain embodiments, L comprises up to 10 atoms, excluding hydrogen atoms. In certain embodiments, L comprises up to 9 atoms excluding hydrogen atoms. In certain embodiments, L comprises up to 6 atoms excluding hydrogen atoms. In certain embodiments, L comprises up to 5 atoms excluding hydrogen atoms. In certain embodiments, L comprises up to 3 atoms excluding hydrogen atoms. In certain embodiments, any of the carbon atoms in L can be substituted.
  • L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene.
  • L is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In certain embodiments, L is a substituted or unsubstituted C 1-30 alkylene. In certain embodiments, L is a substituted or unsubstituted C 1-20 alkylene. In certain embodiments, L is a substituted or unsubstituted C 1-10 alkylene. In certain embodiments, L is a substituted or unsubstituted C 1-30 heteroalkylene. In certain embodiments, L is a substituted or unsubstituted C 1-20 heteroalkylene. In certain embodiments, L is a substituted or unsubstituted C 1-10 heteroalkylene.
  • L is N
  • L is N
  • L is N
  • L is N
  • L is
  • L is
  • L is
  • L is
  • L is
  • L is N
  • L is
  • L is N
  • p is 1-10; and s is 1-10.
  • L is
  • L is
  • L is an unsubstituted C 3 -C 12 alkylene or
  • L is an unsubstituted C 3 -C 12 alkylene or
  • L is an unsubstituted C 4 -C 12 alkylene or
  • L is an unsubstituted C 4 -C 10 alkylene or
  • L is an unsubstituted C 5 -C 7 alkylene or
  • L is an unsubstituted C 5 -C 7 alkylene or
  • L is N
  • L is
  • L is an unsubstituted C 3 -C 12 alkylene. In certain embodiments, L is an unsubstituted C 4 -C 12 alkylene. In certain embodiments, L is an unsubstituted C 4 -C 10 alkylene. In certain embodiments, L is an unsubstituted C 5 -C 7 alkylene. In certain embodiments, L is an unsubstituted C 3 alkylene. In certain embodiments, L is an unsubstituted C 4 alkylene. In certain embodiments, L is an unsubstituted C 5 alkylene. In certain embodiments, L is an unsubstituted C 6 alkylene.
  • L is an unsubstituted C 7 alkylene. In certain embodiments, L is an unsubstituted C 8 alkylene. In certain embodiments, L is an unsubstituted C 9 alkylene. In certain embodiments, L is an unsubstituted C 10 alkylene. In certain embodiments, L is an unsubstituted C 11 alkylene. In certain embodiments, L is an unsubstituted C 12 alkylene.
  • R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • R A is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • R A is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-30 heteroalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
  • R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-30 heteroalkyl.
  • R A is, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-20 heteroalkyl. In certain embodiments, R A is, independently, hydrogen, or substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is, independently, hydrogen.
  • E is an E3 ubiquitin ligase binding moiety.
  • E is inclusive of all moieties that bind, or can bind, any E3 ubiquitin ligase.
  • E is capable of binding an E3 ubiquitin ligase, such as Cereblon or von Hippel-Lindau tumor suppressor (VHL).
  • E is capable of binding to multiple different E3 ubiquitin ligases.
  • E binds to Cereblon.
  • E binds to VHL.
  • CRBN Human Cereblon
  • Human CRBN contains the N-terminal part (237-amino acids from 81 to 317) of ATP-dependent Lon protease domain without the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites.
  • CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocyte, colon, brain, and retina.
  • CRBN is located in the cytoplasm, nucleus, and peripheral membrane.
  • Cereblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins.
  • DDB1 DNA binding protein 1
  • CUL4A Cullin-4A
  • ROC1 regulator of cullins 1
  • This complex ubiquitinates a number of other proteins.
  • Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10).
  • FGF8 fibroblast growth factor 8
  • FGF10 fibroblast growth factor 10
  • E is a modulator, binder, inhibitor, or ligand of Cereblon. In certain embodiments, E is a modulator of Cereblon. In certain embodiments, E is a binder of Cereblon. In certain embodiments, E is an inhibitor of Cereblon. In certain embodiments, E is a ligand of Cereblon. In certain embodiments, E is any modulator, binder, inhibitor, or ligand of Cereblon disclosed in U.S. Patent Application, U.S. Ser. No. 14/792,414, filed Jul. 6, 2015, U.S. Patent Application, U.S. Ser. No.
  • E is a modulator, binder, inhibitor, or ligand of a Cereblon variant. In certain embodiments, E is a modulator, binder, inhibitor, or ligand of a Cereblon isoform.
  • E comprises a heteroaryl ring. In certain embodiments, E comprises a fused bicyclic heteroaryl ring. In certain embodiments, E comprises a fused bicyclic heteroaryl ring and a heterocyclic ring. In certain embodiments, E comprises a phthalimido group, or an analogue or derivative thereof. In certain embodiments, E comprises a phthalimido-glutarimide group, or an analogue or derivative thereof.
  • E is of Formula E-I:
  • A is a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl ring;
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (C ⁇ O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • A is a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl ring;
  • Y is —(CH 2 ) k -——(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —(CH 2 ) k —O—, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—.
  • Y is —(CH 2 ) k —NR B —, —(CH 2 ) k —O—, or —NR B (C ⁇ O)—(CH 2 ) k —O—.
  • Y is —(CH 2 ) k —NH—.
  • Y is —NH—.
  • Y is —(CH 2 ) k —O—.
  • Y is —O—.
  • Y is —NH(C ⁇ O)—(CH 2 )—O—.
  • Y is —NH—, —O—, or —NH(C ⁇ O)—(CH 2 )—O—.
  • E is of Formula E-II or E-III:
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (C ⁇ O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 - C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • E is of formula E-II:
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (C ⁇ O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • E is of Formula E-II-a:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • E is of Formula E-II-b:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • E is of Formula E-II-c:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • E is of Formula E-II-d:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • E is of formula E-II-e:
  • X A is C(O) or C(R 3A ) 2 ;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-e-1:
  • X A is C(O) or C(R 3A ) 2 ;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-e-1:
  • X A is C(O) or C(R 3A ) 2 ;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-f:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-f-1:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-f-2:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-g:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-g-1:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-II-g-2:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of Formula E-III:
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (C ⁇ O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 3 ′ is, independently, C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3;
  • n 1 or 2.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —(CH 2 ) k —O—, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—.
  • Y is —(CH 2 ) k —NR B —, —(CH 2 ) k —O—, or —NR B (C ⁇ O)—(CH 2 ) k —O—.
  • Y is —(CH 2 ) k -NH—.
  • Y is —NH—.
  • Y is —(CH 2 ) k —O—.
  • Y is —O—.
  • Y is —NH(C ⁇ O)—(CH 2 )—O—.
  • Y is —NH—, —O—, or —NH(C ⁇ O)—(CH 2 )—O—.
  • E is of formula E-III-a:
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (C ⁇ O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X l -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —O(CH 2 ) k —NR B (C ⁇ O)—, —NR B (CH 2 ) k —NR B (C ⁇ O)—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, 2 or 3.
  • E is of formula E-III-b:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • E is of formula E-III-c:
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, —NR B (C ⁇ O)—(CH 2 ) k —O—, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • Y is —(CH 2 ) k —NR B —, —O(CH 2 ) k —(C ⁇ O)NR B —, or —(CH 2 ) k —NR B (C ⁇ O)—;
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
  • k 0, 1, 2, 3, 4, 5, or 6.
  • E is of formula E-III-d:
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-III-d-1:
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-III-d-2:
  • X 1 -X 2 is C(R 3A ) ⁇ N or C(R 3A ) 2 —C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-III-e:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-III-e-1:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is of formula E-III-e-2:
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl.
  • E is thalidomide, lenalidomide, pomalidomide, CC-885 (Matyskiela et al., Nature 2016, 535, 252-257), 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yppiperidine-2,6-dione, or an analogue or derivative thereof.
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • VHL The von Hippel-Lindau tumor suppressor
  • VHL comprises the substrate recognition subunit/E3 ubiquitin ligase complex VCB, which includes elongins B and C, and a complex including Cullin-2 and Rbxl.
  • the primary substrate of VHL is Hypoxia Inducible Factor 1 ⁇ (HIF-1 ⁇ ), a transcription factor that upregulates genes, such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine, erythropoietin, in response to low oxygen levels.
  • HIF-1 ⁇ Hypoxia Inducible Factor 1 ⁇
  • VEGF the pro-angiogenic growth factor
  • cytokine red blood cell-inducing cytokine
  • erythropoietin erythropoietin
  • VHL von Hippel-Lindau tumor suppressor protein
  • VHL has two main structural domains: an N-terminal domain composed mainly of ⁇ -sheets ( ⁇ -domain) and a smaller C-terminal domain between amino acids 155-192 composed mainly of ⁇ helices ( ⁇ -domain).
  • the ⁇ -domain consists of three a helices that combines with a fourth ⁇ helix donated by elongin C.
  • the ⁇ -domain is on the opposite side of the a domain and is free to contact other protein.
  • E is a modulator, binder, inhibitor, or ligand of VHL. In certain embodiments, E is a modulator of VHL. In certain embodiments, E is a binder of VHL. In certain embodiments, E is an inhibitor of VHL. In certain embodiments, E is a ligand of Cereblon. In certain 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 certain embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL variant.
  • E is a modulator, binder, inhibitor, or ligand of a VHL isoform. In certain embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL gene-product (e.g., pVHL19).
  • VHL gene-product e.g., pVHL19
  • E comprises a peptide backbone structure. In certain embodiments, E is of the formula:
  • R 5 is a heteroaryl ring
  • R 6 is hydrogen or C 1 -4 alkyl.
  • R 5 is a 5-membered heteroaryl ring comprising at least one nitrogen.
  • R 5 is substituted or unsubstituted oxazolinyl, or substituted or unsubstituted thiazolinyl.

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