Bifunctional molecules for degradation of extracellular proteins in the brain

Abstract

The present disclosure provides compositions and methods for degrading receptors located in the brain for treating, ameliorating, and or preventing a variety of neurodegenerative diseases, neurological disorders, or tauopathies in a subject.

Description

[0001] TITLE OF THE INVENTION

[0002] Bifunctional Molecules for Degradation of Extracellular Proteins in the Brain

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Patent Application No. 63 / 590,101 entitled "BIFUNCTIONAL MOLECULES FOR DEGRADATION OF EXTRACELLULAR PROTEINS IN THE BRAIN." filed October 13, 2023 and U.S. Provisional Patent Application No. 63 / 696,461 entitled "BIFUNCTIONAL MOLECULES FOR DEGRADATION OF EXTRACELLULAR PROTEINS IN THE BRAIN," filed September 19, 2024, the disclosures of which are incorporated herein by reference in their entireties.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under HR00112120014 awarded by the Defense Advanced Research Projects Agency and under GM067543 awarded byNational Institutes of Health. The government has certain rights in the invention.

[0007] SEQUENCE LISTING

[0008] This application includes an electronic sequence listing in an XML file titled “047162-7473WO1 Sequence Listing.xmU’ created October 11. 2024, having a file size of 87,834 bytes, the contents of which is hereby incorporated by reference in its entirety.

[0009] BACKGROUND

[0010] Many neurological diseases are associated with accumulation of pathogenic proteins, and removal of these species could impact disease progression. While the movement of small molecules across the blood-brain barrier is possible through diffusion, larger molecules can access the brain using only receptor-mediated transcytosis, adsorption-mediated transcytosis, or transport proteins. To overcome this barrier, brain-targeting peptides capable of facilitating receptor-mediated transcytosis are needed for transport of larger cargo.

[0011] There is an unmet need in delivering degradation therapies to the brain. The present disclosure solves this unmet need.

[0012] BRIEF SUMMARY

[0013] In one aspect, a compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (I) is provided: wherein:

[0014] R is independently at each occurrence: i) — (L)P— A — RBT, wherein:

[0015] RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 50, wherein the brain targeting peptide is connected to A by its C-terminal or N-terminal amino acid; ii) — (L)P— X, wherein:

[0016] X is a brain targeting ligand; iii) — (L)p— H; or iv) — (L)p— EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;

[0017] L is independently at each occurrence a chemical linker;

[0018] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;

[0019] RAis independently at each occurrence H,

[0020] RNis independently at each occurrence H or

[0021] G is independently at each occurrence R, NHR, CH2R, C(=O)R, C(=O)OR.

[0022] Z is independently at each occurrence CH2 or C(=O);

[0023] R’ is independently at each occurrence H or R; p is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and n is independently at each occurrence 1, 2. 3, 4, 5, or 6.

[0024] Compounds of formula (I) are useful in methods of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or atauopathy in a subject. In certain embodiments, the methods include administering to the subject in need thereof a therapeutically effective amount of a compound of the disclosure and / or of a composition comprising a compound of the disclosure and at least one pharmaceutically acceptable excipient or carrier. The disease or disorder is at least one of primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

[0025] In one aspect, a compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (II) is provided: formula (II), wherein:

[0026] Cy represents a ring selected from the group consisting of a six-membered aromatic ring, a six-membered heteroaromatic ring, a seven-membered carbocyclic ring, a sevenmembered heterocyclic ring, an eight-membered carbocyclic ring, and an eight-membered heterocyclic ring;

[0027] Z1 is a six-membered aromatic or heteroaromatic ring fused to ring Cy. optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br. I, OR". 0C(0)N(R")2, CN, NO, NO2, ONO2, CF3, OCF3, R", N(R")2, SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, 0C(0)N(R")2, C(S)N(R")2, (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(0)N(R")2, N(R")SO2R". N(R")SO2N(R")2, N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(O)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";

[0028] Z2 is N-R4 or NH-R4, wherein one of the following applies: i) if Cy is a six-membered aromatic or heteroaromatic ring, NH-R4 is a substituent on Cy; ii) if Cy is a seven-membered carbocyclic ring, then NH-R4 is a substituent on

[0029] Cy; iii) if Cy is a seven-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy; iv) if Cy is an eight-membered carbocyclic ring, then NH-R4 is a substituent on Cy; v) if Cy is an eight-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy;

[0030] Z3 is at least one substituent on Cy selected from the group consisting of F, Cl, Br, I, OR", OC(O)N(R")2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R", O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R")2, SR", SOR", SO2R", SO2N(R")2, SOsR". C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, OC(O)N(R")2, C(S)N(R")2. (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(0)N(R")2, N(R")SO2R", N(R")SO2N(R")2. N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(0)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R"; R" is independently at each occurrence H or Ci-io hydrocarbyl; q is 0, 1, 2, 3. 4, or 5: w is 0, 1, or 2;

[0031] Y is — (L)P— A — RBT, wherein: i) RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1-50, wherein the brain targeting peptide is connected to A through its C-terminal or N-terminal amino acid; or ii) — (L)P— X, wherein X is a brain targeting ligand;

[0032] R4 is — (L)P— EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;

[0033] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;

[0034] L is independently at each occurrence a chemical linker; and p is independently at each occurrence an integer from 0 to 40. Compounds of formula (II) are useful in methods of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or atauopathy in a subject. In certain embodiments, the methods include administering to the subject in need thereof a therapeutically effective amount of a compound of the disclosure and / or a composition comprising a compound of the disclosure and at least one pharmaceutically acceptable excipient or carrier. The disease or disorder is at least one of primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration. Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

[0035] BRIEF DESCRIPTION OF THE FIGURES

[0036] The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

[0037] FIG. 1 illustrates pharmacokinetic aspects of compounds of the disclosure, in accordance with various embodiments. Uptake of tetrameric or monomeric streptavidin using biotin-tetrameric or biotin-monomeric Angiopep-2 in mouse brain endothelial cells, bEnd.3.

[0038] FIG. 2 is a cartoon depiction of various configurations of compounds of the disclosure, in accordance with various embodiments. Schematic representation of the four combinations of biotinylated Angiopep-2 and streptavidin assessed in FIG. 1.

[0039] FIG. 3 is a structure of a biotin analog of a compound of the disclosure.

[0040] FIG. 4 is a structure of a biotin analog of a compound of the disclosure.

[0041] FIG. 5 shows fluorescence spectra of model compounds according to various embodiments. Uptake of tetrameric streptavidin using biotin-monomeric and biotintetrameric Angiopep-2 in human hepatocytes, HepG2.

[0042] FIG. 6 shows fluorescence spectra of model compounds according to various embodiments. Uptake of anti-DNP antibody using DNP-monomeric and DNP -tetrameric Angiopep-2 with additional controls lacking DNP or Angiopep-2 in human hepatocytes, HepG2.

[0043] FIG. 7 is a structure of a compound of the disclosure, according to various embodiments.

[0044] FIG. 8 is a structure of a compound of the disclosure, according to various embodiments.

[0045] FIG. 9 is a structure of a compound of the disclosure, according to various embodiments.

[0046] FIG. 10 is a structure of a compound of the disclosure, according to various embodiments.

[0047] FIG. 11 shows transcytosis of MoDE across the blood brain barrier followed by endocytosis of a target protein. Upon internalization the MoDE facilitates either receptor- mediated transcytosis or lysosomal trafficking of the target protein.

[0048] FIG. 12 shows the impact of endocytosis inhibitors on uptake of anti-DNP antibody by DNP-tetrameric Angiopep-2 to assess mechanism of internalization.

[0049] FIG. 13 shows there is no competition with receptor associated protein, a LRP1 ligand, during DNP-tetrameric Angiopep-2 mediated uptake of anti-DNP antibody.

[0050] FIGs. 14A-14D shows the LysoLgBit assay demonstrating internalization and lysosomal localization of anti-DNP antibody in HepG2-LgBit cells using DNP-tetrameric Angiopep-2. FIGs. 15A-15C show lysosomal localization and degradation of anti-DNP antibody in cell lysate of human hepatocytes, HepG2.

[0051] FIGs. 16A-16B show the results of mechanistic studies to characterize tetrameric MoDE mediated endocytosis. Competition with excess biotin-tetrameric Angiopep-2 and excess DNP core prevent uptake of anti-DNP antibody by DNP-tetrameric Angiopep-2.

[0052] FIG. 17 is a schematic representation of TfR-targeting TransMoDEs (targeted Transcytosis Molecular Degraders of Extracellular) proteins facilitate removal of target cargo in the brain through lysosomal degradation and transcytosis across blood-brain barrier, in accordance with various embodiments.

[0053] FIGs. 18A-18E show various aspects of molecular docking and SPR measurements to determine the preferred modification site for TfR-targeting TransMoDEs. (FIG. 18 A) Proposed co-structure of TfR (Dark Green) and T12 (Black). The binding pocket (red frame) exhibits optimal size and favorable interactions for T12. Inset: Zoomed-in view of the molecular interaction between T12 and TfR. (Light Blue dashed line indicating hydrogen bonding.) (FIG. 18B and FIG. 18C) SPR illustrated significantly difference in binding behavior between N-azido tagged T12 (101) (FIG. 18B) and C-azido tagged T12 (102) (FIG. 18C). (FIG. 18D) Corresponding plot of normalized response at steady state against concentration demonstrate 101 binds more tightly than 102. (FIG. 18E) Fitted affinity constants from both steady-state and kinetics measurements align with sensorgram observations.

[0054] FIGs. 19A-19D shows TfR-targeting TransMoDEs mediated the uptake of streptavidin AF-647 and a-DNP AF-488 in hcMEC / Ds cells across both concentration- and time-dependent course. (FIG. 19A, FIG. 19B) Flow cytometry analysis reveals that TfR- targeting TransMoDEs modified with biotin (FIG. 19A) and DNP (FIG. 19B) facilitated concentration-dependent internalization of streptavidin (50 nM) and a-DNP (50 nM) at 24 hours. (FIG. 19C, FIG. 19D) Flow cytometry analysis indicates time-dependent uptake of 50 nM streptavidin and a-DNP mediated by 1000 nM biotinylated TransMoDEs 103-105 (FIG. 19C) and 5000 nM DNP-modified TransMoDEs 106. Data are presented as mean ± standard deviation of the change in Median Fluorescence Intensity (AMF1) relative to media control and normalized against no peptide control; n=6 over tw o independent experiments. Significance was determined using ordinary' one-w ay ANOVA for FIG. 19A, FIG. 19B, and FIG. 19C with Dunnetf s multiple comparison test against 101 and unpaired t-test (FIG. 19D). (P0.0001 “****”, PO.001 “***”, PO.01 “**7 P<0.05 “*” and P>0.05iLns”).

[0055] FIGs. 20A-20E show- a mechanistic study of TfR-targeting TransMoDEs-mediated uptake. Both excess monovalent ligand (FIG. 20A) as well as a-TfR. (FIG. 20B) significantly suppressed target cargo internalization (50 nM streptavidin and 50 nM a-DNP) mediated by 1000 nM biotinylated TransMoDEs 103-105 and 5000 nM DNP-modified TransMoDEs 106, respectively, at 24 hours. (FIG. 20C) At 24 hours, HeLa -TfR KO cells (dash) show no uptake of both target 50 nM streptavidin and 50 nM a-DNP whereas the parental HeLa cells (solid) exhibited time-dependent uptake of the cargos upon the addition of 1000 nM biotinylated TransMoDEs 103-105 and 5000 nM DNP-modified TransMoDEs 106, respectively. (FIG. 20D, FIG. 20E) Endocytosis inhibitors related to clathrin (Dark yellow), and actin polymerization (light yellow) significantly reduce the level of mediated-uptake, while inhibitors related to caveolae (light blue), and micropinocytosis (light green) do not significantly influence the uptake of either 50 nM streptavidin mediated by 1000 nM TransMoDE 105 (FIG. 20D), or 50 nM a-DNP mediated by 5000 nM TransMoDE 106 (FIG. 20E). (FIG. 20A-FIG. 20C) Data are presented as mean ± standard deviation of the change in Median Fluorescence Intensity (AMFI) relative to media control and normalized against no peptide control; n=6 over two independent experiments. (FIG. 20D, FIG. 20E) Data are presented as mean ± standard deviation, normalized against no inhibitor control as 100% and no TransMoDE as 0%; n=6 over two independent experiments. Significance was determined using a Kruskal-Wallis nonparametric test P0.0001 “****”, P<0.001 “***”, P<0.01 P<0.05 and P>0.05 "ns" as compared to the No Inhibitor control for (FIG. 20D) and (FIG. 20E).

[0056] FIGs. 21A-21F show TfR-targeting TransMoDEs induce lysosomal internalization and degradation of target cargo. (FIG. 21A and FIG. 21B) Confocal microscopy shows that streptavidin-AF488 (100 nM) and a-DNP AF-488 (100 nM) colocalize with lysotracker AF- 647 under 1000 nM TransMoDE 105 (FIG. 21A) and 5000 nM TransMoDE 106 (FIG. 21B), with Pearson coefficient of 0.64 for (FIG. 21 A) and 0.73 for (FIG. 21B). Images are representative of n=3 from two independent experiments. (FIG. 21 C and FIG. 2 IE) Representative western blots of cell lysates under the same dosing condition as microscopy demonstrate appearance of streptavidin degradation bands (FIG. 21C) and a-DNP degradation band at later time points (FIG. 21E). Top panel shows a-AF488 antibody and bottom panel shows a-P tubulin antibody. (FIG. 21D and FIG. 21F) Quantifications of streptavidin (FIG. 21D) and a-DNP degradation band (FIG. 21F). Data are presented as mean ± standard deviation (n=3). Significance was determined using one-way ANOVA in comparison with the no TransMoDEs control, with PO.OOOl “****” p<0.001 “***”, P<0.01 P<0.05 “*” and P>0.05 “ns”.

[0057] FIGs. 22A-22E show TfR-targeting TransMoDEs facilitate bi-directional transcytosis of streptavidin (50 nM) across an in vitro BBB model. (FIG. 22A) Schematic representation of the transwell assay. (FIG. 22B-FIG. 22E) Time course plot of streptavidin concentration in the basal (FIG. 22B) and apical (FIG. 22D) compartment illustrates that TransMoDE 105 (1000 nM) facilitates a higher level of transcytosis compared to TransMoDE 108 (1000 nM). (FIG. 22C and FIG. 22E) TransMoDE 105 induces significantly higher effective permeability constant (Pe) for streptavidin in both apical to basal and basal to apical direction compared to conditions than when there is only streptavidin or TransMoDE 108 added. Data are presented as mean ± standard deviation; n=6 from two independent experiments. Significance was determined using one-way ANOVA in comparison with +TransMoDE 105, with P0.0001 “****”, PO.001 “***”, P<0.01 “**”, P .05 and P>0.05 “ns”.

[0058] FIGs. 23A-23C show SPR illustrated nanomolar affinity and 1 :2 binding behavior of unmodified T12 (99) to TfR. (FIG. 23 A) Reference subtracted sensorgram response of 99 at increasing concentrations. (FIG. 23B) Corresponding plot of normalized corresponding blank-subtracted steady state response. (FIG. 23C) Fitted affinity constants from both steadystate and kinetics measurements agree with each other in the nM range.

[0059] FIGs. 24A-24B show previously reported TransMoDEs showed concentrationdependent significant uptake of 50 nM streptavidin-AF647 (FIG. 24A) with biotinylated TransMoDE 108 but no uptake for 50 nM a-DNP-AF488 (FIG. 24B) with DNP-modified TransMoDE 110 at 24h in comparison to negative control 109. Data are presented as mean ± standard deviation of the AMedian Fluorescence Intensity (MFI) relative to media control and normalized against no peptide control; n=6 over two independent experiments. Significance was determined using unpaired t-test (A) to 109. (P<0.0001 “****”, PO.001 “***”, P .01 “**”, PO.05 and P>0.05 “ns”).

[0060] FIG. 25 shows TfR (~85 kDa) expression in cell line lysates, with rh-TfR (1 ng) as the positive control. From left to right: hCMEC / Ds, HeLa, HeLa (TfR KO), and rh-TfR.

[0061] FIG. 26 shows biotinylated TransMoDEs (103-105. 1000 nM)-mediated internalization of streptavidin (50 nM) was not influenced by increasing concentration of N- azo-tagged T12 (102), whereas DNP -modified TransMoDEs (106) demonstrated reduced uptake of a-DNP (50 nM) with the presence of 102. Data are presented as mean ± standard deviation of the AMedian Fluorescence Intensity (MFI) relative to media control and normalized against no peptide control; n=6 over two independent experiments. FIGs. 27A-27B show TfR-targeting TransMoDEs-mediated internalization of both streptavidin (50 nM) (FIG. 27A) and a-DNP (50 nM) (FIG. 27B) were not influenced by transferrin. Biotinylated TransMoDEs were added at 1000 nM (FIG. 27A) whereas DNA- modified TransMoDEs were added at 5000 nM (FIG. 27B). Data are presented as mean ± standard deviation of the AMedian Fluorescence Intensity (MFI) relative to media control and normalized against no peptide control; n=6 over two independent experiments.

[0062] FIGs. 28A-28B show that the Pitsop negative, the negative control of clathrin inhibitor pitstop 2, does not inhibit TransMoDE-mediated endocytosis of either streptavidin (FIG. 28A) or a-DNP (FIG. 28B). Data are presented as mean ± standard deviation, with normalization against no inhibitor as 100% and no TransMoDE as 0%; n=6 over two independent experiments. Significance was determined using a Kruskal-Wallis nonparametric test P0.0001 “****”, PC0.001 “***”, P<0.01 P<0.05 “*” and P>0.05 “ns” as compared to the No Inhibitor control for both (A&B).

[0063] FIGs. 29A-29B are images of confocal microscopy that showed AF488 streptavidin (FIG. 29A) and AF488 a-DNP (FIG. 29B) have no correlation with AF647 lysotracker without the addition of TfR-targeting TransMoDEs 105 and 106, respectively. Images are representative of n=3 from two independent experiments, with Pearson coefficient = 0.14 for (FIG. 29A) and 0.4 for (FIG. 29B).

[0064] FIGs. 30A-30B are images of replicate experiments of confocal microscopy that showed AF488 streptavidin have correlation with AF647 lysotracker with the addition of TransMoDE 108. Images are representative of n=3 from two independent experiments, with Pearson coefficient = 0.81 for (FIG. 30A) and 0.83 for (FIG. 30B).

[0065] FIGs. 31A-31B show that confocal microscopy of only the cell sample demonstrates the absence of autofluorescence in the 488 channel. Images are representative of n=3 from two independent experiments.

[0066] FIGs. 32A-32B show replicated experiments of confocal microscopy showed AF488 streptavidin have strong correlation with AF647 lysotracker with the addition of TransMoDE 105 while small to no correlation was observed when no TransMoDE was added.

[0067] FIGs. 33A-33B show replicated experiments of confocal microscopy showed AF488 a-DNP have strong correlation with AF647 lysotracker with the addition of TransMoDE 106 while small to no correlation was observed when no TransMoDE was added.

[0068] FIGs. 34A-34C show TfR-targeting TransMoDEs induce time-dependent uptake and degradation of streptavidin in hcMEC / Ds cell lysates. (FIG. 34A-FIG. 34C) Replicates of western blots show uptake and degradation of AF488 streptavidin (lOOnM) over the 24h time course mediated by TransMoDE 105. Top panel shows a-AF488 antibody and bottom panel shows a-P tubulin antibody.

[0069] FIGs. 35A-35B show quantification of the streptavidin dimer and monomer bands from western blot studies shows significance uptake at 24h mediated by TransMoDE 105. Data are presented as mean ± standard deviation. Significance was determined using one-way ANOVA in comparison with -105.

[0070] FIGs. 36A-36C show that TfR-targeting TransMoDEs induce time-dependent uptake and degradation of a-DNP in hcMEC / Ds cell lysates. (FIG. 36A-FIG. 36C) Replicates of western blots show uptake and degradation of AF488 a-DNP (lOOnM) over the 24h time course mediated by TransMoDE 106. Top panel shows a-AF488 antibody and bottom panel shows a-P tubulin antibody.

[0071] FIG. 37 shows quantification of the 150 kDa a-DNP band from western blot studies shows significance uptake at 24h mediated by TransMoDE 106. Data are presented as mean ± standard deviation. Significance was determined using one-way ANOVA in comparison with -106.

[0072] FIG. 38 shows representative TEER measurements of hcMEC / D? monolayer over 7 days. Value stabilizes after day 5 and reads 29.3 ± 0.5 Q*cm2the day when starting the assay. Data are subtracted over - cell, +collagen control and presented as mean ± standard deviation over n=3.

[0073] FIGs. 39A-39B show' how7the hcMEC / Ds monolayer demonstrated significant blockage over different molecular weights of FITC-dextran. (FIG. 39A) % of each FITC- dextran in the apical, basal, and inserts. (FIG. 39B) Summary table of blocking efficiency. Data are presented as mean ± standard deviation over n=4.

[0074] DETAILED DESCRIPTION

[0075] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0076] Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of ‘'about 0.1% to about 5%” or '‘about 0. 1% to 5%” should be interpreted to include notjust about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y. or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0077] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term '‘or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as '‘A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting: information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

[0078] In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0079] Definitions

[0080] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0081] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5. 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of’ can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4. 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3. 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0082] The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester: a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R. C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR. OC(O)R. C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O-2N(R)C(O)R, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C( NOR)R. and substituted or unsubstituted (Ci-Cioo)hydrocarbyl. wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted.

[0083] The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The substitution can be direct substitution, whereby the hydrogen atom is replaced by a functional group or substituent, or an indirect substitution, whereby an intervening linker group replaces the hydrogen atom, and the substituent or functional group is bonded to the intervening linker group. A non-limiting example of direct substitution is: RR-H RR-C1, wherein RR is an organic moiety / fragment / molecule. A non-limiting example of indirect substitution is: RR-H RR- (LL)zz-Cl, wherein RR is an organic moiety / fragment / molecule, LL is an intervening linker group, and ‘zz’ is an integer from 0 to 100 inclusive. When zz is 0, LL is absent, and direct substitution results. The intervening linker group LL is at each occurrence independently selected from the group consisting of -H, -O-, -OR, -S-. -S(=O)-, -S(=O)2-, -SR, -N(R)-, - NR2, -CR=, -C =, -CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, -C(=NR)-, and combinations thereof. (LL)zz can be linear, branched, cyclic, acyclic, and combinations thereof.

[0084] The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F. Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF OCF?, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SOsR, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(0)N(R)2, 0C(0)N(R)2, C(S)N(R)2. (CH2)O-2N(R)C(0)R. (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)C0N(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(0)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (Ci-Cioo)hydrocarbyl. alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl.

[0085] The term “alkyl” as used herein refers to straight chain and branched alky l groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or. in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyd groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-penty l, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alky l groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0086] The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3). - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

[0087] The term “alkynyl” as used herein refers to straight and branched chain alky l groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms. 2 to about 20 carbon atoms, or from 2 to 12 carbons or. in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - CACH. -C=C(CH3), -C =C(CH2CH3). -CH2C=CH, -CH2C=C(CH3). and -CH2C^C(CH2CH3) among others.

[0088] The term “acyl” as used herein refers to a group containing a carbonyl moiety' wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alky l, aryl, aralky l cy cloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyd, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbony l carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0089] The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to. norbomyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group.

[0090] The term “heterocycloalkyl” as used herein refers to a cycloalkyl group as defined herein in which one or more carbon atoms in the ring are replaced by a heteroatom such as O, N, S, P, and the like, each of which may be substituted as described herein if an open valence is present, and each may be in any suitable stable oxidation state.

[0091] The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl. biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-. 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.

[0092] The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyd and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an ary l group as defined herein.

[0093] The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings where a CH2 group in the ring is replaced by one or more C=O groups, such as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing a C=O group include, but are not limited to, - propiolactam, y-butyrolactam, 5-valerolactam, and c-caprolactam, as well as the corresponding lactones. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl. triazolyl. tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl. and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.

[0094] The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroary l rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C'2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring designated Cx-y can be any ring containing x’ members up to ty’ members, including all intermediate integers between ‘x’ and ty?and that contains one or more heteroatoms, as defined herein. In a ring designated Cx-y, all non- heteroatom members are carbon. Heterocyclyl rings designated Cx-y can also be polycyclic ring systems, such as bicyclic or tricyclic ring systems. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

[0095] Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3 -furyl) , indolyl. oxadiazolyl, isoxazolyl, quinazolinyl. fluorenyl, xanthenyl. isoindanyl. benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2 -thiazolyl, 4- thiazolyl. 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl). pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl. 4-benzo[b] furanyl. 5-benzo[b]furanyl. 6-benzo[b] furanyl. 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b] furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),

[0096] 6-(2,3-dihydro-benzo[b]furanyl), 7-(2.3-dihydro-benzo[b] furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl). 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl. 2-indolyl,

[0097] 3-indolyl, 4-indolyl, 5-indolyl. 6-indolyl, 7-indolyl), indazole (1-indazolyl. 3-indazolyl,

[0098] 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5 -benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1 -benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl,

[0099] 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f|azepine (5H-dibenz[b,f] azepin- 1-yl, 5H-dibenz[b,f|azepine-2-yl, 5H-dibenz[b.f|azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),

[0100] 10,1 l-dihydro-5H-dibenz[b,f| azepine (10,l l-dihydro-5H-dibenz[b,f]azepine-l-yl,

[0101] 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-3-yl,

[0102] 10,1 l-dihydro-5H-dibenz[b,f|azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-5-yl), and the like.

[0103] The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

[0104] The term “heteroarylalkjd” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0105] The term ’ alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy. cyclobutyloxy. cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxy ethoxygroup is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0106] The term “amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)s wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein.

[0107] The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3 . wherein each R is independently selected, and protonated forms of each, except for -NRA . which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An '‘amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An '‘alkylamino” group includes a monoalky lamino, dialkylamino, and trialkylamino group.

[0108] The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0109] The term “haloalk 1” group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalky 1 include trifluoromethyl, 1,1 -di chloroethyl, 1,2-dichloroethyL l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.

[0110] The terms “epoxy-functional” or “epoxy-substituted” as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl. 3-(3,4-epoxycylohexyl)propyl, 2-(3.4- epoxycyclohexyljethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-melhyl-3.4- epoxycyclohexyljpropyL 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- epoxyhexyl.

[0111] The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or CL it is bonded to the atom it is substituting by a single bond.

[0112] The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.

[0113] As used herein, the term '‘hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cbjhydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (Ci-C4)hydrocarbyl means the hydrocarbyl group can be methyl (Ci), ethyl (C2), propyl (C3). or butyl (C4), and (Co-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.

[0114] As used herein, the term “C6-10-5-6 membered heterobiaryl” means a C6-10aryl moiety covalently bonded through a single bond to a 5- or 6-membered heteroaryl moiety. The C6-10aryl moiety and the 5-6-membered heteroaryl moiety7can be any of the suitable aryl and heteroaryl groups described herein. Non-limiting examples of a C6-10-5-6 membered heterobiarvl include

[0115] When the C6-10-5-6 membered heterobiaryl is listed as a substituent (e.g., as an “R” group), the C6-10-5-6 membered heterobiaryl is bonded to the rest of the molecule through the C6-10moiety.

[0116] As used herein, the term '‘5-6 membered- C6-10heterobiaryl “ is the same as a C6-10-5- 6 membered heterobiary l, except that when the 5-6 membered- C6-10heterobiaryl is listed as a substituent (e.g., as an “R” group), the 5-6 membered- Co- 10 heterobiaryl is bonded to the rest of the molecule through the 5-6-membered heteroaryl moiety.

[0117] As used herein, the term “C6-10- C6-10biary l” means a C6-10aryl moiety covalently bonded through a single bond to another C6-10aryl moiety7. The C6-10aryl moiety can be any of the suitable ary l groups described herein. Non-limiting example of a C6-10- C6-10biaryl include biphenyl and binaphthyl.

[0118] The term '‘solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0119] The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations.

[0120] The term '‘room temperature” as used herein refers to a temperature of about 15 °C to

[0121] 28 °C. The term “standard temperature and pressure’' as used herein refers to 20 °C and 101 kPa.

[0122] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

[0123] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0124] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0125] As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0126] As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay.

[0127] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0128] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically7acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0129] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic. 4-hydroxybenzoic. phenylacetic, mandelic, embonic (pamoic). methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic. P-hydroxy butyric, salicylic, galactaric and galacturonic acid.

[0130] Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

[0131] As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository' waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents. such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein in its entirety by reference.

[0132] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0133] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (EDso).

[0134] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0135] As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i. e. , a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g.. for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0136] Non-Limiting Disclosure

[0137] Compounds of the disclosure or otherwise described herein can be prepared by the general schemes described herein, using the synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) described herein and their preparation.

[0138] Extracellular TPD efforts are currently limited to lysosome targeting chimeras (LYTACs), cytokine receptor targeting chimeras (KineTACs). and molecular degraders of extracellular proteins (MoDEs). These bifunctional molecules achieve degradation through receptor mediated uptake and endolysosomal trafficking by the cation-independent mannose- 6-phosphate receptor, the asialoglycoprotein receptor, and cytokine receptor CXCR7.

[0139] Many neurological diseases are associated with the accumulation of pathogenic proteins and removal of these species could impact disease progression. While the movement of small molecules across the blood-brain barrier is possible through diffusion, larger molecules can access the brain using only receptor-mediated transcytosis, adsorption- mediated transcytosis, or transport proteins. To overcome this barrier, brain-targeting peptides capable of facilitating receptor-mediated transcytosis have been utilized for transport of larger cargo.

[0140] For example, the low-density lipoprotein receptor- related protein 1 (LRP1) is capable of both transcytosis and lysosomal trafficking. LRP1 is a scavenger receptor with over 40 endogenous ligands and is involved in processes regulating cellular homeostasis including lipoprotein metabolism and degradation of protease / inhibitor complexes. Currently, LRP1 targeting technologies show7preclinical success in the delivery of a variety7of covalently conj ugated therapeutics, ranging from small molecule chemotherapeutics to antibodies and nanoparticles, to the brain.

[0141] In various embodiments provided herein is a LRP1 ligand, which is modified to include a small molecule moiety7, which is capable of recruiting, internalizing, and / or degrading an extracellular protein of interest. Uptake and lysosomal localization were observed for two model systems: biotin / streptavidin and dinitrophenyl / anti-DNP antibody. Mechanism studies show that upon binding the target protein, MoDE-L triggers clathrin- mediated endocytosis, subcellular localization to the lysosome and target protein degradation (FIG. 12, FIGs. 15A-15C).

[0142] To confirm lysosomal trafficking of the anti-DNP antibody, a novel assay was utilized, using a two-part luciferase- HiBiT. a small peptide that can be covalently attached to the target protein, and LgBiT which was constitutively expressed between the luminal and transmembrane region of the lysosomal protein, Lampl, in HepG2 cells. Luminescence observed in this assay indicates that the HiBiT-target protein was delivered to the lysosome forming a functional luciferase with the LAMPl-LgBiT (FIGs. 14A-14D).

[0143] For evaluation of the mechanism of MoDE-L both the mouse brain endothelial cell line, bEnd.3, due to interest in crossing the blood brain barrier and human hepatocytes, HepG2, were explored. Interestingly, no uptake of anti-DNP antibody was observed in the bEnd.3 cell line. Without wishing to be limited by any theory, in certain embodiments the size or valency of the target protein can be responsible for this variation in uptake. Uptake of streptavidin in mouse brain endothelial cells (FIG. 1) and human hepatocytes (FIG. 5), as well as uptake of anti-DNP antibody in human hepatocytes (FIG. 6) was observed. An additional AF488-labeled low molecular weight band was observed in the HepG2 cell lysate upon treatment (FIG. 15A), indicating that upon endocytosis the anti-DNP antibody is degraded.

[0144] The subcellular localization of streptavidin in lysosomes (FIG. 15B) and the LysoLgBit assay (FIGs. 14A-14D) combined with the appearance of a low molecular weight AF488-labeled degradation band (FIG. 15A) indicates that, in certain embodiments, MoDE-L can act as a degrader of extracellular proteins by way of lysosomal proteases.

[0145] Without wishing to be limited by any theory, in certain embodiments this indicates that tetrameric MoDE can act in an LRP1 -independent manner. Excess tetrameric MoDE and the LRP1 ligand receptor-associated protein (RAP) inhibited tetrameric MoDE mediated uptake of anti-DNP antibody in HepG2 (FIG. 13). In certain embodiments, MoDE-L does not cause endocytosis through the expected receptor (FIG. 13, FIGs. 16A-16B). Additionally, MoDE may target LRP1, other members of the low-density lipoprotein receptor family, transferrin receptor, insulin receptor, Glutlor CD98hc.

[0146] Drugs that specifically target the central nervous system (CNS) must first pass the blood-brain barrier (BBB). The BBB restricts the penetration of molecules at least in part because of tight junctions formed by lateral transmembrane proteins, lack of fenestrations, the negative surface polarity, and the high level of efflux transporters, such as P -glycoprotein (P- gp). The in abi 1 i ty for drug molecules to permeate the BBB is a significant impediment for CNS drug candidates. In certain embodiments, the most common parameter used to quantify penetration of a compound across the BBB is the ratio of the concentration of compound measured in the brain to the concentration of compound measured in the blood at steady state. This ratio is expressed as logBB (log[brain] / [blood]) and determines the total extent of brain exposure, at a steady state. Negative values of logBB generally mean that the compound does not cross the blood-brain barrier. Conversely, positive values of logBB generally mean that the compound crosses the blood-brain barrier. logBB can be predicted or estimated in vitro using the parallel artificial membrane permeability assay (PAMPA) adapted for BBB measurements and / or the immobilized artificial membrane (IAM) technique. Alternatively, logBB can be computed in silico using a variety of computational techniques, such as quantitative structure-activity relationship (QSAR) models, molecular dynamics (MD), and free energy simulations. An example of such in silico techniques is described in, for example. Carpenter, T.S. et al., Biophys J. 2014 Aug 5; 107(3): 630-641.

[0147] In various embodiments, a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or solvate thereof, having the structure of formula (I) is provided.

[0148] In the compound of formula (I) is:

[0149] R is independently at each occurrence: i) — (L)P— A — RBT, wherein:

[0150] RBTis a brain targeting peptide having an amino acid sequence as defined in Tables 1-4 and 6-8 and / or any one sequence of SEQ ID NO: 1 to SEQ ID NO: 50, wherein the brain targeting peptide is connected at the RBT’s C-terminal or N-terminal amino acid to A; ii) — (L)P— X, wherein:

[0151] X is a brain targeting ligand; iii) — (L)p-H; or iv) — (L)P— EPT. wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein; each L is independently at each occurrence a linker;

[0152] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;

[0153] RAis independently at each occurrence H,

[0154] RNis independently at each occurrence H

[0155] G is independently at each occurrence R, NHR, CH2R, C(=O)R, C(=O)OR.

[0156]

[0157] Z is independently at each occurrence CH2 or C(=O);

[0158] R’ is independently at each occurrence H or R; p is independently at each occurrence 0, 1. 2, 3, 4, 5, 6, 7, 8. 9, 10, 11, 12, 13, 14. 15.

[0159] 16, 17, 18, 19, or 20; and n is independently at each occurrence 1, 2, 3, 4, 5, or 6.

[0160] In various embodiments, at least one R in the compound of formula (I) is — (L)P— EPT.

[0161] In various embodiments, only one R in the compound of formula (I) is — (L)P— EPT.

[0162] In various embodiments, only two R in the compound of formula (I) are independently — (L)P— EPT.

[0163] In various embodiments, only three R in the compound of formula (I) are independently — (L)P— EPT.

[0164] In various embodiments, RAis . In various embodiments, Rci s . In various embodiments,

[0165] In various embodiments, n is 1, 2, 3, or 4. In various embodiments, n is 4. In various embodiments, G is NHR. In various embodiments, G is R. In various embodiments, if at least one RAis not H, then each RNis H. In various embodiments, if at least one RNis not H, then each RAis H. In various embodiments, the compound of formula (I) is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0166] In various embodiments, the compound of formula (I) is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0167] In various embodiments, the compound of formula (I) is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof. In various embodiments, the compound of formula (I) is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0168] In various embodiments, the compound of formula (I) is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0169] In various embodiments, A is: wherein the atom marked with * is attached to (L)P; and the atom marked with ** is attached to RBT. In various embodiments, one or more lysine or arginine residues in RBTare optionally capped with an amine protecting group, such as, without limitation, -C(=O)Ci-4. In various embodiments, one or more lysine or arginine residues in RBTare optionally capped with -C(=O)CH3.

[0170] In various embodiments, at least one (L)Pis -C(=O)CH3. In various embodiments, compounds of the disclsoure have a measured, in vitro predicted, or in silico predicted logBB of at least, equal to, or greater than about -0.3, -0.2, - 0.1, 0, 0.1, 0.2. 0.3, 0.4, 0.5, 0.6. 0.7, 0.8, 0.9, 1. 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7. 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5.

[0171] Brain Targeting Ligand (X)

[0172] In various embodiments, X is a brain targeting ligand. The brain targeting ligand, in some embodiments, is a non-peptidic small molecule. As used herein, the term “non- peptidic" means that X does not contain any naturally occurring amino acids. The brain targeting ligand, in some embodiments, has a molecular mass (independent of the linker L) of at least 50, 60, 70, 80, 90, 100, 110, 120, or 130 g / mol. The brain targeting ligand, in some embodiments, has a molecular mass (independent of the linker L) of not greater than 500, 520, 540. 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780. 800, 820, 840, 860, 880, or 900 g / mol.

[0173] The brain targeting ligand, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or ECso) against its target receptor of less than, at least, or equal to about 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 pM. The brain targeting ligand, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or ECso) against its target receptor of less than, at least, or equal to about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or about 0.01 nM.

[0174] In various embodiments, X has a measured, in vitro predicted, or in silico predicted logBB of greater than about -0.3, -0.2, -0.1, 0, 0.1, 0.2, 0.3, 0.4. 0.5, 0.6, 0.7, 0.8. 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5. 1.6, 1.7, 1.8, 1.9. 2, 2.1, 2.2, 2.3. 2.4, or 2.5. All combinations of the molecular weights for X described herein and measured, in vitro predicted, or in silico predicted logBB values described herein for X are contemplated as if they were expressly written out.

[0175] In various embodiments, the brain targeting ligand X is any of the ligands in Table 5.

[0176] In various embodiments, X is an LRP1 targeting ligand. In various embodiments, X is a transferrin receptor targeting ligand. In various embodiments, X is an LDLR targeting ligand. In various embodiments, X is an insulin receptor targeting ligand. In various embodiments, X is a glucose transporter (Glutl) targeting ligand.

[0177] Examples of insulin receptor targeting ligands include, but are not limited to. ceritinib (LDK378), ursolic acid, GW501516, L-783,281, thioctic acid, tyrphostm, BMS-554417, nordihydroguaiaretic acid, and the like.

[0178] Brain Targeting Peptides (RBT)

[0179] In various embodiments, RBThas the amino acid sequence of any of the peptides in Tables 1-4. In various embodiments, RBTis an LRP1 targeting peptide. In various embodiments, RBTis a transferrin receptor targeting peptide. In various embodiments, RBTis an LDLR targeting peptide. In various embodiments, RBTis an insulin receptor targeting peptide. In various embodiments, RBTis a glucose transporter targeting compound. The brain targeting peptide RBTcan be connected to the rest of the compound of the disclosure at either its C-terminal residue or its N-terminal residue.

[0180] Table 1: Examples of LRP1 Targeting Peptides LRP1 targeting peptides are described in, for example, Demeule et al. J Pharmacol

[0181] Exp Ther. 2008. 324(3), 1064-1072; Sakamoto, et al. Biochem Biophys Rep. 2017. 12. 135- 139; Ruan, et al. J Control Release. 2018. 279, 306-315; and Croy, et al. Biochemistry. 2004. 43(23), 7328-7335, all of which are included herein in its entirety by reference. Table 2: Examples of Transferrin Receptor Targeting Peptides

[0182] Transferrin targeting peptides are described in, for example, Lee et al. Eu J Biochemistry. 2001. 268(7), 1899-2191; Tang et al. Acta Biomaterialia. 2019. 83, 379-389;

[0183] Xia et al. J Virol. 2000. 74(23), 11359-11366, Santi et al. Bioconj Chem. 2017. 28, 471-480, and McQuaid et al. PLoS One. 2021. 16(6),e0252341, all of which are included herein in its entirety by reference.

[0184] Table 3: Examples of LDLR (Low-density Lipoprotein Receptor) family Targeting Peptides

[0185] LDLR targeting peptides are described in, for example, Ruan, et al. J Control Release.

[0186] 2018. 279, 306-315; Andre, et al. Biology (Basel). 2020. 9(7), 61; Bockenhoff. et al. J Neurosci. 2014. 34(9). 3122-3129; or David, et al. PLoS ONE. 2018. 13(2), el91052, all of which are included herein in its entirety by reference.

[0187] Table 4: Examples of Insulin Receptor Targeting Peptides

[0188]

[0189] Insulin receptor targeting peptides are described in, for example, Schaffer, et al. Proc Natl Acad Sci USA. 2003. 100(8), 4435-4439; Lawrence, et al. J Biol Chem. 2016.

[0190] 291(30), 15473-15481; and Jensen, et al. Biochemical Journal. 2008. 412(2), 435-445, all of which are included herein in its entirety by reference.

[0191] EG3 is NH2O-(CH2)(OCH2CH2)3ONH2 and EG4 is NH2O-(CH2)(OCH2CH2)4ONH2.

[0192] The EG3 and EG4 linkers involve triethylene or tetraethylene glycol linkages that can be attached to aldehydes incorporated at the lysine side chain or N-terminus of the peptides. Table 5: Examples of Glucose Transporter (Glutl) Targeting Ligands

[0193]

[0194] Other receptors found in the brain that are suitable for targeting include, but are not limited to. Transcobalamin Receptor (CD320) and Basigin (Bsg).

[0195] In various embodiments, RBThas the sequence of SEQ ID NO: 1. In various embodiments, RBThas the sequence of SEQ ID NO: 2. In various embodiments, RBThas the sequence of SEQ ID NO: 3. In various embodiments, RBThas the sequence of SEQ ID NO: 4. In various embodiments, RBThas the sequence of SEQ ID NO: 5. In various embodiments, RBThas the sequence of SEQ ID NO: 6. In various embodiments, RBThas the sequence of SEQ ID NO: 7. In various embodiments. RDThas the sequence of SEQ ID NO: 8. In various embodiments, RBThas the sequence of SEQ ID NO: 9. In various embodiments, RBThas the sequence of SEQ ID NO: 10. In various embodiments, RBThas the sequence of SEQ ID NO: 11. In various embodiments, RBThas the sequence of SEQ ID NO: 12. In various embodiments, RBThas the sequence of SEQ ID NO: 13. In various embodiments, RBThas the sequence of SEQ ID NO: 14. In various embodiments, RBThas the sequence of SEQ ID NO: 15. In various embodiments, RBThas the sequence of SEQ ID NO: 16. In various embodiments. RBThas the sequence of SEQ ID NO: 17. In various embodiments, RBThas the sequence of SEQ ID NO: 18. In various embodiments, RBThas the sequence of SEQ ID NO: 19. In various embodiments, RBThas the sequence of SEQ ID NO: 20. In various embodiments. RBThas the sequence of SEQ ID NO: 21. In various embodiments, RBThas the sequence of SEQ ID NO: 22. In various embodiments, RBThas the sequence of SEQ ID NO: 23. In various embodiments, RBThas the sequence of SEQ ID NO: 24. In various embodiments, RBThas the sequence of SEQ ID NO: 25.

[0196] In various embodiments, RBThas the sequence of SEQ ID NO: 26. In various embodiments, RBThas the sequence of SEQ ID NO: 27.

[0197] In various embodiments, RBThas the sequence of SEQ ID NO: 28.

[0198] In various embodiments, RBThas the sequence of SEQ ID NO: 29.

[0199] In various embodiments, RBThas the sequence of SEQ ID NO: 30.

[0200] In various embodiments, RBThas the sequence of SEQ ID NO: 31.

[0201] In various embodiments, RBThas the sequence of SEQ ID NO: 32.

[0202] In various embodiments. RBThas the sequence of SEQ ID NO: 33.

[0203] In various embodiments, RB1has the sequence of SEQ ID NO: 34.

[0204] In various embodiments, RBThas the sequence of SEQ ID NO: 35.

[0205] In various embodiments, RBThas the sequence of SEQ ID NO: 36.

[0206] In various embodiments. RBThas the sequence of SEQ ID NO: 37.

[0207] In various embodiments, RBThas the sequence of SEQ ID NO: 38.

[0208] In various embodiments, RBThas the sequence of SEQ ID NO: 39.

[0209] In various embodiments, RBThas the sequence of SEQ ID NO: 40.

[0210] In various embodiments, RBThas the sequence of SEQ ID NO: 41.

[0211] In various embodiments, RBThas the sequence of SEQ ID NO: 42.

[0212] In various embodiments, RBThas the sequence of SEQ ID NO: 43.

[0213] In various embodiments, RBThas the sequence of SEQ ID NO: 44.

[0214] In various embodiments, RBThas the sequence of SEQ ID NO: 45.

[0215] In various embodiments. RDThas the sequence of SEQ ID NO: 46.

[0216] In various embodiments, RBThas the sequence of SEQ ID NO: 47.

[0217] In various embodiments, RBThas the sequence of SEQ ID NO: 48.

[0218] In various embodiments, RBThas the sequence of SEQ ID NO: 49.

[0219] In various embodiments, RBThas the sequence of SEQ ID NO: 50.

[0220] In various embodiments, RBTis S374, S378, S453, S454, S455, or S456 as defined in Table 4. The peptides S374, S378, S453, S454, S455, and S456 can be linked to the compound of the disclosure at any suitable location that promotes the activity and efficacy of the compound of the disclosure, such as, for example and without limitation, at a C-terminal residue, an N-terminal residue, or a lysine sidechain. The link can be made with linker L as defined herein.

[0221] EPT (Extracellular Protein Targeter)

[0222] The type of extracellular protein to which the compounds of the disclosure can bind to is not particularly limited. Suitable extracellular protein targeting peptides or extracellular protein targeting ligands known in the art can be used. In various embodiments, EPT is an extracellular protein targeting ligand or extracellular protein targeting peptide listed in Tables 6-8. In various embodiments, EPT is an extracellular protein targeting peptide of nay of SEQ ID NOs: 51-64.

[0223] In various embodiments, EPT is an extracellular protein targeting ligand. In various embodiments, EPT is a tau protein targeting ligand. In various embodiments. EPT is an amyloid beta (A0) protein targeting ligand. In various embodiments, EPT is a CD98hc targeting ligand.

[0224] The extracellular protein targeting ligand, in some embodiments, is a non-peptidic small molecule. As used herein, the term “non-peptidic"’ means that EPT does not contain any naturally occurring amino acids. The extracellular protein targeting ligand, in some embodiments, has a molecular mass (independent of the linker L) of at least 50, 60, 70, 80, 90, 100, 110, 120, or 130 g / mol. The extracellular protein targeting ligand, in some embodiments, has a molecular mass (independent of the linker L) of not greater than 500, 520, 540. 560, 580, 600, 620, 640. 660, 680, 700, 720, 740, 760, 780. 800, 820, 840, 860, 880, or 900 g / mol.

[0225] The extracellular protein targeting ligand, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or EC50) against its target receptor of less than, at least, or equal to about 10, 9, 8, 7, 6. 5, 4, 3, 2 or about 1 pM. The extracellular protein targeting ligand, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or EC 50) against its target receptor of less than, at least, or equal to about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or about 0.01 nM.

[0226] The extracellular protein targeting peptide, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or EC50) against its target receptor of less than, at least, or equal to about 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 pM. The extracellular protein targeting peptide, in various embodiments, has an in vitro or in vivo potency (as measured by IC50 or EC50) against its target receptor of less than, at least, or equal to about 900, 800, 700. 600, 500, 400. 300, 200, 100. 90, 80, 70, 60, 50, 40, 30 20. 10. 9, 8, 7. 6. 5, 4, 3. 2, 1, 0.5. 0.1. 0.05, or about 0.01 nM.

[0227] In various embodiments, the amyloid beta (A ) protein targeting ligand is as described in Liu, Z.; Deng, Q.; Qin. G.; Yang, J.; Zhang, H.; Ren, J.: Qu, X. Biomarker- activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils. Chem. 2023. 9, 2016-2038. DOI:

[0228] 10. 1016 / j.chempr.2023.06.003, which is incorporated herein in its entirety by reference.

[0229] Table 6: Examples of Extracellular Targeting Peptides and Ligands for Targeting Tan

[0230] Protein

[0231] Table 7: Examples of Extracellular Targeting Peptides for Targeting Amyloid Beta The bolded sequences in Table 7 targets amyloid beta.

[0232] Table 8: Examples of Extracellular Targeting Peptides for Targeting CD98hc CD98hc targeting peptides are described in, for example, Chew, K.S., et al. Nature Communications. 2023. 14, 5053, which is included herein in its entirety by reference.

[0233] In various embodiments, EPT is

[0234] Linker (L)

[0235] In various embodiments, L is selected from the group consisting of: i) a group according to the structure: wherein: one of RCON1and RC0N2are each independently H. methyl, or a bond and the other is a bond;

[0236] X2is independently at each occurrence CH2, O, S, NR4, C(O), S(O), S(O)2, - S(O)2O, -OS(O)2. or OS(O)2O;

[0237] X3is independently at each occurrence O, S. or NR4; and

[0238] R4is independently at each occurrence H, C1-C3 alkyl, C1-C3 alkanol, or - C(O)(Ci-Cs alkyl); ii) a group according to the structure: wherein:

[0239] R1is H or C1-C3 alkyl; and n’’ is independently an integer from 0, 1, 2, 3, 4, 5, 6, 7, or 8; iii) a group according to the structure: wherein R1C0N. R2CON, and R3CONare each independently H, -(CH2)MCI-, -

[0240] (CH2)MClaC(O)xA(NR4)xA-(CH2)MC1a-,-(CH2)MCla(NR4)xAC(O)xA-(CH2)MCla-, or -(CH2)MC1aO-(CH2)MC1-C(O)NR4-, with the proviso that R1C0N, R2CON. and R3C0Nare not simultaneously H; each MCI is independently 1, 2, 3, or 4; each MCI a is independently 1. 2, 3. or 4; each XA is independently 0 or 1 ; and

[0241] R4is H, C1-C3 alky l, C1-C3 alkyl substituted by one or two hydroxyl groups, or -

[0242] C(O)(Ci-C3alkyl), with the proviso that MCI a and XA in a moiety are not all simultaneously 0; iv) a group according to the structure: wherein

[0243] Ra is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups, or Ra taken together with R3form a pyrrolidine ring or a hydroxypyrrolidine ring, m is independently an integer from 1 to 15, and each R3is independently an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxy amide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1- methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R-1forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1 -hydroxy ethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl); v) a group according to the structure: wherein:

[0244] Ram is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each na is independently an integer from 1 to 15; and each m is independently an integer from 1 to 100; vi) a group according to the chemical formula: wherein:

[0245] Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)I-S-, or -(CFbji- N(R)-, wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100; or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds; each j is independently an integer from 1 to 100; m’ is an integer from 1 to 100; each n is independently an integer from 1 to 100;

[0246] X1is O, S, or N-R;

[0247] R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; vii) a group with the structure: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; n' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; n” is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and viii) a group with the chemical formula: PEG-[CON]-PEG, wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues and from 2 to 10, and the *** represents an attachment point to A.

[0248] In various embodiments, q is 6.

[0249] In various embodiments, the compound of the disclosure is:

[0250] In various embodiments, the compound of the disclosure is: or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0251] 5 In various embodiments, the compound of the disclosure is:

[0252] or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0253] In various embodiments, the compound of the disclosure is:

[0254] or an enantiomer, diastereoisomer, geometric isomer, salt, and / or solvate thereof.

[0255] Non-limiting Example with Transferrin Targeting Peptides MoDEs (Molecular Degraders of Extracellular proteins) are a class of bifunctional molecules capable of binding receptors that mediate endocytosis at one end and degradation of extracellular proteins at the other. Described herein are MoDE compositions that can be used in the CNS by targeted transcytosis and degradation of extracellular proteins in CNS cells such as brain cells, which are termed TransMoDEs.

[0256] The transferrin receptor (TfR) is an overexpressed glycoprotein present on the endothelial cells of BBB. It plays a crucial role in transporting cellular iron into the CNS through receptor-mediated transcytosis of holo-Transferrin (Tf). Two studies have shown TfR as a viable target for TPD, but both focus on membrane protein degradation in cancer cells. Considering its significant presence and function, TfR was identified as a promising target for TransMoDEs. FIG. 17 illustrates the proposed mechanism of action for TfR- targeting TransMoDEs in the brain. These molecules are designed to recognize TfR on the receptor-binding end and target cargo on the target-binding end. In the blood side, after TfR- targeting TrasMoDEs bind to TfR on the brain endothelial cells (1), the TransMoDE-TfR complex is endocytosed (2) and trafficked (3) across the cells into the brain. Once in the brain (4), the target binding end of TransMoDEs binds to the target cargos of interest (5), which are then endocytosed back into the brain endothelial cells (6) through TfR. The internalized ternary (TfR-TransMoDEs-Cargo) complex can then be either redirected to Lysosome for degradation (7) or transcytosed back into the blood (8). Through this process, TfR-targeting TransMoDEs are expected to remove target cargos of interest from the brain effectively.

[0257] Peptide-based drugs have been extensively studied for CNS penetration, with many utilizing TfR. Among them, T12, a 12-mer peptide (THRPPMWSPVWP, SEQ ID NO: 10), is one of the most promising candidates exhibiting binding affinity (KD) in the nanomolar (nM) range. It facilitates both endocytosis and transcytosis across human and mouse brain endothelial cells without competing with Tf in binding to TfR. In addition to demonstrating nanoparticle-mediated transport. T12 can transport small cargos like GFP through covalent attachment, indicating its great potential as a component of TransMoDEs.

[0258] In various embodiments, a compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (II) is provided: formula (II),

[0259] In the compound of formula (II): Cy represents a ring selected from the group consisting of a six-membered aromatic ring, a six-membered heteroaromatic ring, a seven-membered carbocyclic ring, a sevenmembered heterocyclic ring, an eight-membered carbocyclic ring, and an eight-membered heterocyclic ring;

[0260] Z1 is a six-membered aromatic or heteroaromatic ring fused to ring Cy, optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR", 0C(0)N(R")2, CN. NO, NO2, ONO2, CF3. OCF3, R", N(R")2. SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, 0C(0)N(R")2, C(S)N(R")2, (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(O)N(R")2, N(R")SO2R", N(R")SO2N(R")2, N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(O)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";

[0261] Z2 is N-R4 or NH-R4, wherein one of the following applies: i) if Cy is a six-membered aromatic or heteroaromatic ring, NH-R4 is a substituent on Cy; ii) if Cy is a seven-membered carbocyclic ring, then NH-R4 is a substituent on

[0262] Cy; iii) if Cy is a seven-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy; iv) if Cy is an eight-membered carbocyclic ring, then NH-R4 is a substituent on Cy; v) if Cy is an eight-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy;

[0263] Z3 is at least one substituent on Cy selected from the group consisting of F. Cl. Br, I. OR", OC(O)N(R")2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R", O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R")2, SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, OC(O)N(R")2, C(S)N(R")2. (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R". N(R")N(R")C(O)OR", N(R")N(R")C(O)N(R")2, N(R")SO2R", N(R")SO2N(R")2, N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(0)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";

[0264] R" is independently at each occurrence H or C 1-10 hydrocarbyl; q is 0, 1, 2, 3, 4, or 5: w is 0, 1, or 2;

[0265] Y is — (L)P— A — RBT, wherein: i) RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1-50, wherein the brain targeting peptide is connected to A through its C-terminal or N-terminal amino acid; or ii) — (L)P— X, wherein X is a brain targeting ligand;

[0266] R4 is — (L)P— EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;

[0267] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;

[0268] L is independently at each occurrence a chemical linker; and p is independently at each occurrence an integer from 0 to 40.

[0269] The term "carbocyclic" as used herein means a ring containing only carbon atoms, and one or more degrees of unsaturation may be present in the ring. The heteroatom in the seven- and eight-membered heterocyclic rings can be at least one of N. O, or S. The ring Cy. although depicted as a cyclohexyl ring fused to the triazole in the compound of formula (II), is merely a representation of the indicated 6, 7, and 8-membered ring systems described here. In various embodiments, Cy is a six-membered aromatic ring. In various embodiments, Cy is a six-membered heteroaromatic ring. In various embodiments, Cy is a seven-membered carbocyclic ring. In various embodiments, Cy is a seven-membered heterocyclic ring. In various embodiments, Cy is an eight-membered carbocyclic ring. In various embodiments, Cy is an eight-membered heterocyclic ring.

[0270] With respect to fused ring(s) Zl, when w is 0, no fused rings are present. When w is I, a single fused ring is present such that it forms a six-membered aromatic or heteroaromatic ring when fused to open valences on Cy. When w is 2, two fused rings are present such that they each form a six-membered aromatic or heteroaromatic ring when fused to open valences on Cy. When Zl is heteroaromatic, the heteroatom is nitrogen, and up to three nitrogen atoms can be present in Zl independently such that if two Zl rings are present, they can have the same or different numbers of nitrogen heteroatoms. In various embodiments, w is 0. In various embodiments, w is 1. In various embodiments, w is 2.

[0271] In various embodiments. EPT is an extracellular protein targeting peptide of any of SEQ ID NOs: 51-64. EPT can be an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein as defined herein.

[0272] The variables in the compound of formula (II) can have the same definition(s) as the identical variables present in the compound of formula (I) as described herein.

[0273] In various embodiments, the compound of formula (II) has the following structures:

[0274] This list of compounds of formula (II) is merely intended to be representative, and all possible combinations of rings are contemplated herein

[0275] When Cy is a seven- or eight-membered ring, at least one double bond is present in Cy such that the triazole portion of the compound of formula (II) is aromatic.

[0276] In various embodiments, the compound of formula (II) has the structure:

[0277] In various embodiments, the compound of formula (II) has the structure:

[0278] In various embodiments, In various embodiments, RBThas the amino acid sequence of SEQ ID NO: 10.

[0279] In various embodiments, R4 has the structure wherein t is 4, 5, 6. 7, 8, 9. 10. 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In various embodiments, EPT is

[0280] In various embodiments, the compound of formula (II) is selected from the group consisting of

[0281]

[0282] Structure-based Design and Synthesis of TfR-Tar eting TransMoDEs.

[0283] TfR-targeting TransMoDEs were synthesized through a one pot -click chemistry reaction that assembled three domains together: the TfR-binding domain T12, polyethylene glycol (PEG) linker domain, and the target cargo binding-domain R3 (Scheme 1).

[0284]

[0285] Scheme 1

[0286] To determine optimal linker attachment site on T12, docking studies were conducted between peptide and TfR (adapted from PDB: 3S9N). Potential binding sites on TfR were first identified, and possible three-dimensional conformations of T12 were generated using the Molecular Operating Environment (MOE) softw are package. Different conformations of T 12 were then docked into the binding sites to generate binding poses with corresponding docking scores. Among all docking attempts, the binding pocket highlighted in the red frame (FIG. 18 A) demonstrated consistent binding poses of T12 , with an average higher docking score of -13.2 ± 0.3 than the others, making it to be the most likely binding site. Closer inspection of the binding interaction revealed that the peptide w as primarily buried in the pocket, with the main interaction being the hydrogen bonding between Asp624 (D624) on TfR. and Arg (R) on T12. The N-tenninal Trp (T) of the peptide w as found to be more solvent exposed compared to the C-terminal Pro (P), suggesting that linker attachment on the N-terminus would be preferable.

[0287] To test this hypothesis, a TfR-targeting TransMoDEs was synthesized utilizing both N-terminal and C-terminal ends. T12 w as functionalized at its termini with azide (N3), which would be conjugated with DBCO-(PEG)n-R3 into synthesizing TransMoDEs (101 & 102). Surface Plasmon Resonance (SPR) was employed to measure their binding affinities to TfR, using T12 with no modification (99) as the positive control. Illustrated in FIG. 18B and FIG. 23 A, both 99 and 101 exhibited a fast association phase and a tendency to saturate at higher concentrations, indicating stronger binding to TfR. Conversely, 102 showed the opposite behavior, demonstrating lower affinity (FIG. 18C). Further kinetics and affinity analysis supported these observations (FIG. 18D and FIG. 18E, FIG. 23B and FIG. 23C), proving that 101 has a nanomolar-range KD like 99, whereas 102’s KD was much higher or too unstable to determine.

[0288] Interestingly, both steady-state- and kinetics-derived KD values for 99 and 101 suggest a non-limiting 2: 1 binding stoichiometry (Table 10). Given the homodimeric nature of the protein, it is likely they bind at two sites on TfR. Previous studies on the binding of holo-Tf to TfR also reported the 2: 1 binding and suggested that if these two bindings are independent, then KD2=4KDI. The gap between KD2 and KDI thus suggests, without being bound by theory, that these two binding events are probably intercorrelated, with the second binding site potentially influenced negatively by the first binding event. Further atomic-level studies are needed to investigate this hypothesis. Overall, SPR analysis demonstrated the azide on the N-terminus did not affect the binding pocket between peptide and TfR, suggesting further addition of the DBCO-(PEG)n-Rs on this terminus would likely to not hamper its affinity. Compound 101 was synthesized as depicted in Scheme 1, synthesizing TfR-targeting TransMoDEs with different R3 domains and various PEG linkers to target either streptavidin or a-DNP (Table 9).

[0289] Table 9. TfR-targeting TransMoDEs modifications with different PEG linkers and targeting ends.

[0290] Table 10. Derived kinetics constants of 99, 101, and 102. a Data are best fit to 1 :2 state model for 99 & 101 and 1 : 1 state model for 102. Affinity was derived from the association constant kaand dissociation constant kd (KD= kd / ka).

[0291] TfR-targeting TransMoDEs induce non-covalent cargo internalization into human brain endothelial cells

[0292] TfR-targeting TransMoDEs’ capabilities in inducing uptake of fluorescently labeled streptavidin or a-DNP were tested using flow cytometry. Human brain microvascular endothelial cell lines (hCMEC / Ds) were used, which represent a well-established in vitro model for the BBB and have been extensively used in studies related to CNS-relevant diseases.

[0293] Significant uptake of streptavidin AF-647 and a-DNP AF-488 were both observed at increasing concentrations of TfR-targeting TransMoDEs, which were modified with either biotin (103-105) or DNP (106,107) at Rs, respectively (FIG. 19A and FIG. 19B). For biotinylated TransMoDEs (103-105), saturation and slight decrease in the uptake of streptavidin was observed at higher concentration rather than the hook effect, which is a common phenomenon of signal suppression observed in bifunctional molecules when all binding sites are saturated with binary complexes instead of ternary complexes. This saturation was attributed to the avidity of streptavidin and has been observed previously in other TransMoDEs. There was no significant relationship between PEG lengths and the level of uptake, leading us to hypothesize that PEG=6 is sufficient to minimize the interference between receptor binding pocket and target cargo binding pocket (FIG. 19A). On the other hand. DNP-modified TransMoDEs behaved differently with different PEG lengths, with PEG=4 (106) showing a higher level of internalization in a-DNP AF-488 than PEG=12- containing TransMoDEs(107). This indicated that in the case of DNP -modified TransMoDEs, longer linker length is not suitable as it might interfere with internalization owing to enhanced flexibility. Another difference was the observation of hook effect for both 106 and 107 in a-DNP uptake (FIG. 19B). Time course studies were then conducted on all biotinylated TransMoDEs 103-105, and the DNP modified TransMoDE 106. Time-dependent internalization of target cargo was observed under corresponding TransMoDEs, indicating the specificity of uptake. Notably, previous TransMoDE (TransMoDE 108) demonstrated a slightly lower level of internalization of streptavidin and no internalization of a-DNP into hCMEC / Ds cells (FIGs. 24A-24B). This suggests that TfR-targeting TransMoDEs have improved performance in the internalization of extracellular cargos into human brain endothelial cells.

[0294] Mechanistic Uptake

[0295] The manner of internalization mediated by TfR-targeting TransMoDEs were next explored. TransMoDEs facilitate internalization through the formation of ternary complex on the cell surface, which theoretically could be inhibited by either the target cargo-binding end or the receptor-binding end. As shown in FIG. 20 A, with the addition of excess free biotin and DNP, significant suppression of uptake was observed for all biotinylated and DNP- modified TransMoDEs, aligning with expectations. On the receptor-binding end, coincubation with a-TfR antibody also significantly reduced extracellular protein uptake, illustrating TransMoDEs internalize through TfR (FIG. 20B). Further knock-out (KO) studies supported this conclusion. Almost no uptake was observed in the HeLa-TfR KO cell lines, while the original HeLa cell line, with abundant TfR. expression (FIG. 25), demonstrated two to three times more internalization of both streptavidin and a-DNP with the addition of corresponding TransMoDEs (FIG. 20C). Notably, excess of N-azi do-tagged Ti2 (101) only significantly suppressed a-DNP uptake instead of streptavidin, which could also be attributed to avidity of streptavidin (FIG. 26). By co-incubating with an increasing gradient of holo-Tf. it was shown that TfR-targeting TransMoDEs -mediated internalization does not compete with Tf (FIGs. 27A-27B).

[0296] To gain further insight with respect to mechanism of endocytosis, competition studies were carried out with a variety of endocytosis inhibitors. For these studies, TransMoDEs 105 and 106 were chosen as the representative biotinylated and DNP-modified TransMoDEs respectively. In both cases, significant suppression of fluorescent signal was observed from flow cytometry' with the addition of clathrin-related inhibitors (Pistop2, Dyngo4a, Monensin, Bafilomycin, NFUC1). On the other hand, little to no uptake was observed with caveolae- (Nystatin, Genistein) and micropinocytosis-related inhibitors (5-(N-ethyl-N-isopropyl) amiloride, (EIP A), Amiloride). A significant reduction in uptake was also observed under cytochalasin D, which interferes with actin polymerization (FIG. 20E and FIG. 20F). Thus, it is concluded that TfR-Targeting TransMoDEs facilitate endocytosis significantly via majorly clathrin-mediated mechanism that also involves a component of actin polymerization.

[0297] TfR-targeting TransMoDEs induce non-covalent cargo degradation in human brain endothelial cells

[0298] The ability of these TfR-targeting TransMoDEs to induce lysosomal internalization and degradation following endocytosis was investigated. For this, confocal microscopy was employed and co-stained hCMEC / D? cells with lysosome marker lysotracker-647 after incubation of fluorescently labeled cargo and corresponding TransMoDEs. Minimal to no co- localization was observed without the addition of TransMoDEs (FIG. 29A and FIGs. 32A- 32B). In contrast, strong colocalization was observed between lysotracker-647 and streptavidin-488 after addition of biotinylated TransMoDE 105 (FIG. 21 A, FIGs. 32A-32B), similar to what was observed with the addition of previous TransMoDE 108 (FIGs. 30A- 30B). Similarly, higher correlation between a-DNP-488 and Lysotracker was also observed with the addition of TransMoDE 106. compared to when only a-DNP-488 was present (FIG. 21B, FIG. 29B and FIGs. 33A-33B). These observations demonstrate that both streptavidin and a-DNP are trafficked to lysosomes by corresponding TransMoDEs following endocytosis. Western blots were conducted on the cell lysates to assess whether mediated degradation occurred over the 24-hour period. For streptavidin-AF488, significant increase in band intensities for both dimer and monomer was observed with the addition of TransMoDE 105. Starting from 12 hours, two low er molecular weight bands (<10 kDa, 25-37 kDa) appeared, which were absent in both the starting material band and the control band without TransMoDE 105 (FIG. 21C. FIGs. 34A-34C and FIGs. 35A-35B). Thus, without being bound by theory, it is hypothesized that these bands are degradation products resulted from the intracellular degradation machinery. Quantification revealed significant increase of these two bands at 24 hours compared to the control (No TransMoDE), suggesting that TransMoDE 105 mediates the degradation of streptavidin (FIG. 2 ID). For a-DNP-488, a significant increase in the intensity associated with the full-length antibody was observed over time. (FIG. 21E, FIGs. 36A-36C, FIG. 37). At later time points (12 hours and 24 hours), a band at 37-50 kDa appeared, with significantly higher intensity compared to the no TransMoDEs control (FIG. 2 IF). Considering this band was also absent in both starting material and the a-DNP-488 only lane, this band is likely the degradation product. Collectively, these results demonstrate that TransMoDEs can mediate both ly sosomal internalization and degradation for both streptavidin and a-DNP.

[0299] TfR-targeting TransMoDEs induced transcytosis of non-covalent cargo across an in vitro BBB model.

[0300] The capabilities of these TfR-targeting TransMoDEs in mediating transcytosis of extracellular cargos were further explored. As shown in FIG. 22A, hCMEC / D? cells were seeded on the inserts and cultured for 5 to 7 days. Transepithelial electrical resistance (TEER) was monitored every two days and permeability tests using FITC-dextran w ere performed to ensure a confluent monolayer was achieved (FIG. 38 and FIGs. 39A-39B). Transcytosis was monitored in both directions (apical to basal and basal to apical) with streptavidin alone as the negative control, +TransMoDE 108 as positive comparison, and +TransMoDE 105 as the experimental group. Streptavidin concentrations were calculated from the measured fluorescence intensity at different time points over the 24-hour period.

[0301] In both directions, the slope (k) followed an ascending order: k+TransMoDE 105 kiransMoDE io8> koniy streptavidin (FIG. 22B and FIG. 22C). The level of transcytosis was quantified using permeability coefficients (Pe) derived from slopes. Both apical-to-basal and basal-to- apical transcytosis demonstrated a significant increase in Pewith the addition of TransMoDE 105 when compared to both the negative control (No TransMoDEs) and the condition with TransMoDE 108, illustrating that TransMoDE 105 has a higher capability' in mediating streptavidin transcytosis than TransMoDE 108. Notably, Pe from basal to apical is higher than from apical to basal, which is possibly due to the uneven distribution of TfR on the opposite surfaces of the monolayer.

[0302] The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0303] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g. tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.

[0304] In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0305] In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0306] In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0307] Compounds described herein also include isotopically -labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H.3H.nC,13C,14C,36C1,18F,123I,125I,1?N,15N,15O,170,180.32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such asnC,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0308] In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to. the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons. 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0309] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

[0310] In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0311] In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to. methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0312] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

[0313] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0314] Typically blocking / protecting groups may be selected from: trityl FMOC

[0315] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New7York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994. which are incorporated herein by reference for such disclosure.

[0316] Compositions

[0317] The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0318] Methods of Treatment, Amelioration, and / or Prevention

[0319] The disclosure includes a method of treating, ameliorating, and / or preventing neurodegenerative diseases, neurological disorders, and / or a tauopathy using the compounds of the disclosure.

[0320] In various embodiments, a method for treating, ameliorating, and / or preventing neurological disorders is provided. In various embodiments a method of treating, ameliorating, and / or preventing neurodegenerative diseases is provided. In certain embodiments, a method of treating, ameliorating, and / or preventing a tauopathy is provided. Non-liming examples of neurodegenerative disease, a neurological disorder, and / or a tauopathy include primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis. Hallervorden-Spatz disease, dementia pugilistica. progressive supranuclear palsy, corticobasal degeneration. Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease. In various embodiments, the neurodegenerative disease neurological disorder is Alzheimer’s disease. In various embodiments, the method of treating tauopathy promotes the degradation of tau protein.

[0321] The methods described herein include administering to the subject a therapeutically effective amount of at least one compound described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats, ameliorates, and / or prevents a neurodegenerative disease, a neurological disorder, or a tauopathy. In certain embodiments, administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating a neurodegenerative disease, a neurological disorder, or a tauopathy in the subject. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0322] In certain embodiments, the compound(s) described herein and the therapeutic agent are co-administered to the subject. In other embodiments, the compound(s) described herein and the therapeutic agent are coformulated and co-administered to the subject.

[0323] In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[0324] Combination Therapies

[0325] The compounds useful within the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating a neurodegenerative disease, a neurological disorder, or a tauopathy. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat or reduce the symptoms, of a neurodegenerative disease, a neurological disorder, or a tauopathy.

[0326] In certain embodiments, the compounds described herein can be used in combination with radiation therapy. In other embodiments, the combination of administration of the compounds described herein and application of radiation therapy is more effective in treating or preventing a neurodegenerative disease, a neurological disorder, or a tauopathy than application of radiation therapy by itself. In yet other embodiments, the combination of administration of the compounds described herein and application of radiation therapy allow-s for use of low er amount of radiation therapy in treating the subject.

[0327] In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[0328] Administration / Dosage / Formulations

[0329] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a neurodegenerative disease, a neurological disorder, or a tauopathy. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0330] Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a neurodegenerative disease, a neurological disorder, or a tauopathy in the patent. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability7of the therapeutic compound to treat a neurodegenerative disease, a neurological disorder, or a tauopathy in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0331] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0332] In particular, the selected dosage level depends upon a variety7of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

[0333] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0334] In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound.

[0335] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0336] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0337] In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments. the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two. days, every’ three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account.

[0338] The compound(s) described herein for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg, about 200 pg to about 7,000 mg, about 350 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0339] In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2.000 mg, or less than about 1,000 mg. or less than about 500 mg. or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg. or less than about 30 mg. or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0340] In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

[0341] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g, other analgesic agents.

[0342] Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g. sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapul monary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0343] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry' powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.

[0344] Oral Administration

[0345] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method knoyvn in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by know n techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0346] For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fdlers (e.g, cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g, magnesium stearate, talc, or silica); disintegrates (e.g, sodium starch glycollate); or wetting agents (e.g, sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g, OPADRY™ OY Type, OYC Type, Organic Enteric OY -P Type, Aqueous Enteric OY -A Type, OY -PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g, almond oil, oily esters or ethyl alcohol); and preservatives (e.g, methyl or propyl p-hydroxy benzoates or sorbic acid).

[0347] Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described herein can, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to. inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents.

[0348] Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, pol oxamer 407. or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more dispersing agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form.

[0349] Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-l,3-propanediamine, 2-acrylamido-2 -methylpropane sulfonic acid, alk lbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium laury l sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypoly ethoxyethanol P-40. Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG- 10 sunflower glycerides, pentaethylene glycol monododecy l ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20. polysorbate 80, sorbitan. sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form.

[0350] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % a- lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form.

[0351] Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, com starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%. or 90% w / w relative to weight of the dosage form.

[0352] Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%. 0.5%, 1%, 2%, 3%, 4%, 5%. 10%. 15%. 20%. 25%. 30%. 35%. 40%. 45%. 50%. 55%. 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more lubricating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form.

[0353] Tablets can be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glycery l distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos. 4.256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.

[0354] Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and / or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and / or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent swelling.

[0355] Parenteral Administration

[0356] For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.

[0357] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol.

[0358] Additional Administration Forms

[0359] Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0360] Controlled Release Formulations and Drug Delivery Systems

[0361] In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0362] The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0363] In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary' skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein.

[0364] Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.

[0365] Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0366] Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to. polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0367] The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0368] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

[0369] The term immediate release is used in its conventional sense to refer to a drug formulaton that provides for release of the drug immediately after drug administration.

[0370] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0371] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0372] Dosing

[0373] The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a neurodegenerative disease, a neurological disorder, or a tauopathy in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

[0374] A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0375] It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every' other day administration, a 5 mg per day dose maybe initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

[0376] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily- suspended for a certain length of time (z.e., a "drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-l 00%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0377] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection.

[0378] The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined uantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0379] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and EDJO. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0380] EXAMPLES

[0381] Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein.

[0382] General Methods

[0383] Starting materials were used as received unless otherwise noted. Reagent grade solvents were used for all reactions. Solvent compositions for all reactions and separations are on a volume / volume (v / v) basis. Reaction progress was checked with HPLC-MS. Mass spectrometnc measurements were performed with a Shimadzu Scientific Instruments QToF 9030 LC-MS system, equipped with aNexera LC-40D XS UHPLC, consisting of a CBM-40 Lite system controller, a DGU-405 Degasser Unit, two LC-40D XS UHPLC pumps, a SIL- 40C XS autosampler and a Column Oven CTO-40S. UV data was collected with a Shimadzu Nexera HPLC / UHPLC Photodiode Array Detector SPD M-40 in the range of 190 - 800 nm. A binary gradient was used (Solvent A: Water, HPLC grade Chromasolv, with 0.1 % Formic Acid; Solvent B: Acetonitrile, HPLC grade Chromasolv, with 0.1% Formic Acid). Mass spectra were subsequently recorded with the quadrupole time-of-flight (QToF) 9030 mass spectrometer. The samples were held at 4°C in the autosampler compartment. Chemdraw 18.2 was used for all synthetic schematics, and MestReNova 12.0.1 was used to analyze HRMS spectra.

[0384] Synthetic Methods

[0385] Standard solid phase peptide synthesis was performed to assemble to poly-lysine branched core with orthogonal protecting groups. The C-terminal lysine was coupled with biotin (5 eq Biotin-NHS, 5eq DIPEA overnight RT), or DNP-PEG4-acid (1.5 eq DNP-PEG4- acid, 1.5 eq HATU, 2 eq HO At, 3 eq diisopropylethylamine (DIPEA) overnight at room temperature), or acetylated (9: 1 pyridine: acetic anhydride 5 min at room temperature). Fmoc- NH-PEG6-C00H was coupled using 1.5 eq plus 1.5 eq HATU and 4 eq DIPEA. Fmoc was deprotected for 3x3min at room temperature using 20% piperidine in DMF. Bromoacetic acid, 5 eq, was coupled to the free amines using 5 eq diisopropylcarbodiimide (DIC) for 4h at room temperature.

[0386] In some cases, the protecting group Alloc is used and deprotected using 0. 1 eq tetrakis(triphenylphosphine)-palladium(0), 20 eq phenyl silane in DCM 3x20min at room temperature. In some cases, the protecting group MET is used and deprotected using 1:95:4 TFA:DCM:TIS for 3x30min at room temperature. In some cases, the protecting group Fmoc is used and deprotected using 20% piperidine in DMF for 3x3min at room temperature.

[0387] Angiopep-2 (Ac-C-TFFYGGSRGKRNNFKTEEY-OH), SEQ ID NO: 1, N-terminal Cysteine with N-terminus acetylated, was synthesized using solid phase peptide synthesis. Mono-Angiopep was synthesized using leq monobromo core, leq peptide, 0.5eq TCEP, 20% acetonitrile in 20 mM NH4HCO3, 5mM EDTA, pH 8 for 2 h at 37C. Tetra- Angiopep was synthesized using leq tetrabromo core, 6.4 eq peptide, 2eq TCEP in 5% acetonitrile, 40 mM phosphate buffer, pH 6.7 for 24h.

[0388] T12 was synthesized using the Biotage Initiator+Alstra automated microwave peptide synthesizer with standard Fmoc-based solid phase synthesis methods. Fmoc-Dab(Ns) (1 ClickChemistry, SC 18530) was attached at either N-term or C-term to be clicked with DBCO-(PEG)n-R3 for 1 hour at 37 °C. The full synthetic methods and characterization are provided in the Supporting Information.

[0389] Synthesis of Compound 93

[0390] Dibenzocyclooctyne-amine (DBCO-NH2) (CAS #1255942-06-3) was combined with Biotin-PEGn-NHS (n = 6, CAS#2055045-04-8, 2 eq) and N,N-diisopropylethylamine (DIEA, CAS#7087-68-5, 3 eq) in dimethylformamide (DMF, CAS#68-12-2). The solution was stirred at 37°C for 45 minutes and completion of reaction was monitored by LC-MS. After completion, the mixture was purified by HPLC (acetonitrile / H2O + 0.1% TFA, 0-80% acetonitrile). The product was then confirmed pure by high resolution mass spectrometry liquid chromatography (HRMS LC).

[0391] Compound 93: Biotin-PEGe-DBCO. Theoretical mass (M+H)=839.4089. (M+2H) / 2=

[0392] 419.7064 Observed mass (M+H)= 839.4, (M+2H) / 2= 419.7.

[0393] Synthesis of Compound 94

[0394] Dibenzocyclooctyne-amine (DBCO-NH2) (CAS #1255942-06-3) was combined with Biotin-PEGn-NHS (n = 8, CAS #2143968-03-8, 2 eq) and N,N-diisopropylethylamine (DIEA, CAS#7087-68-5, 3 eq) in dimethylformamide (DMF, CAS#68-12-2). The solution was stirred at 37°C for 45 minutes and completion of reaction was monitored by LC-MS. After completion, the mixture was purified by HPLC (acetonitrile / H2O + 0.1% TFA, 0-80% acetonitrile). The product was then confirmed pure by high resolution mass spectrometry liquid chromatography (HRMS LC).

[0395] Compound 94: Biotin-PEGs-DBCO. Theoretical mass (M+H)=927.4614, (M+2H) / 2= 463.7326. Observed mass (M+H 927.5, (M+2H) / 2= 463.7.

[0396] Dibenzocyclooctyne-amine (DBCO-NH2) (CAS #1255942-06-3) was combined with Biotin-PEGn-NHS (n = 12, CAS# 365441-71-0. 2 eq) and N,N-diisopropylethylamine (DIEA, CAS#7087-68-5, 3 eq) in dimethylformamide (DMF, CAS#68-12-2). The solution was stirred at 37°C for 45 minutes and completion of reaction was monitored by LC-MS. After completion, the mixture was purified by HPLC (acetonitrile / H2O + 0.1% TFA, 0-80% acetonitrile). The product was then confirmed pure by high resolution mass spectrometryliquid chromatography (HRMS LC).

[0397] Compound 95: Biotin-PEGi2-DBCO. Theoretical mass (M+H)=l 102.5629, (M+2H) / 2 552.2868. Observed mass (M+H)= 1102.6, (M+2H) / 2 552.3.

[0398] Synthesis of Compound 96

[0399]

[0400] DBC0-NH2 was combined with DNP-PEGn-NHS (n = 4 CAS#858126-78-0, 2 eq) and DIEA (3 eq) in DMF. The reaction was allowed to proceed, and the mixture was purified as described as for Compounds 93-95. The products were confirmed pure by HRMS. Compound 96: DNP-PEG4-DBCO. Theoretical mass (M+H)=691.2804. Observed mass (M+H)= 691.3.

[0401] Synthesis of Compound 97 DBCO-NH2 was combined with DNP-PEGn-NHS (n = 12, CAS# 1334178-01-6, 2 eq) and DIEA (3 eq) in DMF. The reaction was allowed to proceed, and the mixture was purified as described as for Compounds 93-95. The products were confirmed pure by HRMS.

[0402] Compound 97: DNP-PEG12-DBCO. Theoretical mass (M+H)=l 042.4867, (M+Na)=l 064.4687 (M+2H) / 2= 521.7470. Observed mass (M+H)= 1102.6, (M+Na)= 1064.5, (M+2H) / 2= 521.7.

[0403] Synthesis of Compound 98

[0404]

[0405] T12 (THRPPMWSPVWP, SEQ ID NO: 10) was synthesized on the Wang resin on the peptide synthesizer, with the N -terminal amine Ri Fmoc-protected and C -terminal unmodified. Compound 98 is shown with an N-terminal Fmoc protecting group. Synthesis of Compound 99

[0406] Compound 98 was Fmoc deprotected with 3 mL 20% piperidine in DMF for 3 min, 3 times. Compound was then cleaved from the resin for 3h in the cleavage solution (90:5:5 TFA:TIS:H2O) at room temperature, followed by evaporation under N2. Compound was then precipitated using ice cold diethyl ether (CAS#60-29-7), dried, and resuspended in DMF. Crude mixture was purified on HPLC (acetonitrile / H2O + 0.1% TFA, 20-60% acetonitrile).

[0407] The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 745.871, (M+3H) / 3= 497.5836. Observed mass (M+2H) / 2= 745.4, (M+3H) / 3= 497.3.

[0408] Synthesis of Compound 100

[0409] The Wang resin was first Fmoc deprotected. Fmoc-Dab(N3) (1.5 eq) was then coupled to the free amine using 1.5 eq of hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU, CAS#148893-10-l), 2 eq of l-hydroxy-7-azabenzotriazole (HOAt, CAS#39968-33-

[0410] 7) and 3 eq of DIE A overnight at room temperature. Any left free amine was capped with acetyl group for 5 min with 9: 1 pyridine (CAS#110-86-1) / anhydride (CAS#108-24-7). T12 was then coupled to the chain using the synthesizer, with the N-terminal amine Ri Fmoc- protected and C-terminal unmodified.

[0411] Synthesis of Compound 101

[0412]

[0413] Compound 98 was first Fmoc deprotected at Ri and coupled to Fmoc-Dab(N3) (1.5 eq) as described in Compound 100. After capping any free amines, the Fmoc group at the N- terminus was also deprotected. Compound was then cleaved and purified as described in 99 to provide Compound 101. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 808.8988, (M+3H) / 3= 539.6016. Observed mass (M+2H) / 2= 808.4, (M+3H) / 3= 539.3.

[0414] Synthesis of Compound 102 The Fmoc group on the N-terminus of compound 100 was deprotected. Compound was then cleaved, precipitated, and resuspended the same as in compound 101. Crude mixture was purified on HPLC under the same parameters as 101 to provide compound 102. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 808.8988, (M+3H) / 3= 539.6016. Observed mass (M+2H) / 2= 808.4, (M+3H) / 3= 539.3.

[0415] Synthesis of Compound 103

[0416] Compound 101 (1 eq) and compound 93 (1 eq) were mixed and incubated for Ih at 37 °C. Crude mixture was then purified on HPLC (acetonitrile / H2O + 0.1% TFA, 20-90% acetonitrile) to provide compound 103. The product was confirmed pure by HRMS.

[0417] Theoretical mass (M+2H) / 2= 1227.5979, (M+3H) / 3= 818.7344. Observed mass (M+2H) / 2= 1227.69, (M+3H) / 3= 818.7. Synthesis of Compound 104

[0418] Compound 101 (1 eq) and compound 94 (1 eq) were mixed and incubated for Ih at 37 °C. Crude mixture was then purified on HPLC as described for 103 to provide compound 104. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 1271.6242, (M+3H) / 3= 848.4197. Observed mass (M+2H) / 2=1271.6, (M+3H) / 3=848.4.

[0419] Synthesis of Compound 105

[0420] Compound 101 (1 eq) and compound 96 (1 eq) were mixed and incubated for Ih at 37 °C. Crude mixture was then purified on HPLC as described for 103 to provide compound 105. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 1359.6766, (M+3H) / 3= 906.7868. Observed mass (M+2H) / 2=1359.7, (M+3H) / 3=906.8.

[0421] Synthesis of Compound 106

[0422] Compound 101 (1 eq) and compound 97 (1 eq) were mixed and incubated for Ih at 37 °C. Crude mixture was then purified on HPLC as described for 103 to provide compound 106. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 1153.5337,

[0423] (M+3H) / 3= 769.3582. Observed mass (M+2H) / 2= 1153.5, (M+3H) / 3=769.0. Synthesis of Compound 107

[0424] Compound 101 (1 eq) and compound 98 (1 eq) were mixed and incubated for Ih at 37 °C. Crude mixture was then purified on HPLC as described for 103 to provide compound 107. The product was confirmed pure by HRMS. Theoretical mass (M+2H) / 2= 1329.6385, (M+3H) / 3= 886.7614. Observed mass (M+2H) / 2= 1329.6, (M+3H) / 3= 886.8.

[0425] Synthesis of Compound 108

[0426] Angiopep-2 (TFFYGGSRGKRNNFKTEEY, SEQ ID NO: 1) was synthesized on the tyrosine Wang resin, with Ri Fmoc deprotected, R2 MTT deprotected with 1% trifluoroacetic acid (TFA, CAS#76-05-l), 4% triisopropylsilane (TIS, CAS#6485-79-6), and 95% methylene chloride (CAS#75-09-2) for 3x 30 min, and acetylated afterwards. Alloc at R3 was deprotected with O. leq tetrakis(triphenylphosphine)palladium(0) (CAS# 14221-01-3), 20 eq phenylsilane (CAS#694-53-l) in methylene chloride for 3 x 20min. Biotin-NHS (CAS#35013-72-0, 5eq) was coupled to Rs with 5eq N,N-diisopropylethylamine (CAS#7087- 68-5). Compound 108 was cleaved and purified on HPLC. The product was confirmed pure by HRMS.

[0427] Synthesis of Compound 109

[0428] Compound 109 was synthesized in a manner like compound 108, with the difference that Alloc at Rs was deprotected and capped instead. Compound 109 was cleaved and purified on HPLC. The product was confirmed pure by HRMS.

[0429] Synthesis of Compound 110

[0430] Compound 110 was synthesized in a manner like compound 108, with the difference that Alloc at Rs was deprotected and coupled to DNP-PEG4-acid (CAS # 858126-76-8, 1.5 eq) with 1.5 eq of HATU, 2eq of HO At, and 3 eq of DIPEA overnight at room temperature. Compound 110 was cleaved and purified on HPLC. The product was confirmed pure by HRMS.

[0431] Peptide Synthesis

[0432] TransMoDE peptide precursor 1 was synthesized on tyrosine Wang resin using standard Fmoc-based SPPS methods by ChemPep Inc. The N-terminal amine, R1 = Fmoc, R2 = MTT (4-methyltrityl), and R3 = Alloc (ally loxycarbonyl). Throughout, Fmoc (Rl) was deprotected using 3 x 3 min incubations of 20% piperidine in dimethylformamide (DMF, CAS 68-12-2). MTT (R2) deprotection was conducted using 1 % tri fluoroacetic acid (TFA, CAS 76-05-1), 4% triisopropylsilane (TIS, CAS#6485-79-6) and 95% methylene chloride (CAS 75-09-2) for 3 x 30 min incubations. Alloc (R3) deprotection was conducted using 0.1 eq. tetrakis(triphenylphosphine)palladium(0) (CAS# 14221-01-3). 20 eq. phenylsilane (CAS#694-53-l) in methylene chloride for 3 x 20 min incubations. Acetylation of free amines was achieved using 9: 1 pyridine (CAS#110-86-l) / acetic anhydride (CAS# 108-24-7) for 5 min. Peptides were cleaved from resin using 90:5:5 TFA:TIS:water for 2h at room temperature. The cleavage solution was evaporated under nitrogen followed by precipitation using ice cold diethyl ether (CAS#60-29-7). Peptide was dried under vacuum then resuspended in DMF for purification. The crude mixtures were purified by HPLC (25-75% acetonitrile + 0.1% TFA).

[0433] TransMoDE precursor 1 was Fmoc (Rl) and MTT (R2) deprotected and acetylated as described in the general methods above. Subsequently, Alloc (R3) was deprotected and the resin was treated with Halo-PEG2-Suc (Iris Biotech, CAS# 1488363-39-8, 1.5 eq.), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU, CAS#148893-10-l, 1.5 eq.), l-hydroxy-7-azabenzotriazole (HO At, CAS#39968-33-7, 2 eq.) and N,N- diisopropylethylamine (CAS#7087-68-5, 3 eq.) at room temperature overnight. Crude 2 was cleaved from resin and purified by HPLC.

[0434] HRMS Theoretical mass [M + 2H]2+= 1345.6290, Observed mass = 1346.6275. Analytical HPLC (X = 280) Rt = 5.34 min (5-95% solvent B in solvent A over 6 min).

[0435] TransMoDE 3 Ac.Ac.Biotin

[0436]

[0437] Compound 1 was Fmoc and MTT deprotected followed by acety lation of the two resultant amines. Next Alloc was removed and the resin was treated with biotin-NHS

[0438] (CAS#35013-72-0, 5 eq.) plus N,N-diisopropylethylamine (CAS#7087-68-5, 5 eq.) in DMF at room temperature for 16 h. Compound 3 was cleaved and purified by HPLC.

[0439] HRMS: Theoretical mass [M + 2H]2+= 1306.0981, Observed mass = 1306.6030. Analytical HPLC (X = 280): Rt = 4.95 min (5-95% solvent B in solvent A over 6 min).

[0440] TransMoDE 4 Ac.Biotin.Ac.

[0441] Compound 1 was Fmoc and Alloc deprotected followed by acetylation at these two amines. Next, MTT was removed and the resin was treated with biotin-NHS (5 eq.) and diisopropylethylamine (5 eq.) in DMF at room temperature for 16 h. Compound 4 was cleaved and purified by HPLC.

[0442] HRMS: Theoretical mass [M + 2H]2+= 1306.0981, Observed mass = 1306.6034.

[0443] Analytical HPLC (X = 280): Rt = 4.95 min (5-95% solvent B in solvent A over 6 min).

[0444] TransMoDE 5 Biotin.Ac.Ac.

[0445] Compound 1 was MTT and Alloc deprotected followed by acetylation at these two amines. Next, Fmoc was removed and the resin was treated with biotin-NHS (5 eq.) and diisopropylethylamine (5 eq.) in DMF at room temperature for 16 h. Compound 5 was cleaved and purified by HPLC.

[0446] HRMS: Theoretical mass [M + 2H]2+= 1306.0981, Observed mass = 1306.6029. Analytical HPLC (X = 280): Rt = 4.97 min (5-95% solvent B in solvent A over 6 min).

[0447] TransMoDE 6 Ac.Ac.Ac.

[0448] Compound 1 was Fmoc, MTT and Alloc deprotected followed by acetylation at these three amines. Compound 6 was cleaved and purified by HPLC.

[0449] HRMS: Theoretical mass [M + 2H]2+= 1214.0646, Observed mass = 1214.5704.

[0450] Analytical HPLC (X = 280): Rt = 4.90 min (5-95% solvent B in solvent A over 6 min).

[0451] MoDE 7 Biotin-GN3.

[0452] NH2-GN3 (5.0 mg, 3.57 pmol; see for example WO2019199634 and

[0453] WO20 19199621, which are incorporated herein in their entireties by reference) was combined with biotin-NHS ester (CAS no. 35013-72-0, BroadPharm BP-22106) (2.5 eq., 3.05 mg, 8.94 pmol) and DIEA (3 eq.. 1.87 pL, 10.73 pmol) in DMF (final volume 0.5 mL). The solution was stirred for 30 min and completion of the reaction was monitored by LC-MS. The mixture was purified by HPLC (H20 + 0.1% TFA, 10-90% MeCN) to yield biotin-GN3 7 (1.2 mg, 20.68%).

[0454] HRMS: Theoretical mass [M + H]+= 1623.7583, Observed mass = 1623.7680. Analytical HPLC (X = 200): Rt = 4.29 min (5-95% solvent B in solvent A over 6 min).

[0455] Computational Simulation

[0456] Protein structure of TfR (PDB: 3S9N) was obtained from rcsb.org and further modified as well as quick-prepared (no atom fixation) for molecular docking studies using MOE 2022.02 software. T12 was built in Amber 10 forcefield (Bom solvation), and potential conformations were generated using the LowModeMD method, with hydrogen mass repartitioning enabled (Rejection limit= 20, RMS gradient = 0.1, Energy window = 15). Possible binding sites on TfR were generated using the built-in site finder function. Docking studies were performed between potential sites and existing conformations of T12, with a total of 50 poses generated using proxy triangle placement method, and further refined to 20 poses using rigid receptor refinement at a termination criterion gradient of 0. 1. Resultant poses were ranked by docking score S and were compared within and across potential binding sites.

[0457] SPR (Surface Plasmon Resonance)

[0458] Binding studies were performed on a Biacore S200 SPR system. Immobilization buffer was IX HBS-EP buffer (0.01 M HEPES. 0. 15 M NaCl, 3 mM EDTA. 0.05% v / v Surfactant P20, pH7.4) from Cytiva (BRI 00669), and running buffer was immobilization buffer with 2 % dimethyl sulfoxide (DMSO). Biotinylated Human TfR was purchased from ACROBiosystem (H82E5) and resuspended at I pg / pL in the immobilization buffer. Protein w as immobilized at 25 °C on the surface of one flow cell on the streptavidin (SA) sensor chip (Cytiva, BRI 00531) for 150 seconds at 10 pL / min to reach a level of -6000 RU, while the other cell was flowed with the immobilization buffer under the same condition (reference cell). Various concentrations of peptides, prepared in the running buffer, were injected over both flow' cells at 30 pL / minutes, 25 °C for 280 seconds contact time and 600 seconds dissociation time. Solvent corrections were performed even' 12 cycles to correct responses from the bulk refractive index changes from the peptides in DMSO. After each injection, 50 % DMSO extra wash was used to minimize the carryover across injections. Data were processed using the Biacore S200 evaluation software 1.1.1. The background response w as eliminated with subtraction from the reference cell. Contributions from buffer were eliminated by subtraction from the buffer-only injection response. Kinetics and equilibrium analysis were then performed on the resultant sensorgrams using TraceDrawer 1.1.10 software (Ridgeview Instruments AB), in combination with GraphPad Prism 10, using a one to two-state model on the TfR dimer, producing two sets of KDS.

[0459] Cell Culture hCMEC / D? cells were purchased from Millipore Sigma (SCC066). Flasks were coated under 37 °C in 5 % CO2 with collagen type I, rat tail (Millipore Sigma, 08-115) at 1:20 dilution with IX D-PBS (Gibco, 14190) for at least 1 hour prior to culturing. Cells were maintained in EndoGRO™-MV Complete Culture Media kit (Millipore Sigma, SCME004), supplemented with Ing / mL FGF-2 (Millipore Sigma, GF003) and IX penicillin / streptomycin (Gibco, 15140). Culture medium was changed every 2-3 days, and cells were passaged using 0.25% Trypsin-EDTA (Gibco, 25200). Human TfR knockout cell line-HeLa (CSC-RT1891) and the parental HeLa cell line were purchased from Creative Biogene. Cells were cultured in DMEM (Gibco, 11995) containing 10% heat-inactivated fetal bovine serum (HI FBS) (Sigma, F4135) and IX penicillin / streptomycin at 37 °C with 5 % CO2. Medium was changed every 2 days and cells were passaged using 0.25 % Trypsin-EDTA.

[0460] Biological Reagents

[0461] Streptavidin, Alexa Fluor 647 conjugate (S32357), Alexa Fluor 488 conjugate (S32354), and Dinitrophenyl-KLH Polyclonal Antibody, Alexa Fluor 488 conjugate (Al 1097) were purchased from Thermo Fisher for cell assays. All endocytosis inhibitors and competitors were prepared in DMSO stock and were diluted to the targeted concentrations. Cells were treated with either 50nM AF647 streptavidin and 1000 nM biotinylated TransMoDEs or 50nM AF488 a-DNP and 5000 nM DNP-modified TransMoDEs for 24 hours unless other notes were made. Assay media in this protocol refers to the complete medium+ 0.05% DMSO.

[0462] Endocytosis Assay

[0463] Non-limiting Embodiment: Compounds of Formula (I)

[0464] Cells were seeded at IxlO5cells / well in 48 well plates and were grown 16-20h prior to treatment. TransMoDE and target protein were premixed in assay media at room temperature for 30 minutes prior to addition to cells. Endocytosis inhibitors or competitors were prepared as 100X DMSO stocks and were added for a final concentration of 1% DMSO in all samples. Cells were treated with 5 nM Streptavidin- AF 647 and 500nM TransMoDE for 6h unless otherwise noted. Cells were trypsinized and resuspended in PBS + 1% BSA containing Ipg / mL propidium iodide for flow cytometry.

[0465] A minimum of 1000 cells were measured using an Accuri C6 flow cytometer. Median fluorescence intensities (MFI) were obtained using FlowJo software followed by Microsoft Excel analysis and GraphPad Prism formatting. AMFI was calculated by subtracting the average MFI of the no peptide control from the MFI of each sample.

[0466] Non-limiting Embodiment: Compounds of Formula (II)

[0467] Cells were seeded at 5*104cells / well in a pre-coated 96 well plate (Falcon, 353072) and were grown overnight to confluency before the assay. TfR.-targeting TransMoDEs and targeted extracellular proteins were mixed at least 30 minutes before adding to the cells. After treatment for 24 hours at 37 °C with 5 % CO2, cells were washed with D-PBS, trypsinized, and resuspended in IX D-PBS with 5 % HI FBS, 0.5 mM EDTA (AmericanBio, AB00502), 1 mM NaNs (Sigma- Aldrich, S2002), and supplemented with 1 ng / mL propidium iodide (Promokine, PK-CA707) for flow cytometry.

[0468] Attune Cytpix Flow Cytometer, with the Cytkick Max Autosampler was used for flow experiments. A minimum of 1000 live cells were collected for each well with Attune Cytometric Software v.6.1.1. for further analysis. Flowjo vlO.10, in combination with Microsoft Excel and GraphPad Prism 10 was used to obtain the normalized Amedian fluorescence intensity (MFI).

[0469] Complex of streptavidin and anti-DNP antibody for uptake In bEnd.3.

[0470] Mouse brain endothelial cells (bEnd.3) were seeded at IxlO5cells / well in 48 well plates and grown for 16-20h prior to treatment. Streptavidin (5pM) was incubated with 15pM DNP.Ac.Biotin TransMoDE and 15 .M Ac.Ac.Biotin TransMoDE overnight at 4°C. This complex was purified by Zeba desalting spin column 7k MWCO. Next 2X serial dilutions of the complex were prepared and mixed with 20 nM anti-DNP antibody for a final antibody concentration of 10 nM. The complex was incubated for 30 min at room temperature for 30 minutes. Cells were treated for 24h at 37°C with 5% CO2. Median fluorescence intensities (MFI) were obtained using FlowJo software followed by Microsoft Excel analysis and GraphPad Prism formatting. AMFI was calculated by subtracting the average MFI of the no peptide control from the MFI of each sample.

[0471] Western Blot

[0472] Cells were seeded at 2*105cells / well in a pre-coated 24 well plate (Falcon, 353047). Cells were treated with either 100 nM a-DNP-AF488 and 5000 nM DNP-modified TransMoDE or 100 nM streptavidin-AF488 and 1000 nM biotinylated TransMoDE over a 24-hour time course, followed with IX D-PBS wash for 5 minutes, 3 times. Cells were then lysed on ice for 5 minutes with IX RIPA (Millipore-Sigma, 20-188), supplemented with cOmplete protease inhibitor (Roche, 11836153001). Aggregates were removed from lysates with centrifugation at 4°C for 15 minutes, 15000xg. For degradation experiments probing a- DNP-AF488, samples were diluted 1: 1 with 2x Laemmlli Sample Buffer (Bio-Rad, 1610737) and boiled for 2 minutes. For experiments probing AF488 streptavidin and P-tubulin, samples were diluted with the same buffer containing p-mercaptoethanol and boiled for 10 minutes instead. Approximately 7.5 pL cell lysate w as loaded for each lane on the Any kD™ Mini- PROTEAN® TGX Stain-Free™ Protein Gel (Bio-Rad, 4568125), with 5 pL Precision Plus Protein Dual Color Standards as the ladder. (Bio-Rad. 1610374).

[0473] SDS-PAGE gels were run at 100V with BioRad Mini-PROTEAN Tetra Vertical Electrophoresis Cell System (1658004) using BioRad power supply (1645050). Gels were washed in Milli-Q water for 5 minutes and then transferred using the iBlot™ 3 Western Blot Transfer System (Invitrogen, IB31001) with iBlot™ 3 transfer stacks (Invitrogen, IB34001) at 25V to the PVDF membrane for 6 minutes with low cooling condition, except for probing streptavidin- AF488 degradation, when 3 minutes and medium cooling were used instead. Membranes w ere blocked, washed, and incubated with antibodies using iBind™ Flex Western System (Invitrogen. SLF2000) with buffer prepared in iBind™ Flex Solution kit (Invitrogen, SLF2020X4) for at least 2h 30 minutes. Rabbit a-AF488 polyclonal antibody (Thermo Fisher, A11094) (1: 1000) and a-P-tubulin (Abeam, ab6046) (1:500) were prepared as primary antibodies. HRP -conjugated anti-rabbit IgG was prepared as the secondary antibody (Abeam, ab205718, 1 :2000). Blots were washed with Milli-Q water for 2 minutes afterwards and imaged on the BioRad ChemiDoc touch imaging system. Band intensity was quantified and normalized using imaged 2. 14.0. Equation 2. Signal Normalization on Tubulin:

[0474] Western Blot for degradation, depletion and protein expression (mouse brain endothelial cells)

[0475] Mouse brain endothelial cells (bEnd.3) were seeded at 2x105cells / well in 24 well plates and grown for 16-20h prior to treatment. Cells were treated for 24h at 37°C with 5% CO2 then washed 3x5 min with PBS. Cell lysates were prepared using IX RIPA (Millipore- Sigma, 20-188) + complete protease inhibitor (Roche, 11836153001) for 5 minutes on ice. Lysates were cleared by centrifugation at 15,000xg for 15 min at 4°C. Samples were diluted with 2x Laemelli Sample Buffer (Bio-Rad, 1610737) containing p-mercaptoethanol and boiled for 10 min prior to loading on AnyKd gel (Bio-Rad, 4568125). SDS-PAGE gels were run and transferred to 0.45pm PVDF membrane. Briefly, gels were run at 120V and transferred in transfer buffer (20% MeOH, 25mM tris base, 192 mM glycine) at 4°C for Ih using 300 mA. Blots were blocked for Ih with PBS + 5% BSA. Blots were washed 3x5 min with PBS + 0.2% Tween 20 (AmericanBio, AB02038-00500) after each antibody incubation. Gels were imaged using a ChemiDoc imaging system (Bio-Rad). Band intensity w as measured using Image J software.

[0476] For degradation experiments, approximately 7.5pL cell lysate was loaded to gels for western blot analysis. Cell lysate loading was normalized based on the actin concentration. Blots were probed for AF488 and actin (rabbit anti-488 antibody, Thermo, A-l 1094, 1: 10,000 and rabbit anti-actin, abeam, ab8227, 1: 1,000) for Ih, follow ed by HRP-conjugated anti-rabbit IgG (Abeam, ab205718, 1 : 10,000) for Ih.

[0477] For depletion experiments, cells were treated with pre-mixed 500 nM TransMoDE and 5 nM Streptavidin- AF488 for 24h. Cell lysates and cell culture supernatant were collected, 3.75 L cell culture supernatant was analyzed by western blot.

[0478] Transcytosis across a bEnd.3 monolayer

[0479] Mouse brain endothelial cells (bEnd.3) were seeded at 1x105cells / well in the apical compartment of a 6.5 mm, 0.4pm pore, poly ester membrane transwell plate (Coming, 3470). Media was replaced daily and transendothelial electrical resistance was monitored using the EVOM every other day.

[0480] Equation 1A. Transend othelial electrical resistance (TEER):

[0481] TEERreported(^measured Pblank) ^area

[0482] TEER was calculated using Equation 1A, where Rmeasured is the resistance across a cell monolayer, Rbiank is the resistance across a cell-free membrane and S is the area of the membrane insert (0.36 cm2). The apical compartment contained lOOpL volume while the basal compartment contained 600pL. Streptavidin-AF647 (50nM) and Ac.Ac.Biotin TransMoDE 3 were pre-mixed for 30 minutes prior to addition to cells. Streptavidin- AF647 fluorescence of 50pL aliquots from the apical and basal compartments was monitored at different timepoints using a BMG LabTech plate reader in a 96-well plate. Apparent permeability (Papp) and effective permeability (Pe)was calculated using Equations 2A-4A, where C is the initial concentration at 0 min for the treated compartment. Pno monolayer IS calculated using the Pappequation for a cell-free system.

[0483] Equation 2A. Apparent permeability:

[0484] Equation 3A. Cleared volume:

[0485] Equation 4A. Effective Permeability:

[0486] For a positive control of receptor-mediated transcytosis, Transferrin-AF647, 80kDa, (Thermo, T23366) was prepared at 50nM. For a negative control showing passive migration, Dextran-Fluorescein, 70kDa, (Thermo, D1823) was prepared at 7.24pM.

[0487] Confocal Microscopy

[0488] Cells were seeded at l*105cells / dish on the pre-coated glass bottom MatTek 35mm Petri dishes (P35GC-1.5-14-C) overnight at 37 °C with 5% CO2. Cells were then treated with either 100 nM streptavidin-AF488 or 100 nM a-DNP-AF488 and corresponding TransMoDEs for 24 hours. Following incubation, both sets of samples containing live cells were treated with 100 nM Lysotracker Deep Red (Thermo Fischer, L12492) and 10 mg / mL DAPI (Thermo Fisher, 62248) to stain Ivsosomes and nuclei, respectively. After 30 minutes of staining, the samples were washed with D-PBS and replaced with the culturing medium and then subjected for imaging using a spinning disk confocal microscope (Nikon Ti2-E with Yokogawa Wl) with a 60x oil immersion objective (NA = 1.4). A 488 nm laser was utilized to visualize the extracellular protein internalization. For imaging nuclei and lysosomes, 405 nm and 647 nm lasers with the appropriate filters were employed, respectively. Images were captured with a sCMOS camera (Photometries Prime BSI) at a z-step size of 0.5 pm. All image processing such as cropping, montage preparation, etc for publication were performed via ImageJ 2.14.0. Colocalization analysis and Pearson correlation analysis was performed using the plugin JACoP v2. 1.4.

[0489] Transwell Assay

[0490] Cells were seeded at l*105cells / well in the apical compartment of a 6.5mm Coming transwell plate with 0.4 pm pore polyester insert (3470). Media was replaced every' day. The confluency of hcMEC / Ds monolayer was checked with EVOM and quantified using transendothelial electrical resistance (TEER) every other day. The method of measuring and calculating TEER was the same as previously described. To ensure the confluency of the monolayer, Dextran-Fluorescein (40 kDa, 50 kDa, 70 kDa, 150 kDa) from Thermo Fisher were prepared at 0.5 mg / mL as a negative control to quantify the level of passive migration. For measuring transcytosis of streptavidin, 50 nM streptavidin-AF647 and corresponding TransMoDEs (1000 nM) were premixed 30 minutes before addition to cells via apical compartment (100 pL) or basal compartment (600 pL). The concentration of streptavidin was monitored by taking 50 pL aliquots from the opposite compartment and measured with a BMG LabTech plate reader at different time points over a 24-hour time course. The methods of calculating and equations of deriving effective permeability constant (Pe) with and without the presence of TransMoDEs were detailed previously. The full calculations are provided in the Supporting Information.

[0491] Statistical Analysis

[0492] Significance was determined using either an unpaired t test, one-way ANOVA or Kruskal-Wallis nonparametric test with P<0.0001 “****’ P<0.001 “***”, P<0.01 P<0.05 and P>0.05 "ns".

[0493] The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary’ skill in the art. and that such modifications and variations are considered to be within the scope of embodiments of the present application.

[0494] Enumerated Embodiments

[0495] The following enumerated embodiments are provided, the numbering of which is not to intended to imply importance or priority.

[0496] Embodiment 1 provides a compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer, having the structure of formula (I): wherein:

[0497] R is independently at each occurrence: i) — (L)P— A — RBT, wherein:

[0498] RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 50, wherein the brain targeting peptide is connected to A by its C-terminal or N-terminal amino acid; ii) — (L)P— X, wherein:

[0499] X is a brain targeting ligand; iii) — (L)P— H; or iv) — (L)p — EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;

[0500] L is independently at each occurrence a chemical linker;

[0501] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol. alcohol, triazole, or alkyne group covalently bonded to RBT;

[0502] RAis independently at each occurrence H,

[0503] RNis independently at each occurrence H

[0504] G is independently at each occurrence R, NHR, CH2R, C(=O)R, C(=O)OR.

[0505] Z is independently at each occurrence CH2 or C(=O);

[0506] R’ is independently at each occurrence H or R; p is independently at each occurrence 0, 1. 2, 3, 4. 5, 6, 7, 8. 9, 10, 11, 12, 13, 14. 15. 16, 17, 18, 19, or 20; and n is independently at each occurrence 1, 2, 3, 4, 5, or 6.

[0507] Embodiment 2 provides the compound of embodiment 1, wherein RAis

[0508] Embodiment 3 provides the compound of any one of embodiments 1-2, wherein Rcis

[0509] Embodiment 4 provides the compound of any one of embodiments 1-3, wherein RBis

[0510] Embodiment 5 provides the compound of any one of embodiments 1-4, wherein n is 1, 2, 3, or 4.

[0511] Embodiment 6 provides the compound of any one of embodiments 1-5. wherein n is . Embodiment 7 provides the compound of any one of embodiments 1-6, wherein G is

[0512] NHR.

[0513] Embodiment 8 provides the compound of any one of embodiments 1-7, wherein if at least one RAis not H, then each RNis H. Embodiment 9 provides the compound of any one of embodiments 1-8, wherein if at least one RNis not H, then each RAis H.

[0514] Embodiment 10 provides the compound of any one of embodiments 1-9, having the structure:

[0515] Embodiment 11 provides the compound of any one of embodiments 1-10, having the structure:

[0516] Embodiment 12 provides the compound of any one of embodiments 1-11, having the

[0517] Embodiment 13 provides the compound of any one of embodiments 1-12, having the Embodiment 14 provides the compound of any one of embodiments 1-13, having the

[0518]

[0519] Embodiment 15 provides the compound of any one of embodiments 1-14, wherein A is: and the atom marked with ** is attached to RBT.

[0520] Embodiment 16 provides the compound of any one of embodiments 1-17, wherein L is selected from the group consisting of: i) a group according to the structure:

[0521] wherein:

[0522] RCON1and RCON2are each independently H, methyl, or a bond;

[0523] X2is independently at each occurrence CH2, O, S, NR4, C(O). S(O), S(O)2, - S(O)2O, -OS(O)2, or OS(O)2O;

[0524] X3is independently at each occurrence O, S, or NR4; and

[0525] R4is independently at each occurrence H, C1-C3 alkyd, C1-C3 alkanol, or - C(O)(Ci-C3alkyl); ii) a group according to the structure: wherein:

[0526] R1is H or C1-C3 alkyl; and n” is independently an integer from 0, 1, 2, 3, 4, 5, 6, 7, or 8; iii) a group according to the structure: wherein R1C0N. R2CON, and R3CONare each independently H, -(CH2)MCI-, - (CH2)MC1aC(O)xA(NR4)xA-(CH2)MC1a-.-(CH2)MCla(NR4)xAC(O)XA-(CH2)MCla-, or -(CH2)MC iaO-(CH2)Mc i -C (O)NR4-, with the proviso that R1C0N, R2C0N. and R3C0Nare not simultaneously H; each MCI is independently 1, 2, 3, or 4; each MCI a is independently 1, 2, 3, or 4; each XA is independently 0 or 1 ; and

[0527] R4is H, C1-C3 alkyl, C1-C3 alkyl substituted by one or two hydroxyl groups, or -

[0528] C(O)(Ci-C3 alkyl), with the proviso that MCI a and XA in a moiety are not all simultaneously 0; iv) a group according to the structure: wherein

[0529] Ra is H. C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups, or Ra taken together with R3form a pyrrolidine ring or a hydroxypyrrolidine ring, m is independently an integer from 1 to 15, and each R3is independently an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxy amide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1- methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R3forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1 -hydroxy ethane), tryptophan (methyleneindole), ty rosine (methylene phenol) and valine (isopropyl); v) a group according to the structure: wherein:

[0530] Ram is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each na is independently an integer from 1 to 15; and m is an integer from 1 to 100; vi) a group according to the chemical formula: wherein:

[0531] Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)I-S-, or -(CH2)i- N(R)-, wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100; or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds; j is an integer from 1 to 100; nr is an integer from 1 to 100; n is an integer from 1 to 100;

[0532] X1is O, S, or N-R;

[0533] R is H, C1-C3 alkyl, or C1-C3 alkyd substituted by one or two hydroxyl groups; vii) a group with the structure: wherein n is an integer from 1 to 25; n’ is an integer from 1 to 25; n” is an integer from 0 to 8; and viii) a group with the chemical formula: PEG-[CON]-PEG. wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol

[0534] Embodiment 17 provides the compound of any one of embodiments 1-18, wherein , wherein q is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and the *** represents an attachment point to A.

[0535] Embodiment 18 provides the compound of any one of embodiments 1-17, wherein q is 6.

[0536] Embodiment 19 provides the compound of any one of embodiments 1-18, having the structure:

[0537]

[0538] Embodiment 21 provides the compound of any one of embodiments 1-20, wherein the compound is Embodiment 22 provides the compound of any one of embodiments 1-21, wherein the compound is

[0539]

[0540] Embodiment 23 provides the compound of any one of embodiments 1-22, wherein the compound is

[0541] Embodiment 24 provides the compound of any one of embodiments 1-23, wherein EPT is an extracellular protein targeting peptide of any of SEQ ID NOs: 51 to 64. Embodiment 25 provides a method of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or a tauopathy in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of any of claims 1-24, which is optionally formulated as a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient or carrier.

[0542] Embodiment 26 provides the method of embodiment 25, wherein the disease or disorder is at least one of primary age-related tauopathy (PART) / neurofibrillary tangle- predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica. progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

[0543] Embodiment 27 provides the method of any one of embodiments 25-26, wherein the subject is human.

[0544] Embodiment 28 provides the method of any one of embodiments 25-27, wherein the administering is by a route selected from the group consisting of oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, transdermal, intravesical, intrapulmonary, intraduodenal, intragastrical. intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0545] Embodiment 29 provides the method of any one of embodiments 25-28, wherein the therapeutically effective dose is about 1 to about 1000 mg of the compound.

[0546] Embodiment 30 provides a compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (II): formula (II), wherein:

[0547] Cy represents a ring selected from the group consisting of a six-membered aromatic ring, a six-membered heteroaromatic ring, a seven-membered carbocyclic ring, a seven- membered heterocyclic ring, an eight-membered carbocyclic ring, and an eight-membered heterocyclic ring;

[0548] Z1 is a six-membered aromatic or heteroaromatic ring fused to ring Cy, optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR", 0C(0)N(R")2, CN, NO, NO2, ONO2, CF3, OCF3, R", N(R")2, SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, 0C(0)N(R")2, C(S)N(R")2, (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2. N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(O)N(R")2, N(R")SO2R", N(R")SO2N(R")2, N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(O)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";

[0549] Z2 is N-R4 or NH-R4, wherein one of the following applies: i) if Cy is a six-membered aromatic or heteroaromatic ring, NH-R4 is a substituent on Cy; ii) if Cy is a seven-membered carbocyclic ring, then NH-R4 is a substituent on

[0550] Cy; hi) if Cy is a seven-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy; iv) if Cy is an eight-membered carbocyclic ring, then NH-R4 is a substituent on Cy; v) if Cy is an eight-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy;

[0551] Z3 is at least one substituent on Cy selected from the group consisting of F, Cl, Br, I, OR", OC(O)N(R")2, CN, NO, NO2, ONO2. azido, CF3, OCF3, R", O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R")2. SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, OC(O)N(R")2, C(S)N(R")2, (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(0)N(R")2, N(R")SO2R", N(R")SO2N(R")2. N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R". N(R")C(0)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";

[0552] R" is independently at each occurrence H or C1-10 hydrocarbyl; q is 0, 1, 2, 3. 4, or 5; w is 0, 1, or 2; Y is — (L)P— A — RBT, wherein: i) RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1-50, wherein the brain targeting peptide is connected to A through its C-terminal or N-terminal amino acid; or ii) — (L)P— X, wherein X is a brain targeting ligand;

[0553] R4 is — (L)P— EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;

[0554] A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;

[0555] L is independently at each occurrence a chemical linker; and p is independently at each occurrence an integer from 0 to 40. Embodiment 31 provides the compound of embodiment 30. wherein EPT is an extracellular protein targeting peptide of any of SEQ ID NOs: 1-64.

[0556] Embodiment 32 provides the embodiment of any one of embodiments 30-31, having the structure:

[0557] Embodiment 33 provides the embodiment of any one of embodiments 30-32, having the structure: Embodiment 34 provides the embodiment of any one of embodiments 30-33, wherein

[0558] L is selected from the group consisting of: i) a group according to the structure: wherein: one of RCON1and RCC)N2is H, methyl, or a bond and the other is a bond;

[0559] X2is independently at each occurrence CH2, O, S, NR4, C(O), S(O), S(O)2, - S(O)2O, -OS(O)2. or OS(O)2O;

[0560] X3is independently at each occurrence O, S. or NR4; and

[0561] R4is independently at each occurrence H, C1-C3 alkyl, C1-C3 alkanol, or - C(O)(Ci-Cs alkyl); ii) a group according to the structure: wherein:

[0562] R1is H or C1-C3 alkyl; and n" is independently an integer from 0, 1. 2, 3, 4, 5. 6, 7, or 8; iii) a group according to the structure: wherein R1C0N, R2CON, and R3CONare each independently H, -(CH2)MCI-, - (CH2)MClaC(O)XA(NR4)XA-(CH2)MCla-,-(CH2)MCla(NR4)XAC(O)X -(CH2)Mda-, or

[0563] -(CH2)MciaO-(CH2)Mci-C(O)NR4-, with the proviso that R1C0N, R2('o. and R3C0Nare not simultaneously H; each MCI is independently 1, 2, 3, or 4; each MC I a is independently 1. 2, 3, or 4; each XA is independently 0 or 1 ; and

[0564] R4is H, C1-C3 alky l, Ci-Cs alkyl substituted by one or two hydroxyl groups, or - C(O)(Ci-C3alkyl), with the proviso that MCI a and XA in a moiety are not all simultaneously 0; iv) a group according to the structure: wherein

[0565] Ra is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups, or Ra taken together with R3form a pyrrolidine ring or a hydroxypyrrolidine ring, m is independently an integer from 1 to 15, and each R3is independently an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxy amide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1- methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyd), proline, hydroxyproline (R3forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol. 1 -hydroxy ethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl); v) a group according to the structure: wherein:

[0566] Ram is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each na is independently an integer from 1 to 15; and m is an integer from 1 to 100; vi) a group according to the chemical formula: wherein:

[0567] Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)i-S-, or -(CH2)i- N(R)-, wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100; or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds and no more than two CH(NH2) groups are present in D; j is an integer from 1 to 100; m’ is an integer from 1 to 100; n is an integer from 1 to 100;

[0568] X1is O, S, or N-R;

[0569] R is H, C1-C3 alkyl, or C1-C3 alkyd substituted by one or two hydroxyl groups; vii) a group with the structure: wherein n is an integer from 1 to 25; n’ is an integer from 1 to 25; n” is an integer from 0 to 8; and viii) a group with the chemical formula: PEG-[CON]-PEG, wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues

[0570] Embodiment 35 provides the embodiment of any one of embodiments 30-34, wherein

[0571] L independently selected from: i) a group according to the chemical formula: wherein:

[0572] Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)i-S-, or -(CH2)i- N(R)-, wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100;

[0573] NH2

[0574] - (CH)m- or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds and no more than two CH(NH2) groups are present in D; j is an integer from 1 to 100; m’ is an integer from 1 to 100; n is an integer from 1 to 100;

[0575] X1is O, S, or N-R;

[0576] R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; and ii) a group with the structure: wherein n is an integer from 1 to 25; n' is an integer from 1 to 25; n’?is an integer from 0 to 8.

[0577] Embodiment 36 provides the embodiment of any one of embodiments 30-35, wherein the compound has the structure:

[0578] Embodiment 37 provides the embodiment of any one of embodiments 30-36, wherein RBThas the amino acid sequence of SEQ ID NO: 10.

[0579] Embodiment 38 provides the embodiment of any one of embodiments 30-37, wherein

[0580] R4 has the structure wherein t is 4, 5, 6, 7, 8, 9, 10, 11, 12,

[0581] 13, 14, 15, 16, 17, 18, 19, or 20.

[0582] Embodiment 39 provides the embodiment of any one of embodiments 30-38, wherein

[0583] Embodiment 40 provides the embodiment of any one of embodiments 30-39, wherein A is: the atom marked with ** is attached to RBT.

[0584] Embodiment 41 provides the embodiment of any one of embodiments 30-40, wherein the compound is selected from the group consisting of

[0585] and

[0586]

[0587] Embodiment 42 provides a method of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or a tauopathy in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 30-40, which is optionally formulated as a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient or carrier.

[0588] Embodiment 43 provides the embodiment of embodiment 42, wherein the disease or disorder is at least one of primary age-related tauopathy (PARTj / neurofibrillary tangle- predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica. progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

[0589] Embodiment 44 provides the embodiment of any one of embodiments 42-43, wherein the subject is human.

[0590] Embodiment 45 provides the embodiment of any one of embodiments 42-44, wherein the administering is by a route selected from the group consisting of oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, transdermal, intravesical, intrapulmonary, intraduodenal, intragastricak intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0591] Embodiment 46 provides the embodiment of any one of embodiments 42-45, wherein the therapeutically effective dose is about 1 to about 1000 mg of the compound. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

[0592] While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (I):wherein:R is independently at each occurrence: i) — (L)P— A — RBT, wherein:RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 50, wherein the brain targeting peptide is connected to A by its C-terminal or N-terminal amino acid; ii) — (L)P— X, wherein:X is a brain targeting ligand; iii) — (L)P— H; or iv) — (L)p — EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;L is independently at each occurrence a chemical linker;A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or iii) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;RAis independently at each occurrence HRNis independently at each occurrence H orG is independently at each occurrence R, NHR, CH2R, C(=O)R, C(=O)OR,Z is independently at each occurrence CH2 or C(=O);R?is independently at each occurrence H or R; p is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and n is independently at each occurrence 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1 , wherein RAis3. The compound of claim 1, wherein Rcis4. The compound of claim 1 , wherein RBis5. The compound of claim 1, wherein n is 1, 2. 3, or 4.

6. The compound of claim 5, wherein n is 4.

7. The compound of claim 1, wherein G is NHR.

8. The compound of claim 1, wherein if at least one RAis not H, then each RNis H.

9. The compound of claim 1 , wherein if at least one RNis not H. then each RAis H.

10. The compound of claim 1, having the structure:1 1. The compound of claim 1 , having the structure:

12. The compound of claim 11, having the structure:

13. The compound of claim 1, having the structure:

14. The compound of claim 13, having the structure:

15. The compound of claim 1, wherein A is:wherein the atom marked with * is attached to (L)P; and the atom marked with ** is attached to RBT.

16. The compound of claim 1, wherein L is selected from the group consisting of: i) a group according to the structure:one of RCON1and RCON2is H, methyl, or a bond and the other is a bond;X2is independently at each occurrence CH2. O, S. NR4, C(O). S(O), S(O)2, - S(O)2O, -OS(O)2, or OS(O)2O;X3is independently at each occurrence O, S, or NR4; andR4is independently at each occurrence H, C1-C3 alky l, C1-C3 alkanol, or - C(O)(Ci-C3 alkyl); ii) a group according to the structure:wherein:R1is H or C1-C3 alkyl; and n” is independently an integer from 0, 1, 2, 3, 4, 5, 6, 7, or 8; iii) a group according to the structure:wherein R1C0N, R2CON, and R3CONare each independently H, -(CH2)MC1-, - (CH2)MC1aC(O).XA(NR4)xA-(CH2)MC1a-,-(CH2)MCla(NR4)xAC(O)xA-(CH2)MC1a-, or-(CH2)MciaO-(CH2)Mci-C(O)NR4-. with the proviso that R1C0N, R2CON. and R3C0Nare not simultaneously H;each MCI is independently 1, 2, 3. or 4; each MCI a is independently 1, 2, 3, or 4; each XA is independently 0 or 1 ; andR4is H, C1-C3 alkyl, C1-C3 alkyl substituted by one or two hydroxyl groups, or -C(O)(Ci-C3alkyl), with the proviso that MCI a and XA in a moiety are not all simultaneously 0; iv) a group according to the structure:whereinRa is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hy droxyl groups, or Ra taken together with R3form a pyrrolidine ring or a hydroxypyrrolidine ring, m is independently an integer from 1 to 15, and each R3is independently an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxy amide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1- methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl ), proline, hydroxyproline (R3forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1 -hydroxy ethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl); v) a group according to the structure:wherein:Ram is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups;each na is independently an integer from 1 to 15; and m is an integer from 1 to 100; vi) a group according to the chemical formula:wherein:Z and Z'are each independently a bond, -(CH2)i-0-. -(CH2)i-S-. or -(CH2)i- N(R)-,wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O. S, or N-R; each i is independently 0 to 100;or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds; j is an integer from 1 to 100; m’ is an integer from 1 to 100; n is an integer from 1 to 100;X1is O, S, or N-R;R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; vii) a group with the structure:wherein n is an integer from 1 to 25;n' is an integer from 1 to 25; is an integer from 0 to 8; and viii) a group with the chemical formula: PEG-[CON]-PEG, wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues andwherein q is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and the *** represents an attachment point to A.The compound of claim 17, wherein q is 6.

20. The compound of claim 1 , wherein21. The compound of claim 1, wherein the compound is22. The compound of claim 1 , wherein the compound is25. A method of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or a tauopathy in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1, which is optionally formulated as a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient or carrier.

26. The method of claim 25. wherein the disease or disorder is at least one of primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy , tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

27. The method of claim 25, wherein the subject is human.

28. The method of claim 25, wherein the administering is by a route selected from the group consisting of oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, transdermal, intravesical, intrapulmonary. intraduodenal, intragastrical. intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

29. The method of claim 25, wherein the therapeutically effective dose is about 1 to about 1000 mg of the compound.

30. A compound, or a salt, solvate, geometric isomer, enantiomer, and / or diastereomer thereof, having the structure of formula (II): formula (II).wherein:Cy represents a ring selected from the group consisting of a six-membered aromatic ring, a six-membered heteroaromatic ring, a seven-membered carbocyclic ring, a sevenmembered heterocyclic ring, an eight-membered carbocyclic ring, and an eight-membered heterocyclic ring;Z1 is a six-membered aromatic or heteroaromatic ring fused to ring Cy. optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br. I, OR". 0C(0)N(R")2, CN, NO, NO2, ONO2, CF3, OCF3, R", N(R")2, SR", SOR", SO2R", SO2N(R")2, SO3R", C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, 0C(0)N(R")2, C(S)N(R")2, (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(0)N(R")2, N(R")SO2R". N(R")SO2N(R")2, N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(O)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";Z2 is N-R4 or NH-R4, wherein one of the following applies: i) if Cy is a six-membered aromatic or heteroaromatic ring, NH-R4 is a substituent on Cy; ii) if Cy is a seven-membered carbocyclic ring, then NH-R4 is a substituent onCy; iii) if Cy is a seven-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy; iv) if Cy is an eight-membered carbocyclic ring, then NH-R4 is a substituent on Cy; v) if Cy is an eight-membered heterocyclic ring, then the nitrogen atom in N-R4 is a ring atom in Cy;Z3 is at least one substituent on Cy selected from the group consisting of F, Cl, Br, I, OR", OC(O)N(R")2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R", O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R")2, SR", SOR", SO2R", SO2N(R")2, SOsR". C(O)R", C(O)C(O)R", C(O)CH2C(O)R", C(S)R", C(O)OR", OC(O)R", C(O)N(R")2, OC(O)N(R")2, C(S)N(R")2. (CH2)O-2N(R")C(0)R", (CH2)O-2N(R")N(R")2, N(R")N(R")C(O)R", N(R")N(R")C(O)OR", N(R")N(R")C(0)N(R")2, N(R")SO2R", N(R")SO2N(R")2. N(R")C(O)OR", N(R")C(O)R", N(R")C(S)R", N(R")C(0)N(R")2, N(R")C(S)N(R")2, N(C(O)R")C(O)R", N(OR")R", C(=NH)N(R")2, C(O)N(OR")R", and C(=NOR")R";R" is independently at each occurrence H or Ci-io hydrocarbyl; q is 0, 1, 2, 3. 4, or 5: w is 0, 1, or 2;Y is — (L)P— A — RBT, wherein: i) RBTis a brain targeting peptide having the amino acid sequence of any one of SEQ ID NO: 1-50, wherein the brain targeting peptide is connected to A through its C-terminal or N-terminal amino acid; or ii) — (L)P— X, wherein X is a brain targeting ligand;R4 is — (L)P— EPT, wherein EPT is an extracellular protein targeting ligand, an extracellular protein targeting peptide, or a means for binding to an extracellular protein;A is i) a bond; ii) an amino acid which is aspartic acid, glutamic acid, arginine, lysine, cysteine, serine, or tyrosine; or hi) a non-natural amino acid containing a carboxylic acid, amine, thiol, alcohol, triazole, or alkyne group covalently bonded to RBT;L is independently at each occurrence a chemical linker; and p is independently at each occurrence an integer from 0 to 40.

31. The compound of claim 30, wherein EPT is an extracellular protein targeting peptide of any of SEQ ID NOs: 51-64.

32. The compound of claim 30, having the structure:

33. The compound of claim 30, having the structure:

34. The compound of claim 1, wherein L is selected from the group consisting of: i) a group according to the structure:wherein: one of RCON1and RCC)N2is H, methyl, or a bond and the other is a bond;X2is independently at each occurrence CH2, O, S, NR4, C(O), S(O), S(O)2, - S(O)2O, -OS(O)2. or OS(O)2O;X3is independently at each occurrence O, S, or NR4; andR4is independently at each occurrence H, C1-C3 alkyl, C1-C3 alkanol, or - C(O)(Ci-C3 alkyl); ii) a group according to the structure:wherein:R1is H or C1-C3 alkyl; and n” is independently an integer from 0, 1, 2, 3, 4, 5, 6, 7, or 8; iii) a group according to the structure:wherein R1C0N. R2CON, and R3CONare each independently H, -(CH2)MCI-, - (CH2)MClaC(O)xA(NR4)xA-(CH2)MCla-,-(CH2)MGla(NR4)xAC(O)xA-(CH2)MCla-, or-(CH2)MClaO-(CH2)MCl-C(O)NR4-, with the proviso that R1C0N, R2C0N. and R3C0Nare not simultaneously H; each MCI is independently 1, 2. 3, or 4; each MCI a is independently 1 , 2, 3, or 4; each XA is independently 0 or 1 ; andR4is H, C1-C3 alkyl, C1-C3 alkyl substituted by one or two hydroxyl groups, or -C(O)(Ci-C3 alkyl), with the proviso that MCI a and XA in a moiety are not all simultaneously 0; iv) a group according to the structure:whereinRa is H. C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups, or Ra taken together with R3form a pyrrolidine ring or a hydroxypyrrolidine ring, m is independently an integer from 1 to 15, and each R3is independently an amino acid side chain from a D- or L-amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R3forms a cyclic ring with Ra and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1 -hydroxy ethane), tryptophan (methyleneindole), tyrosine (methylene phenol) and valine (isopropyl);V) a group according to the structure:wherein:Ram is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each na is independently an integer from 1 to 15; and m is an integer from 1 to 100; vi) a group according to the chemical formula:wherein:Z and Z’ are each independently a bond, -(CH2)i-0-. -(CH2)i-S-. or -(CH2) - N(R)-,wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O. S, or N-R; each i is independently 0 to 100;or a bond, with the proviso that Z, Z’, and D are not each simultaneously bonds and no more than two CH(NH2) groups are present in D; j is an integer from 1 to 100; m’ is an integer from 1 to 100; n is an integer from 1 to 100;X1is O, S, or N-R;R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; vii) a group with the structure:wherein n is an integer from 1 to 25; n’ is an integer from 1 to 25; n” is an integer from 0 to 8; and viii) a group with the chemical formula: PEG-[CON]-PEG. wherein each PEG is independently at each occurrence 1 to 12 ethylene glycol residues and35. The compound of claim 34, wherein L independently selected from: i) a group according to the chemical formula:wherein:Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)i-S-, or -(CH2)i-N(R)-,wherein: each R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; each R2is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100;NH2- (CH)m- or a bond, with the proviso that Z, Z\ and D are not each simultaneously bonds and no more than two CH(NH2) groups are present in D; j is an integer from 1 to 100; m’ is an integer from 1 to 100; n is an integer from 1 to 100;X1is O, S, or N-R;R is H, C1-C3 alkyl, or C1-C3 alkyl substituted by one or two hydroxyl groups; and ii) a group with the structure:wherein n is an integer from 1 to 25; n’ is an integer from 1 to 25; n'’ is an integer from 0 to 8.

36. The compound of claim 34, wherein the compound has the structure:

37. The compound of claim 36, wherein RBThas the amino acid sequence of SEQ ID NO:10.

38. The compound of claim 30, wherein R4 has the structurewherein t is 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

39. The compound of claim 38, wherein EPT is40. The compound of claim 30, wherein A is:wherein the atom marked with * is attached to (L)P; and the atom marked with ** is attached to RBT.

41. The compound of claim 30, wherein the compound is selected from the group consisting of42. A method of preventing, treating, and / or ameliorating a neurodegenerative disease, a neurological disorder, and / or a tauopathy in a subject, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of claim 30, which is optionally formulated as a pharmaceutically acceptablecomposition comprising at least one pharmaceutically acceptable excipient or carrier.

43. The method of claim 42, wherein the disease or disorder is at least one of primary age-related tauopathy (PART) / neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, lipofuscinosis, Huntington’s disease, Alzheimer’s disease, and argyrophilic grain disease.

44. The method of claim 42, wherein the subject is human.

45. The method of claim 42, wherein the administering is by a route selected from the group consisting of oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, transdermal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

46. The method of claim 42. wherein the therapeutically effective dose is about 1 to about 1000 mg of the compound.

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