Methods of detecting neurological disorders via binding to phosphorylated tau protein

Abstract

To provide methods and compositions for determining whether a patient suffers from a neurological disease or whether a disorder is provided.SOLUTION: Provided herein are methods and compositions for determining whether a patient suffers from a neurological disease or whether a disorder is provided, the methods comprising detecting the presence of a phosphorylated tau protein in a tissue of the patient, where the detecting comprises contacting the phosphorylated tau protein with a compound described herein.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 902,265, filed September 18, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Neurological disorders are diseases of the brain, spinal cord, and peripheral nervous system. In terms of epidemiology and individual morbidity, neurological conditions impose the greatest social costs. The best known of these are Alzheimer's disease and Parkinson's disease. Other neurodegenerative conditions include age-related conditions (e.g., Parkinson's dementia, vascular dementia, amyotrophic lateral sclerosis), genetic syndromes (e.g., Down's syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic encephalopathy), and conditions that are usually considered purely psychiatric in nature, such as schizophrenia and depression.

[0003] Microtubule-associated protein tau (MAPT) is a family of proteins that stabilize microtubules during assembly and disassembly. MAPT transcripts are differentially expressed in the nervous system depending on the neuronal maturation stage and neuronal type. MAPT gene mutations are associated with several neurological disorders, such as Alzheimer's disease, Pick's disease, frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy. For example, tau protein in the diseased brains of patients with Alzheimer's disease may be abnormally phosphorylated compared to that of normal brains. Thus, there is a need for materials and methods for detecting phosphorylated tau protein. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, a method is provided for determining whether a patient suffers from a neurological disease or disorder, comprising detecting the presence of phosphorylated tau protein in the tissue of the patient, and the detecting comprises contacting phosphorylated tau protein with a compound as described herein.The compound can be a compound of formula I, II, Ia, Ib, Ic, Id, or Ie.In some embodiments, the compound is compound 1, 2, 3, 4, or 5.

[0005] In some embodiments, the neurological disease or disorder is selected from age-related disease or disorder, genetic disease or disorder, injury-related disease or disorder, and psychiatric disease or disorder. In some embodiments, the age-related disease or disorder is selected from Parkinson's dementia, vascular dementia, and amyotrophic lateral sclerosis, the genetic disease or disorder is Down's syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the psychiatric disease or disorder is selected from schizophrenia and depression. The neurological disease or disorder can be Alzheimer's disease or chronic traumatic encephalopathy (CTE). The neurological disease or disorder can be tauopathy.

[0006] In some embodiments, a method is provided for preparing a patient for diagnosis of a neurological disease or disorder, comprising administering to the patient a compound described herein. The compound can be a compound of formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is compound 1, 2, 3, 4, or 5. In some embodiments, the administration is intravenous or localized to the retina of the eye. In some embodiments, the administration is topical. [Brief description of the drawings]

[0007] [Figure 1A] Retinal sections from 3RTau mice of different ages stained with 3RTau Ab, compound 5 and DAPI at 3 months (Figure 1A), 6 months (Figure 1B) and 12 months (Figure 1C) are shown. [Figure 1B]Retinal sections from 3RTau mice of different ages stained with 3RTau Ab, compound 5 and DAPI at 3 months (Figure 1A), 6 months (Figure 1B) and 12 months (Figure 1C) are shown. [Figure 1C] Retinal sections from 3RTau mice of different ages stained with 3RTau Ab, compound 5 and DAPI at 3 months (Figure 1A), 6 months (Figure 1B) and 12 months (Figure 1C) are shown. [Figure 2A] Shown are retinal sections from a 3RTau mouse (12 months) stained with 3RTau Ab, compound 5 and DAPI (FIG. 2A) and retinal sections from a wild-type mouse (12 months) stained with 3RTau Ab, compound 5 and DAPI (FIG. 2B). [Figure 2B] Shown are retinal sections from a 3RTau mouse (12 months) stained with 3RTau Ab, compound 5 and DAPI (FIG. 2A) and retinal sections from a wild-type mouse (12 months) stained with 3RTau Ab, compound 5 and DAPI (FIG. 2B). [Diagram 3] 3RTau mouse (12 months) retinal sections stained with 3RTau Ab, compound 5 and DAPI are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] definition The following description describes exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0009] As used herein, the following words, phrases, and symbols are intended to have the meanings generally set forth below, except to the extent that the context in which they are used indicates otherwise.

[0010] The term “alkyl,” by itself or as part of another substituent, refers to straight-chain (i.e., unbranched) or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and has a specified number of carbon atoms (i.e., C1 to C6).10 means 1 to 10 carbons. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0011] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical, or combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, the nitrogen and sulfur atoms of which may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Two or more heteroatoms may be consecutive.

[0012] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise specified. Additionally, in the case of heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, tetrahydropyran, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. Examples of heterocycloalkyls include, but are not limited to, glucose, mannose, allose, altrose, gulose, idose, galactose, and talose. [ka] These include, but are not limited to:

[0013] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0014] The term "aryl," unless otherwise specified, means a polyvalent unsaturated aromatic hydrocarbon substituent that may be monocyclic or polycyclic (preferably 1-3 rings) fused together (i.e., fused ring aryl) or covalently linked together. Fused ring aryl refers to multiple rings fused together, at least one of the fused rings being an aryl ring.

[0015] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 4 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaromatic ring). 5,6-fused ring heteroarylene refers to two rings fused together, where one ring has five ring members and the other ring has six ring members, and where at least one ring is a heteroaryl ring. Similarly, 6,6-fused ring heteroarylene refers to two rings fused together, where one ring has six ring members and the other ring has six ring members, and where at least one ring is a heteroaryl ring. and 6,5-fused ring heteroarylene refers to two rings fused together, one ring having six ring members and the other ring having five ring members, with at least one ring being a heteroaryl ring. The heteroaryl group can be bonded to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5 ...

[0033] Examples of aryl and heteroaryl ring systems include aryl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0016] An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.

[0017] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).

[0018] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0019] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0020] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless otherwise indicated, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl, the last-mentioned group contains the atom by which that moiety is attached to the remainder of the molecule.

[0021] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0022] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, the compounds are understood by those skilled in the art to include both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0023] Any formula or structure given herein is also intended to represent unlabeled form of the compound as well as isotopically labeled form.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom with a selected atomic weight or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, but 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, such as 3 H, 13 C, and 14Those incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0024] The present disclosure also includes "deuterated analogs" of compounds of formula I in which one to n hydrogens attached to a carbon atom have been replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of formula I when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, e.g., by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0025] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful for PET or SPECT studies.The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents.It is understood that deuterium in this context is considered as a substituent in the compounds described herein.

[0026] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0027] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0028] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0029] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be made by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharma-ceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, for example, alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted Examples of suitable amines include, but are not limited to, primary, secondary, and tertiary amines such as (alkenyl)amines (i.e., N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0030] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents added (e.g., substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the sequential substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, the substituents of the group are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0031] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where a conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Auxiliary active ingredients can also be incorporated into the composition.

[0032] A "solvate" is formed by the interaction of a solvent with a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0033] Phosphorylated tau protein Neurological diseases, including neurodegenerative diseases and injury-related disorders, are associated with the release and / or accumulation of phosphorylated tau protein. Phosphorylated tau protein can be detected by contacting a compound as described herein, which, when activated by light, causes the release of a detectable signal. In general, the compositions and methods described herein are useful for detecting phosphorylated tau protein in any tissue of a patient. However, phosphorylated tau protein can accumulate in the retina of a patient. Such presence of phosphorylated tau protein in the retina can be detected with a compound that binds to phosphorylated tau protein and whose binding is then detected by means such as laser-activated fluorescent scanning of the retina, as experimental examples show.

[0034] "Microtubule-associated protein tau", "MAPT", "tau protein", or "tau" is a family of proteins that stabilize microtubules during assembly and disassembly and are classified as microtubule-associated proteins (MAPs). Tau isoform sequences include NP_001116538.2, NP_001116539.1, NP_001190180.1, NP_001190181.1, NP_005901.2, NP_058518.1, NP_058519.3, and NP_058525.1. Tau proteins are important for the stabilization and assembly of microtubules, which in turn affect the intraneuronal transport of cargo. Tau may also be involved in signaling pathways by interacting with actin through its acidic N-terminus and protruding from microtubules for the extension and stabilization of neurites during brain development. Tau proteins provided herein may include any isoform, or any combination of isoforms. MAPT transcripts are differentially expressed in the nervous system depending on the neuronal maturation stage and neuron type. MAPT gene mutations are associated with several neurological disorders, such as Alzheimer's disease, Pick's disease, frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy. Tau proteins may or may not contain post-translational modifications. The tau protein family is characterized by an N-terminal segment shared by all members, a sequence of approximately 50 amino acids inserted into the N-terminal segment that is developmentally regulated in the brain, a characteristic tandem repeat region consisting of three or four tandem repeats of 31-32 amino acids, and a C-terminal tail.

[0035] The human tau gene is located at 17q21 on the long arm of chromosome 17. The gene contains 16 exons, with exon 21 believed to be included as part of the promoter. The primary tau transcript contains 13 exons, with exons 4A, 6, and 8 not transcribed in humans. Exons 21 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive, while exons 2, 3, and 10 are alternatively spliced, generating six different mRNAs that are translated into six different tau isoforms. These isoforms differ by the presence or absence of one or two 29 amino acid repeats (0N, 1N, or 2N) encoded by exons 2 and 3 in the amino-terminal portion in combination with three microtubule-binding repeats (R1, R3, and R4) or four (R1-R4) repeat regions in the carboxy-terminal portion. The fourth microtubule-binding domain is encoded by exon 10. Six tau protein isoforms are known to exist in human brain tissue: (2+3+10+) isoform (having 441-amino acids), (2+3+10-) isoform (having 410-amino acids), (2+3-10+) isoform (having 412-amino acids), (2+3-10-) isoform (having 381-amino acids), (2-3-10+) isoform (having 383-amino acids), and (2-3-10-) isoform (having 352-amino acids). The tau can be a mutant tau. The mutation can be an FTDP-17 mutation. Examples of mutations include G272V, N279K, N296, P201L, P301S, G303V, S305N, L315R, S320F, P332L, V337M, E342V, S352L, K369I, G389R, R5H, R5L, K257T, I260V, L266V, G272V, delK280, N296H, N296N, delN296, P301L, P301S, K317M, G335V, Q336R, R406W and R427M.

[0036] "Phosphorylated tau protein" or "phosphorylated tau" is a tau protein having at least one amino acid residue modified by a phosphate group. Tau is believed to contain as many as 85 amino acid residues that are compatible with phosphorylation. Typically, the phosphate group is a post-translational modification and may be attached to the side chain of an amino acid residue. The phosphorylated amino acid residue may be, for example, a serine (S), threonine (T), or tyrosine (Y) residue, or a combination thereof. Phosphorylated tau protein may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, at least 20, at least 25, at least 30, at least 40, or at least 50 moles of phosphate per mole of protein. Phosphorylated tau protein may contain at least 3 moles of phosphate per mole of protein. The phosphorylated tau protein may comprise one or more phosphorylated amino acid residues selected from Thr39, Ser46Pro, Thr50Pro, Thr69Pro, Thr153Pro, Thr175Pro, Thr181Pro, Ser198, Ser199, Ser202Pro, Thr205Pro, Ser208, Ser210, Thr212Pro, Ser214, Thr217Pro, Thr231Pro, Ser235Pro, Ser237, Ser241, Ser262, Ser285, Ser305, Ser324, Ser352, Ser356, Ser396Pro, Ser400, Thr403, Ser404Pro, Ser409, Ser412, Ser413, Ser416, and Ser422Pro. The phosphorylated tau protein may comprise phosphorylated Ser422. The phosphorylated tau protein provided herein may be aggregated or non-aggregated. The phosphorylated tau protein provided herein may be soluble. The tau protein or phosphorylated tau protein may be 3-repeat tau, 4-repeat tau, or a combination thereof. In some embodiments, the tau protein or phosphorylated tau protein may comprise a mixture of 3-repeat tau and 4-repeat tau, with 4-repeat tau being more prevalent.In some embodiments, tau protein or phosphorylated tau protein can comprise a mixture of 3-repeat tau and 4-repeat tau, with 3-repeat tau being more prevalent.Phosphorylated tau protein can be fibrillar, for example as neurofibrillary tangle (NFT).NFT can be found in the somatodendritic compartment of neurons.

[0037] Thus, according to some embodiments of the present disclosure, a method is provided for determining whether a patient suffers from a neurological disease or disorder. The method involves detecting the presence of phosphorylated tau protein in a patient's tissue by contacting the patient's tissue with a compound described herein. The contacting can be in vivo or ex vivo. The contacting can be by administration to the patient, for example, by topical administration or intravenous administration. It is contemplated that the accumulation of phosphorylated tau protein can occur in the retina of the eye. Thus, the detection can target phosphorylated tau protein in the retina.

[0038] In another embodiment, a method is provided for preparing a patient for diagnosis of a neurological disease or disorder, comprising administering to the patient a compound that specifically binds to phosphorylated tau protein. The compound can be administered to the patient's eye. Once the compound is administered to the patient, its binding to phosphorylated tau protein can be detected by any method, including those described herein, and the binding indicates the accumulation of phosphorylated tau protein, which is an indicator of a neurological disease or disorder.

[0039] Phosphorylated tau binding compound The present disclosure further provides a compound that can bind to phosphorylated tau.In one embodiment, the compound can be selected from the compounds described in WO2011 / 072257, WO2015 / 143185, or WO2017 / 004560, which are incorporated by reference in their entirety.

[0040] In one embodiment, the compound may be selected from the compounds described in WO2015 / 143185, which compounds are described below.

[0041] In some embodiments, the disclosure provides a compound of formula I, or a salt or solvate thereof: [ka] During the ceremony, EDG is an electron donating group, Each Ar is independently selected from C1 to C6, each of which is optionally substituted with one or more R1. 14 Arylene or C1-C 14 Heteroarylene, Each R1 is independently halogen, -OR2, -NR3R4, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally substituted with one or more R5; R2, R3 and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene, each of which other than hydrogen is optionally substituted with one or more R5; Each R5 is independently selected from halogen, -OR6, -NR7R8, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C10 Arylene, or C1-C 10 Heteroarylene, R6, R7, R8 and R 84 are independently hydrogen, C1-C 10 is alkyl, R 84 is hydrogen or C1-C 10 is alkyl, EWG is an electron withdrawing group, WSG is a water-soluble group, X is C=O or SO2, or X and R 84 and combine to form pyridinyl, Y is NH or S; each x is independently an integer from 0 to 10; each w is independently an integer from 1 to 5; each y is independently an integer from 0 to 10; and z is an integer from 1 to 10.

[0042] In some embodiments, the disclosure provides a compound of formula II, or a salt or solvate thereof: [ka] , During the ceremony, EDG is an electron donating group, Ar2 and each Ar1 are independently C1 to C 14 Arylene or C1-C 14 Heteroarylene, Each optionally contains one or more R 41 is replaced by Each R 41 are independently halogen, -CN, -OR 42 , -NR 43 R 44 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 45 is replaced by R 42 , R 43 and R 44 are independently hydrogen, C1 to C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene, each of which other than hydrogen is optionally represented by one or more R 45 is replaced by Each R 45 are independently halogen, -OR 46 , -NR 47 R 48 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, R 46 , R 47 and R 48 are independently hydrogen or C1-C 10 is alkyl, EWG is an electron withdrawing group, Y is absent, O, NH, or S; WSG is hydrogen or a water soluble group; x is an integer from 0 to 10; y is an integer from 0 to 10; and z is an integer from 1 to 10.

[0043] In some embodiments, R 84is hydrogen. In some embodiments, R 84 is C1~C 10 In some embodiments, R 84 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, neptyl, or decyl. 84 is methyl.

[0044] The substituent EDG is an electron donating group, as known in the art. In some embodiments, EDG is any atom or functional group that can donate a portion of its electron density to a conjugated pi-system, thus making the pi-system more nucleophilic.

[0045] In some embodiments, EDG, -OR9, -NR 10 R 11 , -SR 12 , -PR 13 R 14 , -NR 15 C(O)R 16 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 17 is replaced by Each R 17 are independently halogen, -OR 18 , -NR 19 R 20 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10Heteroarylene, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 and R 20 are independently hydrogen, C1 to C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, Each of these other than hydrogen may optionally be one or more R 21 is replaced by R 10 and R 11 are optionally joined together and optionally R 21 forming a heterocycloalkyl or heteroaryl substituted with R 21 each independently represents a halogen, -OR 22 , -NR 23 R 24 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 25 is replaced by R 22 , R 23 and R 24 Each of is independently hydrogen or C1-C 10 is alkyl, Each R 25 are independent, C1~C 10 Alkyl, C1-C10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 It is a heteroarylene.

[0046] In some embodiments, the EDG is [ka] is selected from the group consisting of:

[0047] In some embodiments, the EDG is [ka] In some embodiments, the EDG is [ka] It is.

[0048] EWG is an electron withdrawing group. In some embodiments, an electron withdrawing group as used herein is any atom or group that can attract electron density from adjacent atoms towards itself, either by resonance or inductive effects.

[0049] In some embodiments, EWG is halogen, -CN, -NO2, -SO3H, -CR 26 R 27 R 28 , -COR 29 , or -COOR 30 is selected from the group consisting of Each R 26 , R 27 and R 28 are independently hydrogen or halogen; R 29 are halogens, hydrogen, C1-C 10Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 31 is replaced by R 30 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 32 is replaced by Each R 31 and R 32 are independent, C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 It is a heteroarylene.

[0050] In some embodiments, the EWG is selected from the group consisting of -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3, and -CN. In some embodiments, the EWG is F, Cl, or Br. In some embodiments, the EWG is -CN.

[0051] WSG is a water-soluble group. In some embodiments, the WSG group serves to modify the solubility of the compound in an aqueous system.

[0052] In some embodiments, WSG is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 33 is replaced by Each R 33 are independently halogen, -OR 34 , -NR 35 R 36 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 37 is replaced by Each R 34 , R 35 and R 36 are independent, C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene may optionally be one or more R 37 is replaced by Each R 37are independently halogen, -OR 38 , -NR 39 R 40 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, -(C1-C6 alkyl)(C1-C 10 Heterocycloalkyl), C1-C 10 Arylene, or C1-C 10 Heteroarylene, R 38 , R 39 and R 40 Each of is independently hydrogen or C1-C 10 It is an alkyl.

[0053] In some embodiments, the WSG comprises: [ka] It is.

[0054] In some embodiments, the WSG is polyethylene glycol, polypropylene glycol, a copolymer of polyethylene glycol and polypropylene glycol, or an alkoxy derivative thereof.

[0055] In some embodiments, the WSG [ka] In the formula, n is an integer from 1 to 50, and R 81 is hydrogen, C1-C 10 Alkyl, C1-C 10 Alkenyl, or C1-C 10 alkynyl, and in each occurrence, alkyl, alkenyl, or alkynyl optionally includes one or more C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 In some embodiments, R is substituted with heteroarylene. 81 is hydrogen. In some embodiments, R 81 is methyl. In some embodiments, R 81 is ethyl. In some embodiments, R 81 In some embodiments, 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, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, n is an integer value of 2 to 10, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 20 to 30, 20 to 40, 20 to 50, 30 to 40, 30 to 50, or 40 to 50. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 3 or 6.

[0056] In some embodiments, the WSG comprises: [ka] It is.

[0057] In some embodiments, the WSG comprises: [ka] It is.

[0058] In some embodiments, the WSG [ka] where each R 82are independently hydrogen or C1-C 10 It is an alkyl.

[0059] In some embodiments, each R 82 is independently hydrogen, methyl, ethyl, propyl, or butyl.

[0060] In some embodiments, the WSG comprises: [ka] It is.

[0061] In some embodiments, the WSG comprises: [ka] It is.

[0062] In some embodiments, the WSG [ka] where each R 83 is hydrogen or C1-C 10 In some embodiments, each R 83 is independently hydrogen, methyl, ethyl, propyl, or butyl.

[0063] In some embodiments, the WSG comprises: [ka] It is.

[0064] In some embodiments, the WSG comprises: [ka] It is.

[0065] In some embodiments, WSG is -(C 10 Alkylene)-R 33 -R 37 In some embodiments, WSG is -(C 10 Alkylene)-R 33 -R 37 and R 33 is C1~C 10 In some embodiments, WSG is -(C 10 Alkyl)-R 33 -R 37 and R 33 is C1~C 10 Heteroarylene, R 37 is -(C1-C6 alkyl)(C1-C 10 In some embodiments, WSG is -CH-R 33 -R 37 In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is triazole, imidazole, or pyrazole. In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is triazole. In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is 1,2,4-triazole. In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is 1,2,3-triazole. In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is 1,2,3-triazole, R 37 is -(C1-C6 alkyl)(C1-C 10 In some embodiments, WSG is -CH-R 33 -R 37 and R 33is 1,2,3-triazole, R 37 is -(C1 alkyl)(C1-C 10 In some embodiments, WSG is -CH-R 33 -R 37 and R 33 is 1,2,3-triazole, R 37 is -(C1 alkyl)(C1-C 10 Heterocycloalkyl) and C1-C 10 The heterocycloalkyl is a tetrahydropyran derivative.

[0066] In some embodiments, the WSG [ka] where each R 87 is hydrogen, C1-C 10 Alkyl, or -C(=O)C1~C 10 In some embodiments, each R 87 is independently hydrogen, methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. 87 is independently hydrogen or methyl. In some embodiments, each R 87 is independently methyl or acetate.

[0067] In some embodiments, the WSG comprises: [ka] It is.

[0068] In some embodiments, the WSG comprises: [ka] It is.

[0069] In some embodiments, WSG is -(C 10 Heteroalkyl)-R 33 -R 37 In some embodiments, WSG is -(C 10 Heteroalkyl)-R 33 -R 37 and R 33 is C1~C 10 In some embodiments, WSG is -(C 10 Heteroalkyl)-R 33 -R 37 and R 33 is C1~C 10 Heteroarylene, R 37 is -(C1-C6 alkyl)(C1-C 10 heterocycloalkyl).

[0070] In some embodiments, the WSG [ka] and p 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, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, p is an integer value of 2 to 10, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 20 to 30, 20 to 40, 20 to 50, 30 to 40, 30 to 50, or 40 to 50. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 3 or 6. In some embodiments, p is 3.

[0071] In some embodiments, the WSG comprises: [ka] and R 33 is C1~C 10 In some embodiments, R 33 is C5 heteroarylene. In some embodiments, R 33 is triazole, imidazole, or pyrazole. In some embodiments, R 33 is triazole. In some embodiments, R 33 is 1,2,4-triazole. In some embodiments, R 33 is 1,2,3-triazole. In some embodiments, R 33 is 1,2,3-triazole and p is 3. In some embodiments, R 33 is 1,2,3-triazole, R 37 is -(C1-C6 alkyl)(C1-C 10 In some embodiments, R 33 is 1,2,3-triazole, R 37 is -(C1 alkyl)(C1-C 10 In some embodiments, R 33 is 1,2,3-triazole, R 37 is a tetrahydropyran derivative. In some embodiments, R 33 is 1,2,3-triazole, R 37 teeth, [ka] It is.

[0072] In some embodiments, the WSG comprises: [ka] and R 33 is 1,2,3-triazole, R 37 teeth, [ka] and p is 3.

[0073] In some embodiments, the WSG comprises: [ka] where each R 87 is hydrogen, C1-C 10 Alkyl, or -C(=O)C1~C 10 In some embodiments, each R 87 is independently hydrogen, methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. 87 is independently hydrogen or methyl. In some embodiments, each R 87 is independently methyl or acetate.

[0074] In some embodiments, the WSG comprises: [ka] It is.

[0075] In some embodiments, the WSG comprises: [ka] It is.

[0076] In some embodiments, X is C=O or SO. In some embodiments, X is C=O. In some embodiments, X is SO.

[0077] In some embodiments, Y is NH or S. In some embodiments, Y is NH. In some embodiments, Y is S.

[0078] The variable w in formula I is an integer from 1 to 5. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.

[0079] The variable x in Formula I is an integer from 0 to 10. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0080] The variable y in Formula I is an integer from 0 to 10. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10.

[0081] The variable z in Formula I is an integer from 1 to 10. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0082] In some embodiments, x is 0, w is 1, y is 0, z is 1, X is C=O, and Y is NH.

[0083] In some embodiments, x is 0, w is 1, y is 0, z is 1, X is SO2, and Y is NH.

[0084] In some embodiments, x is 0, w is 2, y is 0, z is 1, X is C=O, and Y is NH.

[0085] In some embodiments, x is 0, w is 2, y is 0, z is 1, X is SO2, and Y is NH.

[0086] In some embodiments, the disclosure provides a compound of formula Ia, or a salt or solvate thereof: [ka] , In the formula, EDG, Ar, R 84 , x, w, y, z, EWG, and WSG are defined as above.

[0087] In some embodiments, the disclosure provides a compound of formula Ib, or a salt or solvate thereof: [ka] , In the formula, EDG, Ar, R 84 , x, w, y, z, EWG, and WSG are defined above.

[0088] In some embodiments, the disclosure provides a compound of formula Ic, or a salt or solvate thereof: [ka] , In the formula, EDG, Ar, R 84 , X, Y, EWG, and WSG are defined above.

[0089] In some embodiments, the disclosure provides a compound of formula Ic, or a salt or solvate thereof: [ka] During the ceremony, EDG is, a) optionally, one or more R 17 or b) -NR 10 R 11 and In the formula, each R 17 are independently halogen, -OR 18 , -NR 19 R 20 , C1~C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R 10 , R 11 , R 18 , R 19 and R 20 Each of the is independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally represented by one or more R 21 is replaced by R 21 each independently represents a halogen, -OR 22 , -NR 23 R 24 , C1~C 10 Alkyl, C1-C 10heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally further represented by one or more R 25 is replaced by R 22 , R 23 and R 24 Each of is independently hydrogen or C1-C 10 is alkyl, R 25 Each of C1 to C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; Ar is an arylene of up to 14 carbon atoms or a heteroarylene of up to 14 carbon atoms, each of which is optionally substituted with one or more R1; Each R1 is independently halogen, -OR2, -NR3R4, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally substituted with one or more R; R2, R3, and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally substituted with one or more R; Each R5 is independently selected from halogen, -OR6, -NR7R8, C1-C 10 Alkyl, C1-C10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R6, R7, R8 and R 84 are independently hydrogen or C1-C 10 is alkyl, EWG is selected from the group consisting of -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3H and -CN; WSG is i) [ka] , ii) polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof; iii) [ka] (In the formula, n is an integer of 1 to 50, and R 81 But hydrogen, C1-C 10 Alkyl, C1-C 10 Alkenyl, or C1-C 10 Alkynyl, where the alkyl, alkenyl, or alkynyl is optionally one or more C1-C 10 Alkyl, C1-C 10 substituted with heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less; iv) [ka] , v) [ka] , vi) -(C1~C 10 Alkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 carbons or less); vii) [ka] , viii) -(C1~C 10 Heteroalkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 or less carbons); or ix) [ka] and X is C=O or SO2, or X and R 84 and combine to form pyridinyl, Y is NH or S.

[0090] In some embodiments, the disclosure provides a compound of formula Id, or a salt or solvate thereof: [ka] , In the formula, EDG, R 84 , Ar, EWG, and WSG are defined as above.

[0091] In some embodiments, the disclosure provides a compound of formula Ie, or a salt or solvate thereof: [ka] , In the formula, EDG, R 84 , Ar, EWG, and WSG are defined as above.

[0092] In some embodiments, the compound is [ka] [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0093] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0094] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0095] In some embodiments, the compound is [ka] [ka] where p is an integer having a value of 1 to 50. In some embodiments, p is an integer having a value of 1 to 10, e.g., p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer having a value of 2 to 10, e.g., p is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0096] In some embodiments, the compound is [ka] [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0097] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0098] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0099] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0100] In some embodiments, the compound is [ka] [ka] is selected from the group consisting of:

[0101] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0102] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0103] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0104] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0105] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0106] In some embodiments, the compound is [ka] wherein n is an integer having a value from 1 to 50. In some embodiments, n is an integer having a value from 1 to 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value from 2 to 10, e.g., n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0107] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0108] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0109] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0110] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0111] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0112] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0113] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0114] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0115] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0116] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0117] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0118] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0119] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0120] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0121] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0122] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0123] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0124] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0125] In some embodiments, the compound is [ka] It is.

[0126] In some embodiments, the compound is (E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0127] In some embodiments, the compound is [ka] It is.

[0128] In some embodiments, the compound is (E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

[0129] In some embodiments, the compound is [ka] It is.

[0130] In some embodiments, the compound is (E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0131] In some embodiments, the compound is [ka] It is.

[0132] In some embodiments, the compound is (E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

[0133] In some embodiments, the compound is [ka] It is.

[0134] In some embodiments, the compound is (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0135] In some embodiments, the compound is [ka] It is.

[0136] In some embodiments, the compound is (E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

[0137] In some embodiments, the compound is [ka] It is.

[0138] In some embodiments, the compound is (E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0139] In some embodiments, the compound is [ka] It is.

[0140] In some embodiments, the compound is (E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

[0141] In some embodiments, the compound is [ka] It is.

[0142] In some embodiments, the compound is (E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecane-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecane-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0143] In some embodiments, the compound is [ka] It is.

[0144] In some embodiments, the compound is (E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecane-19-yl)-2-(6-(piperidin-1-yl)naphthalene-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecane-19-yl)-2-(6-(piperidin-1-yl)naphthalene-2-yl)prop-1-ene-1-sulfonamide.

[0145] In some embodiments, the compound is [ka] It is.

[0146] In some embodiments, the compound is (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0147] In some embodiments, the compound is [ka] It is.

[0148] In some embodiments, the compound is (E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

[0149] In some embodiments, the compound is [ka] It is.

[0150] In some embodiments, the compound is (R,E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide. In some embodiments, the compound is (R,Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

[0151] In some embodiments, the compound is [ka] It is.

[0152] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

[0153] [ka] It is.

[0154] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

[0155] In some embodiments, the compound is [ka] It is.

[0156] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

[0157] In some embodiments, the compound is [ka] It is.

[0158] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

[0159] In some embodiments, the compound is [ka] It is.

[0160] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

[0161] In some embodiments, the compound is [ka] It is.

[0162] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

[0163] In some embodiments, the compound is [ka] It is.

[0164] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

[0165] In certain embodiments, the compound is [ka] In certain embodiments, the compound is a pharma- ceutically acceptable salt or solvate of compound 23.

[0166] In certain embodiments, the compound is [ka] In certain embodiments, the compound is a pharma- ceutically acceptable salt or solvate of compound 24.

[0167] In certain embodiments, the compound is [ka] It is.

[0168] In certain embodiments, the compound is [ka] It is.

[0169] In certain embodiments, the compound is [ka] It is.

[0170] In some embodiments, each Ar1 is independently substituted or unsubstituted naphthylene or substituted or unsubstituted phenylene. In some embodiments, Ar2 is substituted or unsubstituted naphthylene or substituted or unsubstituted phenylene. In some embodiments, Ar2 is substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazinyl, or substituted or unsubstituted pyrazidinyl. In some embodiments, Ar2 is substituted or unsubstituted pyridyl.

[0171] In some embodiments, the substituent EDG in formula II can be an electron donating group. In some embodiments, EDG is any electron donating group known in the art. In some embodiments, it is any atom or functional group that can donate some of its electron density to a conjugated pi-system via resonance or inductive electron withdrawal, thus making the pi-system more nucleophilic. In some embodiments, EDG is -OR 49 , -NR 50 R 51 , -SR 52 , -PR 53 R 54 , -NR 55 C(O)R 56 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally further represented by one or more R 57 Each R 57 are independently halogen, -OR 58 , -NR 59 R 60、 C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 58 , R 59 , R 60 Each of the is independently hydrogen, C1-C 10 Alkyl, C1-C10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene, each of which other than hydrogen is optionally represented by one or more R 61 is replaced by R 50 and R 51 are optionally joined together and optionally R 61 forming a heterocycloalkyl or heteroaryl substituted with R 61 each independently represents a halogen, -OR 62 , N.R. 63 R 64 , C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally further represented by one or more R 65 is replaced by R 62 , R 63 and R 64 Each of is independently hydrogen or C1-C 10 alkyl, and each R 65 are independent, C1~C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 It is a heteroarylene.

[0172] In some embodiments, Y is absent, O, NH, or S. In some embodiments, Y is absent (i.e., Y is a bond). In some embodiments, Y is O. In some embodiments, Y is NH. In some embodiments, Y is S.

[0173] The variable x in Formula II is an integer from 0 to 10. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0174] The variable y in Formula II is an integer from 0 to 10. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10.

[0175] The variable z in Formula II is an integer from 1 to 10. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0176] In some embodiments, x is 0, y is 0, z is 1, and Y is O.

[0177] In some embodiments, x is 0, y is 0, z is 1, and Y is S.

[0178] In some embodiments, x is 0, y is 0, z is 1, and Y is NH.

[0179] In some embodiments, x is 0, y is 0, z is 1, and Y is absent.

[0180] In some embodiments, x is 0, y is 0, z is 2, and Y is O.

[0181] In some embodiments, x is 0, y is 0, z is 2, and Y is S.

[0182] In some embodiments, x is 0, y is 0, z is 2, and Y is NH.

[0183] In some embodiments, x is 0, y is 0, z is 2, and Y is absent.

[0184] In one aspect, the disclosure provides a compound of formula IIa: [ka] , where EDG, Ar1, Ar2, Y, EWG, and WSG are defined above for Formula II.

[0185] In one aspect, the disclosure provides a compound of formula IIb: [ka] , where EDG, Ar1, Ar2, EWG, and WSG are defined above for Formula II.

[0186] In some embodiments, the compound according to formula II is [ka] [ka] where n is an integer with a value from 0 to 50. In some embodiments, n is an integer with a value from 0 to 10, e.g., n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0187] In some embodiments, the compound is [ka] is selected from the group consisting of:

[0188] In some embodiments, the compound is [ka] [ka] wherein R 85 is H or CN.

[0189] In some embodiments, the compound is [ka] [ka] wherein R 85 is H or CN, and R86 teeth [ka] where n is an integer with a value from 0 to 50. In some embodiments, n is an integer with a value from 0 to 10, e.g., n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0190] In some embodiments, the compound is [ka] wherein R 85 is H or CN, and R 86 is H.

[0191] In some embodiments, the compound is [ka] wherein R 85 is H or CN, and R 86 teeth [ka] where n is an integer with a value from 0 to 50. In some embodiments, n is an integer with a value from 0 to 10, e.g., n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0192] In some embodiments, the compound is [ka] It is.

[0193] In some embodiments, the compound is 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)-nicotinonitrile.

[0194] In some embodiments, the compound is [ka] It is.

[0195] In some embodiments, the compound is 4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

[0196] In some embodiments, the compound comprises: [ka] [ka] or a salt or solvate thereof.

[0197] Neurological diseases and disorders and their treatment Provided herein is a method for determining whether a patient suffers from a neurological disease or disorder, comprising detecting the presence of phosphorylated tau protein in a patient's tissue, wherein the detecting comprises contacting the phosphorylated tau protein with a compound described herein. The compound can be a compound of formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is a compound of formula Ic. In some embodiments, the compound is compound 1, 2, 3, 4, or 5. The contacting can be in vivo. The tissue can be an ocular tissue. In some embodiments, the neurological disease or disorder is selected from an age-related disease or disorder, a genetic disease or disorder, an injury-related disease or disorder, and a psychiatric disease or disorder. In some embodiments, the age-related disease or disorder is selected from Parkinson's dementia, vascular dementia, and amyotrophic lateral sclerosis, the genetic disease or disorder is Down's syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the psychiatric disease or disorder is selected from schizophrenia and depression.The neurological disease or disorder can be tauopathy.In some embodiments, the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE).

[0198] The neurological disease or disorder may be a tauopathy. Tauopathies are a class of neurological diseases associated with pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. The tangles are formed by hyperphosphorylation of tau, which may cause tau protein to dissociate from microtubules and form aggregates in an insoluble form. Aggregations of hyperphosphorylated tau protein are sometimes called paired helical filaments. The exact mechanism of tangle formation is not fully understood, and it is still controversial whether the tangle is the primary causative factor of the disease or plays a more peripheral role. Tauopathies have been found in many neurological disorders, including post-traumatic degeneration, infectious diseases, metabolic diseases, and motor neuron degeneration. The spatial distribution, temporal appearance, and structural changes of tau protein manifest differently among various neurological diseases. Patients with AD have twisted, hyperphosphorylated, single aperiodic tau filaments, whereas patients with progressive supranuclear palsy and frontotemporal dementia (FTD) tend to have only straight tau filaments. Tauopathies often overlap with synucleinopathies, possibly due to interactions between synuclein and tau proteins. Non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex" because they are associated with frontotemporal dementia or frontotemporal lobar degeneration. A marker of tau hyperphosphorylation is tau pS422. Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) and shares many similarities with tauopathies, including tau hyperphosphorylation and aggregation, such as neurofibrillary tangles (NFTs).

[0199] The neurological disease or disorder may be a neurodegenerative disease or disorder. In some embodiments, the neurological disease or disorder is Alzheimer's disease (AD). AD is considered a secondary tauopathy. Alzheimer's disease is characterized by symptoms of memory loss in the early stages of the disease. Neurofibrillary tangles were an early descriptor of AD. When tau becomes hyperphosphorylated, the protein dissociates from microtubules in axons. Tau can then misfold and begin to aggregate, forming neurofibrillary tangles (NFTs). When tau dissociates, microtubules also become unstable, and the combination of neurofibrillary tangles and destabilized microtubules disrupts processes such as axonal transport and neurotransmission. The extent of NFT involvement in AD is defined by the Braak stage. Braak stages I and II are used when NFT involvement is primarily confined to the transentorhinal region of the brain, stages III and IV when limbic regions such as the hippocampus become involved, and stages V and VI when widespread neocortical involvement is demonstrated. AD is also classified as an amyloidosis due to the presence of senile plaques. In addition, certain Apoε4 carriers are at increased risk of developing AD. APOε4 is believed to be less efficient than other isoforms in clearing Aε and may therefore correlate with increased amyloid burden, tau phosphorylation, synaptic toxicity, and reduced synaptic density. Experiencing a traumatic brain injury (TBI) is another risk factor for developing AD, and studies have shown that those who have experienced TBI have a significantly increased risk of AD.

[0200] As AD progresses, symptoms include confusion, loss of long-term memory, paraphasia, loss of vocabulary, aggression, irritability, and / or mood swings. In more advanced stages of the disease, there is loss of bodily function. Patients with Alzheimer's disease (AD) exhibit many characteristic neurological disorders, such as increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. AD-related disorders include senile dementia of the AD type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-associated memory impairment (AAMI). In some embodiments, determining whether a patient is suffering from Alzheimer's disease comprises detecting the presence of phosphorylated tau protein in the patient's tissue, and the detecting comprises contacting the phosphorylated tau protein with a compound described herein.

[0201] In some embodiments, the neurological disease or disorder is frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS). In some embodiments, the neurological disease or disorder is frontotemporal dementia. In some embodiments, the neurological disease or disorder comprises memory loss. In some embodiments, the neurological disease or disorder is age-related memory loss. In some embodiments, the neurological disease or disorder is FTLD-TDP type A. In some embodiments, the neurological disease or disorder is FTLD-TDP type B. In some embodiments, the neurological disease or disorder is FTLD-TDP type C. In some embodiments, the neurological disease or disorder is FTLD-TDP type D.

[0202] In some embodiments, the neurological disease or disorder is Parkinson's disease. In some embodiments, the neurological disease or disorder is Parkinson's dementia. In some embodiments, the neurological disease or disorder is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the patient with a neurological disease or disorder has suffered a traumatic brain injury before, during, or after the onset of the neurological disease or disorder. In some embodiments, the neurological disease or disorder comprises neuronal dysfunction. Neuronal dysfunction may comprise atrophy or other reduction in effective function of neurons. For example, Alzheimer's disease is known to exhibit neuronal dysfunction, particularly in cortical neurons, such as hippocampal neurons and neurons adjacent to the hippocampus.

[0203] In some embodiments, the neurological disease or disorder is traumatic axonal injury (TAI), traumatic brain injury (TBD), dementia (e.g., general dementia), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), primary age-related tauopathy (PART), neurofibrillary tangle-predominant senile dementia, progressive supranuclear palsy (PSP), corticobasal degeneration, Richico-Bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic grain dementia (AGD), or corticobasal degeneration.

[0204] The neurological disease or disorder may be an injury-related condition, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). Traumatic brain injury (TBI) is a chronic disease due to injury to the brain caused by an external force, such as a crash, blow, impact, rapid acceleration or deceleration, or projectile penetration. The injury that leads to a TBI can cause a reduced or altered state of consciousness, resulting in temporary or permanent deficits in cognitive, sensorimotor, and psychosocial functioning. CTE is a progressive degenerative disease seen in people who have suffered repeated brain trauma, including blows to the head that did not cause TBI symptoms. Physical aspects of CTE include shrinkage of the brain, atrophy of the frontal and temporal lobes, enlargement of the ventricles, and atrophy of the hippocampus, thalamus, brain stem, and cerebellum. Individuals with CTE have symptoms of dementia, memory loss, aggression, confusion, depression, and suicidal ideation, which may occur many years after the injury.

[0205] The neurological disease or disorder may be ocular, for example glaucoma, ocular hypertension, macular degeneration, diabetic retinopathy, age-related macular degeneration (AMD) or retinitis pigmentosa.

[0206] Further examples of neurological diseases or disorders include Alexander disease, Alper's disease, depression, perinatal asphyxia, Parkinson's disease dementia ("PD dementia"), amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), spongiform encephalopathies (e.g., bovine spongiform encephalopathy (mad cow disease), kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, Canavan disease, Cockayne syndrome, corticobasal degeneration, and the like. dementia, fragile X syndrome, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Pelizaeus-Merzbacher disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal cord degeneration secondary to pernicious anemia, schizophrenia ataxia, spinocerebellar ataxia (several types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, laryngeal spinal cord, drug-induced parkinsonism, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial, type 1 (PARK1), Parkinson's disease 3, autosomal dominant with Lewy bodies (PARK3), Parkinson's disease 4, autosomal dominant with Lewy bodies (PARK4), Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive early-onset (PARK2), Parkinson's disease 7, autosomal recessive early-onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), or mitochondrial Parkinson's disease.

[0207] Once a patient's neurological disease or disorder is determined, certain procedures can be provided to treat or improve the symptoms of the neurological disease or disorder, or to slow or stop its progression. Once a neurological disease or disorder is diagnosed, the progression of the disease or disorder can also be monitored by the methods described herein. Once diagnosed, the treating physician can also suggest additional treatments known to the practitioner, including those described herein.

[0208] "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of the disease or condition), b) improving, delaying or preventing the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or delaying the worsening or progression of a disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of a disease or condition), and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the condition, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, delaying disease progression, improving quality of life, and / or prolonging survival).

[0209] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to patients (including humans) who are at risk for the disease or condition or who have a family history of the disease or condition.

[0210] "Patient" refers to an animal, such as a mammal (including a human), who has been or will be the subject of treatment, observation or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the patient is a mammal. In one embodiment, the patient is a human.

[0211] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof means an amount sufficient to effect treatment when administered to a patient to provide a therapeutic benefit, such as amelioration of symptoms or delay of disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition of a neurological disease or disorder. A therapeutically effective amount may vary depending on the patient and the disease or condition being treated, the patient's weight and age, the severity of the disease or condition, and the method of administration, but can be readily determined by one of ordinary skill in the art.

[0212] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosing of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used to set up in vivo treatment protocols, either for experimental purposes or in the clinic. Other ex vivo applications for which the compounds and compositions described herein may be suitable are described below and will be apparent to those skilled in the art. Selected compounds may be further characterized to determine safety or tolerated dosage in human or non-human patients. Such properties may be determined using methods commonly known to those of skill in the art.

[0213] Detection of phosphorylated tau Provided herein is a method for diagnosing a neurological disease or disorder, comprising administering a compound described herein to a patient's tissue. The compound can be a compound of formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is a compound of formula Ic. In some embodiments, the compound is compound 1, 2, 3, 4, or 5. The method can include detecting the binding of the compound to phosphorylated tau protein. The binding can cause the emission of a detectable signal when activated by light. The signal can be a fluorescent signal or an infrared signal. The administration can be intravenous or can be localized to the retina of the eye.

[0214] Detection of phosphorylated tau protein can be performed using a probe capable of selectively binding to phosphorylated tau, referred to herein as a phosphorylated tau probe. The probe comprises a compound described herein.

[0215] In one embodiment, a phosphorylated tau probe, such as a compound described herein, when bound to phosphorylated tau can be detected via its emitted fluorescent signal upon activation by laser light. Exemplary phosphorylated tau binding compounds are described herein.

[0216] The in situ detection of the binding of phosphorylated tau probe, for example, the compound described herein, to phosphorylated tau protein in the retina of a patient can be facilitated by using a retinal imaging device, which is preferably handheld or portable.The retinal imaging device can include a lens and an image sensor, and optionally a laser light source.When the light source emits laser light to tissue, such as the retina, phosphorylated tau accumulates therein, and if it is bound to phosphorylated tau binding probe, for example, the compound described herein, the accumulation can be easily detected and quantified by the lens and image sensor that collects and senses the fluorescent signal.

[0217] The method for determining whether a patient suffers from a neurological disease or disorder can be carried out by any method described herein. In some embodiments, the contacting causes the emission of a detectable signal when activated by light. In some embodiments, the detectable signal is a fluorescent signal. In some embodiments, the phosphorylated tau protein comprises at least 3 moles of phosphate per mole of protein. In some embodiments, the phosphorylated tau protein is 3-repeat tau, 4-repeat tau, or a combination thereof.

[0218] Administration and Pharmaceutical Compositions In some embodiments, the compounds described herein are administered to the eye. In some embodiments, the pharmaceutical compositions of the present disclosure administered to the eye are delivered to the retina, intraocular space, ocular surface, interconnecting nerve distribution, conjunctiva, lacrimal gland, or meibomian gland. In some embodiments, the compounds are administered topically to the eye. In some embodiments, the compounds are administered as eye drops. Administration can be topical.

[0219] The compounds may also be formulated for, but not limited to, intravenous and subcutaneous use. Intravenous administration may be by bolus or continuous infusion.

[0220] The compounds may be effective over a wide dosage range. In some embodiments, in adult applications, dosages of 0.01-1000 mg, 0.5-100 mg, 1-50 mg, and 5-40 mg per day are exemplary dosages that may be used. An exemplary dosage is 10-30 mg per day. In juvenile applications, dosages may be the same as or less than adult dosages. In some embodiments, an effective amount of the compound corresponds to about 50-500 mg of the compound per adult patient. The exact dosage will depend on the route of administration, the form in which the compound is administered, the patient being treated, the weight of the patient being treated, and the preference and experience of the attending physician.

[0221] In some embodiments, the effective amount of the compound corresponds to about 0.01-1000 mg of compound per human patient per dose. In some embodiments, the effective amount of the compound is 50-500 mg per human per dose. In some embodiments, the effective amount is about 0.01-100 mg, 0.01-200 mg, 0.01-300 mg, 0.01-400 mg, 0.01-500 mg, 0.01-600 mg, 0.01-700 mg, 0.01-800 mg, 0.01-900 mg, 0.01-1000 mg, 0.1-100 mg, 0.1-200 mg, 0.1-300 mg, 0.1-400, 0.1-500 mg, 0. ... 00mg, 0.1~700mg, 0.1~800mg, 0.1~900mg, 0.1~1000mg, 1~100mg, 1~200mg, 1~300mg, 1~400mg, 1~500mg, 1~600mg, 1~7 00mg, 1~800mg, 1~900mg, 100~200mg, 100~300mg, 100~400mg, 100~500mg, 100~600mg, 100~700mg, 100~800mg, 100~900 mg, 100~1000mg, 200~300mg, 200~400mg, 200~500mg, 200~600mg, 200~700mg, 200~800mg, 200~900mg, 200~1000mg, 30 0~400mg, 300~500mg, 300~600mg, 300~700mg, 300~800mg, 300~900mg, 300~1000mg, 400~500mg, 400~600mg, 400~700mg , 400-800mg, 400-900mg, 400-1000mg, 500-600mg, 500-700mg, 500-800mg, 500-900mg, 500-1000mg, 600-700mg, 600-800mg, 600-900mg, 600-1000mg, 700-800mg, 700-900mg, 700-1000mg, 800-900mg, 800-1000mg, or approximately 900-1000mg.In some embodiments, the effective amount is about 50-100 mg, 50-400 mg, 50-500 mg, 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500, 300-400 mg, 300-500 mg, or 400-500 mg per adult per dose.

[0222] In some embodiments, the compound is administered in a single dose. In some embodiments, the compound is administered in multiple doses. In some embodiments, the dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In some embodiments, the dosing is about once a month, once every two weeks, once a week, or once every two days. In other cases, the compound and another agent are administered together about once per day to about six times per day. In some embodiments, the administration of the compound and agent continues for less than about seven days. In yet other cases, the administration continues for about 6, 10, 14, 28 days, 2 months, 6 months, or a year or more. In some embodiments, continuous dosing is achieved and maintained as long as necessary.

[0223] In some embodiments, the compound is administered 1-10 times, 1-4 times, or once per day. In some embodiments, the compound is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In some embodiments, the compound is administered as drops. In some embodiments, the size of the administered drops is in the range of about 10-100 μL, about 10-90 μL, about 10-80 μL, about 10-70 μL, about 10-60 μL, about 10-50 μL, about 10-40 μL, about 10-30 μL, about 20-100 μL, about 20-90 μL, about 20-80 μL, about 20-70 μL, about 20-60 μL, about 20-50 μL, about 20-40 μL, or about 20-30 μL. An example of the present disclosure administers droplets in the range of about 10 to about 30 μL. An example of the present disclosure administers droplets in the range of about 10 to about 100 μL. An example of the present disclosure administers droplets in the range of about 20 to about 50 μL. An example of the present disclosure administers droplets in the range of about 20 to about 40 μL. An example of the present disclosure administers droplets in the range of about 10 to about 60 μL. In some embodiments, the ophthalmic formulations of the present disclosure are administered at a few drops per administration, e.g., 1-3 drops per administration, 1-3 drops per administration, 1-4 drops per administration, 1-5 drops per administration, 1-6 drops per administration, 1-7 drops per administration, 1-8 drops per administration, 1-9 drops per administration, 1-10 drops per administration, 3-4 drops per administration, 3-5 drops per administration, 3-6 drops per administration, 3-7 drops per administration, 3-8 drops per administration, 3-9 drops per administration, 3-10 drops per administration, 5-6 drops per administration, 5-7 drops per administration, 5-8 drops per administration, 5-9 drops per administration, 5-10 drops per administration, 7-8 drops per administration, 7-9 drops per administration, or 9-10 drops per administration. In one example, the formulations of the present disclosure are administered at about 1 drop per administration and 1-6 times per day.

[0224] Pharmaceutical Compositions / Formulations In some embodiments, the compound described herein is formulated into pharmaceutical composition.In some embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compound into pharmaceutically usable preparations.The suitable formulation depends on the route of administration selected. Any pharma- ceutically acceptable techniques, carriers, and excipients may be used as suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0225] Provided herein is a pharmaceutical composition comprising the compound as described herein and pharmaceutically acceptable diluent, excipient or carrier.In certain cases, the compound as described herein is administered as a pharmaceutical composition, in which one or more compounds are mixed with other active ingredients, such as in combination therapy.In specific cases, the pharmaceutical composition comprises one or more compounds as described herein.

[0226] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain cases, the pharmaceutical composition facilitates administration of the compound to an organism. In some cases, for carrying out the methods of treatment or use provided herein, a therapeutically effective amount of one or more compounds described herein is administered in a pharmaceutical composition to a mammal having a disease or condition to be detected, diagnosed or treated. In specific cases, the mammal is a human. In certain cases, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the patient, the potency of the compound used, and other factors. The compounds described herein are used as components of a mixture, alone or in combination with one or more therapeutic agents.

[0227] In some embodiments, one or more compounds are formulated in an aqueous solution.In a specific case, the aqueous solution is selected from physiologically compatible buffers such as, by way of example only, Hanks' solution, Ringer's solution, acetate aqueous buffer, citrate aqueous buffer, carbonate aqueous buffer, phosphate aqueous buffer or saline buffer.

[0228] In some embodiments, the compounds described herein are formulated for ocular administration. In some embodiments, the ophthalmic formulations are liquid (solutions, suspensions, powders for reconstitution, sol-to-gel systems), semi-solid (ointments and gels), solid (ocular inserts), and intraocular dosage forms (injections, irrigation solutions and implants).

[0229] Provided herein is an ophthalmic formulation comprising the compound described herein and an ophthalmologically acceptable component.The ophthalmic formulation can be administered in any form suitable for ophthalmic administration, for example, as a solution, suspension, ointment, gel, liposomal dispersion, colloidal microparticle suspension, etc., or in an ocular insert, for example, a controlled release polymer matrix, which is optionally biodegradable.

[0230] By "pharmacologically acceptable" or "ophthalmically acceptable" is meant an ingredient that is not biologically or otherwise undesirable, i.e., the ingredient may be incorporated into the ophthalmic formulations of the present disclosure and administered topically to the eye of a patient without causing undesirable biological effects or interacting in a deleterious manner with any of the other ingredients of the formulation composition in which it is contained. When the term "pharmacologically acceptable" is used to refer to an ingredient other than a pharmacologically active drug, it means that the ingredient has met the necessary standards of toxicological and manufacturing testing or that it is included in the Inactive Ingredient Guide prepared by the US Food and Drug Administration.

[0231] Ophthalmic formulations can be adapted for topical administration to the eye in the form of suspension or emulsion.Ophthalmic formulations can include ophthalmologically acceptable carriers.Such carriers include, for example, water, mixtures of water such as phosphate buffer, boric acid, sodium chloride, and sodium borate, and water-miscible solvents such as lower alcohols, aryl alcohols, polyalkylene glycols, carboxymethylcellulose, polyvinylpyrrolidone, and isopropyl myristate.Ophthalmic formulations can also include one or more excipients such as emulsifiers, preservatives, wetting agents, thickeners, etc. For example, the ophthalmic formulation may include polyethylene glycol 200, 300, 400 and 600, Carbowax 1,000, 1,500, 4,000, 6,000 and 10,000, antimicrobial components such as quaternary ammonium compounds, phenylmercuric salts, thimerosal, methyl and propyl parabens, benzyl alcohol, phenylethanol, buffers such as sodium borate, sodium acetate, gluconate buffer, and other agents such as sorbitan monolaurate, triethanolamine, oleic acid, polyoxyethylene sorbitan monopalmitate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, and ethylenediaminetetraacetic acid. The ophthalmic formulation may be isotonic. The ophthalmic formulation may also include surfactants or stabilizers. Surfactants include Carbopol®. Stabilizers include sodium bisulfite, sodium metabisulfate, and sodium thiosulfate.

[0232] The formulation may also include an effective amount of a penetration enhancer that enhances the penetration of the formulation components through cell membranes, tissues, and extracellular matrices, including the cornea. An "effective amount" of a penetration enhancer refers to a concentration sufficient to provide a measurable increase in the penetration of one or more formulation components through membranes, tissues, and extracellular matrices, as just described. Suitable penetration enhancers include, by way of example, methylsulfonylmethane (MSM; also known as methylsulfone), a combination of MSM and dimethylsulfoxide (DMSO), or in less preferred embodiments, a combination of MSM and DMSO, with MSM being especially preferred.

[0233] Kits and Packages Also provided herein are kits and packages that include the disclosed compounds, a retinal imaging device, and, optionally, suitable packaging. In one embodiment, the kit further includes instructions for use.

[0234] The retinal imaging device may include a lens and an image sensor for detecting the emitted signal (thus forming a suitable retinal scanner). In some embodiments, the retinal imaging device detects a fluorescent signal. In some embodiments, the retinal imaging device further includes a laser light source that can be used to activate the fluorescent signal. EXAMPLES

[0235] The following examples are included to illustrate specific embodiments of the present disclosure.Those skilled in the art should understand that the techniques disclosed in the following examples represent techniques that work well in implementing the disclosure, and therefore can be considered to constitute specific modes for its implementation.However, those skilled in the art should understand in light of the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the disclosure.

[0236] Example 1: Tau protein retinal staining Retinas from 3-repeat tau ("3RTau") mice of different ages (3 months, 6 months, and 12 months) were mounted on slides. Retinas were washed twice for 5 minutes with PBS. A solution of 98% formic acid was added for 5 minutes for antigen retrieval. Harvested samples were washed twice for 5 minutes with distilled water. Samples were equilibrated for 15 minutes with 1x PBS and then blocked for 1 hour with 10% goat / donkey serum in 1x PBST (depending on the antibody). Samples were then incubated overnight at 4°C with 3-repeat tau antibody in 10% goat serum in 1x PBST and then rinsed three times for 5 minutes each with 1x PBST. Samples were incubated with secondary antibody (Alexa Fluor 568 anti-mouse) in 1x PBST for 1 hour, then covered with foil and rinsed three times for 5 minutes with 1x PBST. Samples were stained with Compound 5 working solution for 30 minutes at room temperature, covered with foil and washed 3 times with 1x PBS for 5 minutes each. Samples were stained with DAPI (300 nM or 100 ng / mL) for 10 minutes in the dark, then tissues were washed 3x10 minutes with PBS. Antifade DAKO mounting medium was added, covered with a cover slip and kept under foil until imaging. Images were obtained using a Leica confocal microscope.

[0237] Hyperphosphorylated 3RTau was detected in the retinas of 3RTau transgenic mice of different ages. Figures 1A, 1B, and 1C show the appearance of fluorescent aggregates (approximately 5-10 µm in diameter) in retinal sections of 12-month-old 3RTau mice, which were absent in control retinal sections. Immunofluorescence with 3RTau antibody shows the presence of accumulated tau aggregates in blood vessels and neurons of 3RTau mice, as expected. Merged images show colocalization of compound 5 and 3RTau antibody in the cell bodies of neurons. Analysis using Image J to assess the degree of colocalization, and statistical tests of relationship revealed a Pearson correlation coefficient (PCC) of 0.67 for 3RTau mice compared to 0.04 for control mice (PCC measures the correlation between pixel values ​​for the two reporter channels, where -1 = complete anti-colocalization, 0 = non-colocalization, and 1 = complete colocalization).

[0238] With increasing age, immunoreactivity with 3RTau Ab in the retina increases. In 12-month-old transgenic mice, 3Rtau staining was robust compared to 6-month-old and 3-month-old transgenic mice. Retinal 3Rtau immunoreactivity colocalizes with Compound 5. Colocalization of Compound 5 and 3RTau antibody was observed by immunostaining confirming specificity for tau. Interestingly, at 3 months, tau aggregates were observed near the optic nerve head, whereas at 12 months, increases in tau were more prevalent toward the periphery of the retina. In wild-type mice of comparable age, no immunostaining with 3RTau Ab was detected. In conclusion, this study has the potential for Compound 5 to be used as a diagnostic agent to detect hyperphosphorylated tau in the retina. The results shown in Figures 1A, 1B, and 1C provide evidence that the compounds described herein have the potential to diagnose Alzheimer's and other tauopathies and to monitor disease progression.

[0239] Example 2: Imaging Fluorescence imaging studies of the samples were performed on a Leica DMI 4000B microscope (Leica, Germany) equipped with a TCS SPE camera and Leica 10, 20, and 40x objectives. The following lasers were used to visualize the fluorescent probes associated with DAPI (blue, nuclear stain), compound 5 (green) and 3RTau (red): 408, 488, and 568 nm. Z-stack images were taken at 40x magnification in 0.5 μm increments to visualize the entire thickness of the tissue.

[0240] Figures 1A, 1B, and 1C show retinal sections from 3RTau mice of different ages stained with 3RTau Ab, compound 5, and DAPI at 3 months (Figure 1A), 6 months (Figure 1B), and 12 months (Figure 1C).

[0241] Figures 2A and 2B show retinal sections from a 3RTau mouse (12 months) stained with 3RTau Ab, compound 5 and DAPI (Figure 2A) and a wild-type mouse (12 months) retinal section stained with 3RTau Ab, compound 5 and DAPI (Figure 2B).

[0242] FIG. 3 shows retinal sections from 3RTau mice (12 months old) stained with 3RTau Ab, compound 5 and DAPI.

[0243] Example 3: Synthesis Synthesis of compound 23 [ka] Synthesis of (6-bromonaphthalen-2-yl)methanol (27) To a solution of LiAlH4 (8.2 g, 217 mmol in 500 mL of THF) at 0° C., a solution of methyl 6-bromo-2-naphthoate (26) (50.0 g, 189 mmol) in 500 mL of anhydrous THF was added dropwise under N2. The reaction mixture was stirred at 0° C. for 1 h. When the reaction was complete as monitored by TLC, the mixture was treated with H2O, 15% NaOH, H2O (1:1:3, v / v / v). After filtration, the filtrate was concentrated, extracted with EA, and dried over NaSO4. The crude product was purified from (PE:EA=3:1) to give the title compound.

[0244] Synthesis of 6-bromo-2-naphthaldehyde (28) To a suspension of (6-bromonaphthalen-2-yl)methanol (27) (42.0 g, 177 mmol) and silica gel (76.4 g) in DCM (500 mL) was added PCC (76.4 g, 354 mmol). The reaction was stirred at RT (room temperature, 25±5° C.) for 1.5 h. Upon completion, it was filtered through a pad of silica and concentrated under reduced pressure to give the title compound.

[0245] Synthesis of 6-(piperidin-1-yl)-2-naphthaldehyde (29) To dry and degassed toluene (300 mL) were added Pd(OAc)2 (1.5 g, 6.3 mmol), BINAP (4.4 g, 7.1 mmol), 6-bromo-2-naphthaldehyde (28) (30.0 g, 127.8 mmol), Cs2CO3 (60.0 g, 183.9 mmol) and piperidine (12.7 g, 149.5 mmol). The reaction was stirred at 115 °C for 8 h. After cooling, the mixture was filtered, washed with EA, then concentrated to one third of the volume, to which was added 200 ml of 6N hydrochloric acid with thorough stirring. The aqueous phase was separated and extracted 3 times with DCM, then made alkaline with 5N NaOH and extracted with EA. The organic phase was concentrated to give the crude material, which was further purified by silica gel chromatography (PE:EA=20:1 to 2:1) to give the title compound.

[0246] Synthesis of 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide (31) In a pear-shaped flask, 30 (6.0 g, 40 mmol) was added to methyl 2-cyanoacetate (4.0 g, 40 mmol) with stirring. The mixture was stirred at room temperature overnight and concentrated to give the crude material, which was used directly in the next step.

[0247] Synthesis of (E)-2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide (Compound 23) To a solution of 6-(piperidin-1-yl)-2-naphthaldehyde (29) (7.0 g, 29.3 mmol) and 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide (31) (7.9 g, 36.5 mmol) in anhydrous THF (250 mL) was added piperidine (0.5 g, 5.9 mmol) and the resulting mixture was refluxed for 12 h. The reaction was then concentrated under reduced pressure to give the crude material which was purified by silica gel chromatography to give the title compound. Exact mass 437.23; m / e 437.23 (100%), 438.23 (28.9%), 439.24 (4.7%); elemental analysis (C 25 H31 N3O4): C 68.63%, H 7.14%, N 9.60%, O 14.63%.

[0248] Synthesis of compound 24 [ka] Synthesis of 33 To 1 g (2.3 mM) of compound 23 in 15 mL of THF at 0 degrees was added 1.6 g (3 mM) of tetrabenzyl pyrophosphate prepared using a Merck Organic Synthesis preparation, giving a deep red solution. Sodium hydride (100 mg, 2.5 mM, 60% in oil) was added. After 15 min warming to room temperature, solids started to precipitate. DMF (5 mL) was added and stirred at room temperature for 1 h. Water (200 mL) and ethyl acetate (200 mL) were added. The ethyl acetate layer was dried and evaporated. Purification by ISCO® on an 80 g silica gel cartridge using 0-100% hexane / ethyl acetate gave the title compound. Compound 8 1 The H NMR spectrum is presented in Figures 1A-1C. MS (m / z) 701.3 [M+H] + .

[0249] Synthesis of compound 24 To 1 gram of (compound 33) was added argon degassed 95% ethanol (150 mL). 120 mg of 10% Pd / C was added and hydrogen gas was bubbled through the reaction mixture for 5 min. The mixture was then stirred under a hydrogen balloon for 3 h. The reaction mixture was degassed with argon and evaporated. Purification was carried out by preparative LC / MS on a 25×250 mm C18 column using 0-100% water containing 2 g / L ammonium acetate. After free drying, compound 24 was obtained. 1 The H NMR spectrum (DO) is presented in Figures 2A-B.

[0250] Synthesis of compound 25 [ka] A solution of compound 33 (5 mmol, 3.49 g, 1 equiv.) in anhydrous CH2Cl2 (100 ml) was cooled to 0° C. under argon, and trimethylsilyl bromide (50 mmol, 6.8 ml, 10 equiv.) was added via syringe. The reaction mixture was stirred at 0° C. for 30 min, and the completion of the conversion was monitored by HPLC. The mixture was then quenched with MeOH (ca. 50 mL) and stirred for 10 min. The solution was evaporated to dryness. This process was repeated four times.

[0251] The organic solvent was evaporated under vacuum, the residue was suspended in a trace of MeOH, and EtOAc was added to induce precipitation of the phosphonic acid. The residue was filtered and washed with EtOAc (×2). The residue was then dried under vacuum to give the desired phosphate.

[0252] The phosphonic acid was treated with NHOAc (25 mmol, 1.93 g, 5 eq.) and 150 ml water at room temperature and stirring was continued for an additional 15 min resulting in a clear red / orange solution. The reaction mixture was then lyophilized to give the final product. LC-MS: (ES, m / z) 518 [M+1] + . 1H-NMR:(400MHz,CD3OD)δ 8.31-8.22(m,2H),8.08(dd,J=8.8,1.9Hz,1H),7.81(d,J=9.2Hz,1H),7.74(d,J=8.8Hz,1H),7.40(dd,J=9.2,2.5Hz,1H), 7.18(d,J=2.5Hz,1H),4.08-3.98(m,2H),3.79-3.65(m,8H),3.58(t,J=5.5Hz,2H),3.45-3.39(m,4H),1.86-1.63(m,6H).

[0253] Example 4: In vivo assay Experimental Design: In vivo fluorescent retinal imaging experiments are performed on ketamine-anesthetized mice as shown in the table. [Table 1]

[0254] Since the balance of 3R and 4R tau isoforms is affected in many tauopathy diseases, including AD, both 3RTau and 4RTau tg models will be used to examine the interaction of the fluorescent compounds described herein with either variant of tau. Female tg mice may be used, as they have been reported to develop amyloid plaques faster than males. Real-time in vivo fluorescence imaging of the retina will be captured using a Phoenix Micron IV imaging system. Mice will be given increasing IV doses selected from pilot pharmacokinetic studies with biocompatible formulations of the compounds described herein, and retinal fluorescence will be determined at different times after administration. Systemic and retinal concentrations will be measured in satellite animals (WT control strain) to understand the relationship between dose, concentration, and response. After live imaging is completed, mice will be sacrificed for ex vivo brain and retina analysis to confirm the presence of tau via immunofluorescence (IF) microscopy using antibodies that recognize total tau, hyperphosphorylated tau, and tau conformational epitopes (3RTau and 4RTau). * * *

[0255] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0256] The disclosure illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc., should be read broadly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description rather than limitation, and it is not intended to use such terms and expressions to exclude 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 disclosure as claimed.

[0257] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0258] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to be illustrative, and not limiting, of the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains. The present invention provides, for example, the following items. (Item 1) 1. A method for determining whether a patient is suffering from a neurological disease or disorder, comprising detecting the presence of phosphorylated tau protein in tissue of said patient, said detecting comprising contacting said phosphorylated tau protein with a compound of formula Ic; [ka] During the ceremony, EDG, a) optionally, one or more R 17 or b) -NR 10 R 11 and In the formula, each R 17 are independently halogen, -OR 18 , -NR 19 R 20 , C1~C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R 10 , R 11 , R 18 , R 19 and R 20each independently represents hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally represented by one or more R 21 is replaced by R 21 each independently represents a halogen, -OR 22 , -NR 23 R 24 , C1~C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene optionally comprises one or more R 25 is replaced by R 22 , R 23 and R 24 Each of is independently hydrogen or C1-C 10 is alkyl, R 25 Each of C1 to C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; Ar is arylene of up to 14 carbon atoms or heteroarylene of up to 14 carbon atoms, each of which is optionally substituted with one or more R1; Each R1 is independently halogen, -OR2, -NR3R4, C1-C 10 Alkyl, C1-C 10heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally substituted with one or more R; R2, R3, and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally substituted with one or more R; Each R5 is independently halogen, -OR6, -NR7R8, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R6, R7, R8 and R 84 are independently hydrogen or C1-C 10 is alkyl, EWG is selected from the group consisting of -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3H and -CN; WSG, i) [ka] ii) polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof; iii) [ka] (In the formula, n is an integer of 1 to 50, and R 81 But hydrogen, C1-C 10Alkyl, C1-C 10 Alkenyl, or C1-C 10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally one or more C1-C 10 Alkyl, C1-C 10 substituted with heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less; iv) [ka] v) [ka] vi) -(C1~C 10 Alkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 carbons or less); vii) [ka] viii) -(C1~C 10 Heteroalkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 or less carbons); or ix) [ka] and X is C=O or SO2, or X and R 84 and combine to form pyridinyl, The method wherein Y is NH or S. (Item 2) 2. The method of claim 1, wherein the contacting is in vivo. (Item 3) 2. The method of claim 1, wherein the tissue is an ocular tissue. (Item 4) 2. The method of claim 1, wherein the contacting, when activated by light, causes emission of a detectable signal. (Item 5) 5. The method of claim 4, wherein the detectable signal is a fluorescent signal. (Item 6) The method of any one of the preceding items, wherein the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE). (Item 7) 2. The method of claim 1, wherein the neurological disease or disorder is selected from an age-related disease or disorder, a genetic disease or disorder, an injury-related disease or disorder, and a psychiatric disease or disorder. (Item 8) The method of claim 7, wherein the age-related disease or disorder is selected from Parkinson's dementia, vascular dementia, and amyotrophic lateral sclerosis, the genetic disease or disorder is Down's syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the psychiatric disease or disorder is selected from schizophrenia and depression. (Item 9) 2. The method of claim 1, wherein the phosphorylated tau protein comprises at least 3 moles of phosphate per mole of protein. (Item 10) 2. The method of claim 1, wherein the phosphorylated tau protein is 3-repeat tau, 4-repeat tau, or a combination thereof. (Item 11) 1. A method for preparing a patient for diagnosis of a neurological disease or disorder, comprising administering to a tissue of the patient a compound of formula Ic, [ka] During the ceremony, EDG, a) optionally, one or more R 17 or b) -NR 10 R 11 and In the formula, each R 17 are independently halogen, -OR 18 , -NR 19 R 20 , C1~C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R 10 , R 11 , R 18 , R 19 and R 20 each independently represents hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally represented by one or more R 21 is replaced by R 21 each independently represents a halogen, -OR 22 , -NR 23 R 24 , C1~C 10 Alkyl, C1-C 10heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene optionally comprises one or more R 25 is replaced by R 22 , R 23 and R 24 Each of is independently hydrogen or C1-C 10 is alkyl, R 25 Each of C1 to C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; Ar is arylene of up to 14 carbon atoms or heteroarylene of up to 14 carbon atoms, each of which is optionally substituted with one or more R1; Each R1 is independently halogen, -OR2, -NR3R4, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally substituted with one or more R; R2, R3, and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less, each of which, other than hydrogen, is optionally substituted with one or more R; Each R5 is independently halogen, -OR6, -NR7R8, C1-C 10 Alkyl, C1-C10 heteroalkyl, cycloalkyl of 10 or fewer carbons, heterocycloalkyl of 10 or fewer carbons, arylene of 10 or fewer carbons, or heteroarylene of 10 or fewer carbons; R6, R7, R8 and R 84 are independently hydrogen or C1-C 10 is alkyl, EWG is selected from the group consisting of -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3H and -CN; WSG, i) [ka] ii) polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof; iii) [ka] (In the formula, n is an integer of 1 to 50, and R 81 But hydrogen, C1-C 10 Alkyl, C1-C 10 Alkenyl, or C1-C 10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally one or more C1-C 10 Alkyl, C1-C 10 substituted with heteroalkyl, cycloalkyl of 10 carbons or less, heterocycloalkyl of 10 carbons or less, arylene of 10 carbons or less, or heteroarylene of 10 carbons or less; iv) [ka] v) [ka] vi) -(C1~C 10 Alkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 carbons or less); vii) [ka] viii) -(C1~C 10 Heteroalkyl)-R 33 -R 37 (In the formula, R 33 is a heteroarylene of 10 or less carbons; R 37 is -(C1-C6 alkyl)(heterocycloalkyl of 10 or less carbons); or ix) [ka] and X is C=O or SO2, or X and R 84 and combine to form pyridinyl, The method wherein Y is NH or S. (Item 12) 12. The method of claim 11, further comprising detecting binding of the compound of formula Ic to phosphorylated tau protein. (Item 13) 13. The method of claim 12, wherein the bond, when activated by light, causes emission of a detectable signal. (Item 14) 14. The method of claim 13, wherein the signal is a fluorescent or infrared signal. (Item 15) 12. The method of claim 11, wherein the administration is intravenous. (Item 16) 12. The method of claim 11, wherein the administration is localized to the retina of the eye. (Item 17) 12. The method of claim 11, wherein the administration is topical. (Item 18) The method according to any one of items 11 to 17, wherein the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE). (Item 19) 12. The method of claim 11, wherein the neurological disease or disorder is selected from an age-related disease or disorder, a genetic disease or disorder, an injury-related disease or disorder, and a psychiatric disease or disorder. (Item 20) 20. The method of claim 19, wherein the age-related disease or disorder is selected from Parkinson's dementia, vascular dementia, and amyotrophic lateral sclerosis, the genetic disease or disorder is Down's syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the psychiatric disease or disorder is selected from schizophrenia and depression. (Item 21) 13. The method of claim 12, wherein the phosphorylated tau protein comprises at least 3 moles of phosphate per mole of protein. (Item 22) 13. The method of claim 12, wherein the phosphorylated tau protein is 3-repeat tau, 4-repeat tau, or a combination thereof.

Claims

[Claim 1] The invention described in the specification.

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