Amyloid-targeting agents

Abstract

This paper provides the design and synthesis of novel molecular rotor fluorophores that are useful for detecting amyloid or amyloid-like proteins.The fluorophores are designed to exhibit enhanced fluorescence emission when associated with amyloid or amyloid-like proteins compared to unbound compounds.Also disclosed herein is a method for treating diseases associated with amyloid or amyloid-like proteins.Disclosed are compounds that are fluorescent-based small molecules that meet criteria.When used in diagnostic assays, these compounds can accurately assess the presence and extent of amyloid plaque accumulation.

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 Application No. 63 / 480,453, filed January 18, 2023, the entirety of which is hereby incorporated by reference. [Background technology]

[0002] background The accumulation of amyloid plaques in the brain is a hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, Down syndrome, and Creutzfeldt-Jakob disease (CJD). Currently, several approaches exist for clinically diagnosing these diseases and monitoring their progression, including targeting amyloid deposits with small molecule imaging agents. One such approach involves fluorescence-based small molecule imaging of amyloid, a low-cost, readily available, non-radioactive technique for the detection of amyloid deposits.

[0003] Ideally, fluorescence-based small molecules should possess enhanced emission brightness, spectroscopic properties specific to amyloid plaques, and binding specificity to amyloid in neuronal tissues to provide meaningful diagnostic data. In addition, such small molecules should exhibit excellent chemical and hydrolytic stability in physiologically relevant solutions over the time periods required to assess the presence and extent of amyloid plaque accumulation obtained in such labeling assays. Summary of the Invention [Means for solving the problem]

[0004] overview The present invention discloses a compound that is a fluorescent-based small molecule that meets the above criteria.When used in diagnostic assays, these compounds can accurately assess the presence and extent of amyloid plaque accumulation.Specifically, the compound is represented by Formula I or II: [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein W 1 is O, N(R 14 ), or C(R 4 )2, R 14 is hydrogen, alkyl, halomethyl having 1 to 3 halo groups, -COOH, -CONH2, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 is selected from hydrogen, halo, haloalkyl having 1 to 3 halo groups, or cyano; R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, —CN, —C(O)R 1A , -C(O)OR 1A , -C(O)NR 1A R 1B , -OR 1A , -NHC(O)NR 1A R 1B , -NR 1A R 1B , -NHNR 1A R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1Bare each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is —C(O)— or —SO—; Y is CH, NH, or S; WSG is a water-soluble group, however, When Z is -C(O)-, Y is not NH; In Formula I, Y is CH2 and W 1 When is O, N(CH3), or CH2, R 2 Even hydrogen C1~ 10 Not alkyl, In Formula II, Y is CH2 and W 1 is O, N(CH3), or CH2, and R 3 , R 5 , R 6 If is hydrogen, then R 2 is hydrogen and C 1~10 Not alkyl] is disclosed.

[0005] The present disclosure also provides pharmaceutical compositions comprising a compound of Formula I or II described herein, or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. Also provided is a method for determining whether a patient has a neurological disease or disorder, comprising administering to the patient a compound of Formula I or II described herein, or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, or a pharmaceutical composition thereof. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 shows intravital retinal imaging images of tau in a 3R Tau transgenic mouse model after IV injection of Compound 1.

[0007] [Figure 2] FIG. 2 shows intravital retinal imaging images of tau in a 3R Tau transgenic mouse model after IV injection of compound 1a. DETAILED DESCRIPTION OF THE INVENTION

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

[0009] The following words, phrases and symbols, as used herein, are generally intended to have the following meanings, unless otherwise indicated by the context in which they are used.

[0010] A dash (e.g., "-" or "-") indicates a bond and may be a point of attachment for a substituent. For example, -C(O)NH is bonded through a carbon atom. Chemical groups may be depicted with or without one or more dashes without losing their usual meaning. In a structure, a wavy line drawn across a line indicates a point of attachment for a substituent or group.

[0011] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0012] Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0013] "Alkyl," by itself or as part of another substituent, refers to straight (i.e., unbranched) or branched chains, or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, having the specified number of carbon atoms (e.g., C1-C 10 means 1 to 10 carbons), and can include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and homologs and isomers of n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0014] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0015] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" refers to an aliphatic group having one triple bond and one double bond.

[0016] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

[0017] "Cyano" refers to -CN.

[0018] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl, alkenyl, or alkynyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. Cycloalkyl also refers to a ring system containing multiple carbocyclic rings fused together in which one of the fused rings is aromatic, but the ring system is not completely aromatic. As used herein, cycloalkyl refers to a ring system containing 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

[0019] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0020] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms are replaced by halogen. For example, if an alkyl residue is substituted with more than one halogen, the haloalkyl can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, respectively, which may or may not be the same halogen. Examples of haloalkyl include, but are not limited to, difluoromethyl (-CHF), trifluoromethyl (-CF), fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0021] "Heteroalkyl," alone or in combination with another term, means, unless otherwise stated, a straight or branched chain consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of N, O, S, P, and Si, where the N and S atoms can be optionally oxidized and N can be optionally quaternized. The heteroatom(s), i.e., N, O, S, P, and Si, can be included at any non-terminal position of the heteroalkyl group or at the position to which the heteroalkyl group is attached. Two or more heteroatoms can be consecutive in the chain. Examples of heteroalkyl 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, and -O-CH2-CH3.

[0022] "Heteroaryl" refers to an aromatic group, including groups having aromatic tautomers or resonance structures, having a single ring, multiple rings, or multiple fused rings containing one or more ring heteroatoms independently selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. As used herein, heteroaryl contains 3 to 20 ring atoms (i.e., 3-20-membered heteroaryl), 3 to 12 ring atoms (i.e., 3-12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from N, O, and S. Heteroaryl does not encompass or overlap with aryl, as defined above. A heteroaryl group can be attached 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-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 4-furyl ... aryl, 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, 6-quinolyl, pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

[0023] The term "heterocyclyl" refers to cyclic versions of "heteroalkyl." Additionally, for heterocyclyl, a heteroatom can occupy the position at which the heterocyclyl 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 heterocyclyl 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 heterocyclyls include, but are not limited to, glucose, mannose, allose, altrose, gulose, idose, galactose, and talose. [ka] These include, but are not limited to, the following:

[0024] "Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to a double-bonded O, written as, for example, (=O) or (O). When tautomeric forms of the compounds exist, the hydroxyl and oxo groups are interchangeable.

[0025] "Thiol" refers to -SH.

[0026] Each of the above terms (eg, "alkyl," "heteroalkyl," "aryl" and "heteroaryl") can include both substituted and unsubstituted forms of the indicated radical.

[0027] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0028] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where said event or circumstance does not occur. Also, the term "optionally substituted" refers to the fact that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0029] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound can exist in equilibrium with an imidic acid tautomer, and a carbonyl-containing compound can exist in equilibrium with an enol tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compounds include all 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.

[0030] Also, any formula or structure given herein is intended to represent the unlabeled form and isotopically labeled form of the compound.Isotopically labeled compounds have the structure illustrated by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass 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, for example: 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, but not limited to, 3 H and 14 Isotopically labeled compounds incorporating a radioactive isotope such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, including drug or substrate tissue distribution assays, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radiation treatment in patients.

[0031] The present disclosure also includes deuterated analogs of compounds of Formula I, for example, in which one to n hydrogens bonded to a carbon atom (where n is the number of hydrogens in the molecule) have been replaced with deuterium. Such compounds can exhibit increased resistance to metabolism when administered to mammals, particularly humans, and can be useful for extending the half-life of any compound of Formula I. 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, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0032] Deuterium-labeled or substituted compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, can confer certain advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18F-labeled compounds can be useful for PET or SPECT studies.The isotope-labeled compounds of the present disclosure and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotopically labeled reagents by carrying out the procedures disclosed in the following schemes or examples and preparations.In this context, it is understood that deuterium is considered as a substituent in the compounds described herein.

[0033] 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", it is understood that the position has hydrogen at 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.

[0034] In some embodiments, the compounds are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0035] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "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.

[0036] 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 salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, when a compound described herein is obtained as an acid addition salt, 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 produced 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 base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare pharmaceutically acceptable non-toxic 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically 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, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH(alkyl)), dialkylamines (i.e., HN(alkyl)), trialkylamines (i.e., N(alkyl)), alkenylamines (i.e., NH(alkenyl)), dialkenylamines (i.e., HN(alkenyl)), trialkenylamines (i.e., N(alkenyl)), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl)), or mixtures of alkylamines, alkenylamines, cycloalkylamines, and / or arylamines. Specific examples of suitable amines include, by way of example only, diisopropylamine, triethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0037] The term "substituted" means that any one or more hydrogen atoms on the specified atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. Unless otherwise stated, the one or more substituents can be any substituent provided herein, or a combination thereof. Polymers or similar indefinite structures arrived at by defining a substituent with an infinite number of additional substituents added (e.g., a 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 encompassed herein. The term "substituted alkyl" is not intended to include "haloalkyl" as described herein.

[0038] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0039] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0040] A "prodrug" refers to any compound that, when administered to a biological system, yields the parent compound as a result of spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), photolysis, and / or metabolic chemical reaction(s). Thus, a prodrug is a covalently modified analog or latent form of the biologically active parent compound.

[0041] "Water-soluble group" or "WSG" refers to any group that alters the water solubility of a compound of Formula I or II. Examples include, but are not limited to, sugars, polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof. Other examples include compounds of Formula I or II. [ka] [In the formula, n is an integer of 1 to 50, and R 86 is H, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, C 1~10 Heterocyclyl, C 6~10 Aryl, or C 1~10 heteroaryl, each of which, except for hydrogen, is selected from one or more C 1~10 Alkyl, C1~10 Haloalkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, C 1~10 Heterocyclyl, C 6~10 Aryl, or C 1~10 In some embodiments, R 86 is a prodrug moiety. Examples of prodrugs include, but are not limited to, phosphate prodrugs. compound

[0042] The present disclosure provides compounds useful for the detection and treatment of neurological diseases and disorders.

[0043] In some embodiments, the present disclosure provides compounds of formula I or II: [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein W 1 is O, N(R 14 ), or C(R 4 )2, R 14 is hydrogen, alkyl, halomethyl having 1 to 3 halo groups, -COOH, -CONH2, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 is selected from hydrogen, halo, haloalkyl having 1 to 3 halo groups, or cyano; R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, —CN, —C(O)R 1A , -C(O)OR 1A , -C(O)NR 1A R 1B, -OR 1A , -NHC(O)NR 1A R 1B , -NR 1A R 1B , -NHNR 1A R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is —C(O)— or —SO—; Y is CH, NH, or S; WSG is a water-soluble group, however, When Z is -C(O)-, Y is not NH; In Formula I, Y is CH2 and W 1 When is O, N(CH3), or CH2, R 2 Even hydrogen C1~ 10 Not alkyl, In Formula II, Y is CH2 and W 1 is O, N(CH3), or CH2, and R 3 , R 5 , R 6 If is hydrogen, then R 2 is hydrogen and C 1~10 Not alkyl] to provide.

[0044] In some embodiments, the present disclosure provides a compound of Formula I or II [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof [W 1 is O, N(R 14 ), or C(R 4 )2, R 14 is hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCI3, —OCF3, —OCBr3, —OCl3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halo, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -SO v1 R 1A , -SO v1 NR 1A R 1B , -CN, -C(O)R 1A , -C(O)OR 1A , -C(O)NR 1A R 1B , -OR 1A , -ONR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1 , -NR 1A R 1B , -NHNR 1A R 1B , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B are each independently hydrogen, halo, -CF3, -CBr3, -CCI3, -CCl3, -CHF2, -CHBr2, -CHCl2, -CHI2, -CH2F, -CH2Br, -CH2Cl, -CH2I, -OCF3, -OCBr3, -OCCl3, -OCI3, -OCHF2, -OCHBr2, -OCHCl2, -OCHI2, -OCH2F, -OCH2Br, -OCH2Cl, -OC H 2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 1 is -F, -Cl, -Br, or -I, n1 is independently an integer of 0 to 4, m1 is independently 1 or 2; v1 is independently 1 or 2; Z is —C(O)— or —SO—; Y is CH, NH, or S; WSG is a water-soluble group].

[0045] In some embodiments, when Z is -C(O)-, then Y is not NH.

[0046] In some embodiments, the present disclosure provides a compound of formula I or II described herein, wherein Z is -C(O)-. In some embodiments, Y is CH. In some embodiments, Y is S. In some embodiments, the present disclosure provides a compound of Formula I or II [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof [W 1 is O, N(R 14 ), or C(R 4 )2, R 14 is hydrogen, alkyl, halomethyl having 1 to 3 halo groups, -COOH, -CONH2, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 is selected from hydrogen, halo, haloalkyl having 1 to 3 halo groups, or cyano; R 2 , R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, —CN, —C(O)R 1A , -C(O)OR 1A , -C(O)NR 1A R 1B , -OR 1A , -NHC(O)NR 1A R 1B , -NR 1A R 1B , -NHNR 1A R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR1B , -NR 1A OR 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is —C(O)— or —SO—; Y is CH, NH, or S; WSG is [ka] and m is an integer having a value of 1 to 10.

[0047] In some embodiments, when Z is -C(O)-, then Y is not NH.

[0048] In some embodiments, in Formula I, Y is CH2 and W 1 When is O, N(CH3), or CH2, R 2 Even hydrogen C1~ 10 It's not alkyl.

[0049] In some embodiments, in Formula II, Y is CH and W 1 is O, N(CH3), or CH2, and R 3 , R 5 , R 6 If is hydrogen, then R 2 is hydrogen and C 1~10 It's not alkyl.

[0050] In some embodiments, the present disclosure provides a compound of formula I or II described herein, wherein Z is -C(O)-. In some embodiments, Y is CH. In some embodiments, Y is S.

[0051] In some embodiments, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , Z, and Y are as described herein].

[0052] In some embodiments, the present disclosure provides a compound of formula Ia [ka] or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, wherein WSG, R 1 , R 2 , Z, and Y are as described herein].

[0053] In some embodiments, the present disclosure provides a compound of formula Ib [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , and R 2 as described herein].

[0054] In some embodiments, the present disclosure provides a compound of formula Ic [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1, and R 2 as described herein].

[0055] In some embodiments, the present disclosure provides a compound of formula Id [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , and R 2 as described herein].

[0056] In some embodiments, the present disclosure provides a compound of formula Ie [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , and R 2 as described herein].

[0057] In some embodiments, the present disclosure provides a compound of formula If [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , and R 2 as described herein].

[0058] In some embodiments, R 1 is hydrogen. In some embodiments, R 2is hydrogen, halo, -CF3, -CBr3, -CCI3, -CCl3, -CHF2, -CHBr2, -CHCl2, -CHI2, -CH2F, -CH2Br, -CH2Cl, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NHNH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl.

[0059] In some embodiments, the present disclosure provides a compound of Formula II [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5 , R 6 , Z, and Y are as described herein].

[0060] In some embodiments, the present disclosure provides a compound of formula IIa [ka] or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, wherein WSG, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z, and Y are as described herein].

[0061] In some embodiments, the present disclosure provides a compound of formula IIb [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5, and R 6 as described herein].

[0062] In some embodiments, the present disclosure provides a compound of formula IIc [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5 , and R 6 as described herein].

[0063] In some embodiments, the present disclosure provides a compound of formula IId [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5 , and R 6 as described herein].

[0064] In some embodiments, the present disclosure provides a compound of formula IIe [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5 , and R 6 as described herein].

[0065] In some embodiments, the present disclosure provides a compound of formula IIf [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein WSG, W 1 , R 1 , R 2 , R 3 , R 5 , and R 6 as described herein].

[0066] In some embodiments, R 1 is hydrogen, halo, —CF, —CBr, —CCI, —CCl, —CHF, —CHBr, —CHCl, —CHI, —CHF, —CHBr, —CHCl, —CHI, or —CN. 1 is —CF or unsubstituted methyl. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halo, -CF, -CBr, -CCI, -CCl, -CHF, -CHBr, -CHCl, -CHI, -CHF, -CHBr, -CHCl, -CHI, -CN, -OH, -NH, -COOH, -CONH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen.

[0067] In some embodiments, the present disclosure provides a WSG comprising: [ka] and m is an integer having a value of 1 to 10.

[0068] In some embodiments, the present disclosure provides a WSG comprising: [ka] wherein m is an integer having a value of 1 to 10, and each R 1’ But independently, H, [ka] wherein each X is independently O or S; Each R 11 are independently hydrogen, C 1~10 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are selected from 1 to 4 R 21 or each XR 11 are independently -XP(X)(R 12 )2, Each R 12 are independently hydroxy, thiol, -XP(X)(R 13 )2, C 1~10 Alkyl, -OC 1~10 Alkyl, and -SC 1~10 alkyl, Each R 13 are independently hydroxy, thiol, C 1~10 Alkyl, -OC 1~10 Alkyl, and -SC 1~10 alkyl, Each R 21 are independently halo, hydroxy, thiol, -NO2, -N3, cyano, C 1~10 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 1~8 Haloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, -OC 1~10 Alkyl, -OC2~6 Alkenyl, -OC 2~6 Alkynyl, -OC 3~10 Cycloalkyl, -OC 1~8 Haloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -NH, -NH(R 31 ), -N(R 31 )2, -C(O)(R 31 ), -C(O)O(R 31 ), -C(O)OH, -C(O)NH2, -C(O)NH(R 31 ), -C(O)N(R 31 )2, -NHC(O)(R 31 ), -NHC(O)O(R 31 ), -NHC(O)NH(R 31 ), -S(R 31 ), -NHS(O) y (R 31 ), -N(C 1~10 alkyl)S(O) y (R 31 ), -S(O) y N(R 31 )2, -S(O)NH(R 31 ), and -S(O) y (R 31 ) and each R 31 are independently, C 1~10 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 1~8 selected from haloalkyl, aryl, heteroaryl, and heterocyclyl; each y is independently 1 or 2] The present invention provides a compound of formula I or II as described herein, selected from the group consisting of:

[0069] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

[0070] In some embodiments, the present disclosure provides a compound of formula [ka] or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein p is 0 or 1; W 1 is a bond, O, N(R 14 ), C(R 4 )2, CH2-O-, CH2-N(R 14 ), or CH2-C(R 4 )2, R 14 is hydrogen, alkyl, halomethyl having 1 to 3 halo groups, -COOH, -CONH2, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 is selected from hydrogen, halo, haloalkyl having 1 to 3 halo groups, or cyano; R 2is hydrogen, halo, haloalkyl having 1 to 3 halo groups, -CN, -C(O)R 1A , -C(O)OR 1A , -C(O)NR 1A R 1B , -OR 1A , -NHC(O)NR 1A R 1B , -NR 1A R 1B , -NHNR 1A R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is —C(O)— or —SO—; Y is CH, NH, or S; WSG is a water-soluble group].

[0071] In some embodiments, when Z is -C(O)-, then Y is not NH.

[0072] In some embodiments, in Formula I, Y is CH2 and W 1 When is O, N(CH3), or CH2, R 2 Even hydrogen C1~ 10 It's not alkyl.

[0073] In some embodiments, in Formula II, Y is CH and W1 is O, N(CH3), or CH2, and R 3 , R 5 , R 6 If is hydrogen, then R 2 is hydrogen and C 1~10 It's not alkyl.

[0074] In some embodiments, the present disclosure provides a compound of formula I or II described herein, wherein Z is -C(O)-. In some embodiments, Y is CH. In some embodiments, Y is S.

[0075] The ketone compounds of Formula IIa are contemplated to have increased fluorescence at excitation wavelengths of 450 nm and / or 488 nm and to have fewer metabolites that may cause adverse effects.

[0076] General synthesis The compounds of the present disclosure can be prepared using the methods disclosed herein and their routine modifications that become apparent in light of the present disclosure and methods known in the art.In addition to the teachings of the present specification, conventional well-known synthetic methods can also be used.The synthesis of typical compounds of Formula I or II, for example, compounds having the structure described by Formula I or II or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be carried out as known in the art, as described in the examples.

[0077] Exemplary embodiments of compounds according to the present disclosure can be synthesized using the following reaction schemes and / or examples. In view of the descriptions herein, it is apparent that the schemes can be modified by substituting materials with other materials having similar structures to yield correspondingly different products. A description of the synthesis follows, providing examples of how steps can be modified to yield desired products. Group labels (e.g., R 1) are for illustrative purposes only and, unless otherwise specified, do not necessarily correspond in name or function to labels used elsewhere to describe compounds of Formula I or II, or embodiments or fragments thereof.

[0078] Where process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. In addition, as will be apparent to one skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. Numerous protecting groups are described, for example, in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0079] The materials and reagents for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Other materials can be found in standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5 th Edition, 2001), as well as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0080] Scheme 1 shows an exemplary synthetic route for the synthesis of compounds provided herein (eg, compounds of Formula I or II). Scheme I [ka]

[0081] Compound A, a halo-substituted naphthalene, is coupled with piperidine compound B under suitable reaction conditions, for example, under palladium catalysis and a base, such as CsCO, in a solvent such as toluene, to give compound C, a piperidine-substituted naphthalene. Reduction of the ester of compound C using a metal hydride reagent under suitable reaction conditions, for example, in a solvent such as THF, gives compound D. Compound E (R 1 is H). Coupling of compound E with compound F under suitable reaction conditions in a suitable solvent such as THF in the presence of a base such as piperidine gives a compound of formula I or II (R 1 is H). Compound E (R 1 is H) to give compound K(R 1 is alkyl). Compound K is coupled with compound F under suitable reaction conditions in a suitable solvent such as THF in the presence of a base such as piperidine to give a compound of formula I or II (R 1 is alkyl).

[0082] Alternatively, the piperidine group can be added to the naphthalene after aldehyde formation, as shown in Scheme II below. Scheme II [ka]

[0083] Compound A, a halo-substituted naphthalene, is reduced under suitable reaction conditions, for example, under a metal hydride agent in a solvent such as THF, to give compound G. Compound H(R 1 is H). Compound H is coupled with piperidine compound B under suitable reaction conditions, such as a palladium catalyst and a base, such as Cs2CO3, in a solvent such as toluene, to give compound M (R 1is H). Compound H(R is H) can be obtained by reaction of compound H(R with a suitable trifluoromethyl compound, for example (CF3)SiMe3, in a solvent such as THF under suitable reaction conditions. 1 is H) to give compound N(R 1 is CF3). Compound N is coupled with compound F under suitable reaction conditions in a suitable solvent such as THF in the presence of a base such as piperidine to give a compound of formula I or II (R 1 Alternatively, compound H(R is CF) can be prepared by the reaction of compound H(R with a suitable alkyl magnesium halide in a solvent such as THF under suitable reaction conditions. 1 is H) to give compound J (R 1 is alkyl). Coupling of compound J with compound B under suitable reaction conditions gives compound K. Coupling of compound K with compound F under suitable reaction conditions, for example, in a solvent such as toluene, under palladium catalysis and a base such as Cs2CO3, gives a compound of formula I or II (R 1 is alkyl).

[0084] Prodrugs of compounds of Formula I or II can be prepared by the methods disclosed in WO2020 / 093008, see, for example, Scheme III below. Scheme III [ka]

[0085] In Scheme III, compound O, an exemplary compound of formula I or II, is reacted with compound P under suitable reaction conditions to produce compound Q (R 85 is a prodrug moiety, e.g., a phosphate prodrug described herein. In some cases, Compound O is deprotonated using a base and then contacted with Compound P.

[0086] Detectable target proteins The compounds described herein may be useful for detecting or treating neurological diseases or disorders. In this regard, the compounds described herein may be prodrugs.

[0087] Many neurological diseases, including neurodegenerative diseases and injury-related disorders, can be detected by the compounds and methods described herein. Neurological diseases or disorders can be characterized by certain peptides, proteins, or protein accumulations, which are described herein as detectable proteins. Detectable proteins or their accumulations can include, for example, amyloid beta protein, alpha-synuclein (aSyn), TAR DNA-binding protein 43 (TDP43), or phosphorylated tau protein. Amyloid beta protein, alpha-synuclein (aSyn), TAR DNA-binding protein 43 (TDP43), or phosphorylated tau protein can be detected by contacting with the compounds described herein. Generally, the compounds and methods described herein are useful for detecting amyloid beta protein, alpha-synuclein (aSyn), TAR DNA-binding protein 43 (TDP43), or phosphorylated tau protein, or their accumulations, in patient tissues or samples. Such presence of amyloid beta protein or phosphorylated tau protein can be detected using a compound capable of binding to amyloid beta protein or phosphorylated tau protein and then detecting that binding.

[0088] Amyloid beta protein (Aβ) is a polypeptide that generally contains about 40 amino acid residues, e.g., about 36-43, about 39-43, or about 40-42 amino acid residues. Isoforms include Aβ(1-40) and Aβ(1-42). In some embodiments, the Aβ is Aβ(1-42). Aβ is thought to be generated by enzymatic cleavage of a larger precursor protein, beta amyloid precursor protein (APP), which is encoded by a gene on human chromosome 21. APP isoforms include NP_000475.1, NP_001129488.1, NP_001129601.1, NP_001129602.1, NP_001129603.1, NP_001191230.1, NP_001191231.1, NP_001191232.1, NP_958816.1, and NP_958817.1. Aβ is thought to be generated by the action of beta and gamma secretase enzymes on APP. Aβ has been found in deposits, such as plaques, in the brains of individuals with Alzheimer's disease. Aβ is thought to be involved in the pathogenesis of neurological diseases. Aβ is also thought to be toxic to neurons.

[0089] Proteins detected by the compounds of the present disclosure include amyloid beta peptide (Aβ), prion peptide (PrP), alpha-synuclein, IAPP (amylin), huntingtin, calcitonin (ACal), atrial natriuretic factor (AANF), apolipoprotein A1 (ApoA1), serum amyloid A (SAA), medin (AMed), prolactin (APro), transthyretin (ATTR), lysozyme (ALys), beta 2 microglobulin (Aβ2M), gelsolin (AGel), keratoepithelin (Aker), cystatin (ACys), immunoglobulin light chain AL (AL), S-IBM, or superoxide dismutase. In some embodiments, the amyloid peptide detected is Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase.

[0090] "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 in the stabilization and assembly of microtubules, which in turn affect the intraneuronal transport of cargo. Tau can also participate in signaling pathways by interacting with actin via its acidic N-terminus, which protrudes from microtubules for neurite outgrowth and stabilization during brain development. The 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 maturation stage and type of neuron. MAPT gene mutations have been associated with several neurological disorders, including 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 (which 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.

[0091] The human tau gene is located at 17q21 on the long arm of chromosome 17. The gene is thought to contain 16 exons, including exon 21 as part of the promoter. The primary tau transcript contains 13 exons; exons 4A, 6, and 8 are 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, resulting in six distinct mRNAs that are translated into six distinct tau isoforms. These isoforms differ by the absence or presence (0N, 1N, or 2N) of one or two 29-amino acid repeats encoded by exons 2 and 3 in the amino-terminal portion, in combination with either three microtubule-binding repeats (R1, R3, and R4) or four repeat regions (R1-R4) 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). Tau may be mutant tau. The mutation may be an FTDP-17 mutation. Exemplary 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.

[0092] "Phosphorylated tau protein" or "phosphorylated tau" refers to a tau protein in which at least one amino acid residue is modified with a phosphate group. Tau is believed to contain as many as 85 amino acid residues compatible with phosphorylation. Generally, the phosphate group is a post-translational modification and can be attached to the side chain of an amino acid residue. The phosphorylated amino acid residue can be, for example, a serine (S), threonine (T), or tyrosine (Y) residue, or a combination thereof. A phosphorylated tau protein can 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. A phosphorylated tau protein can 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 predominant.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 predominant.Phosphorylated tau protein can be fibrillar, for example, as neurofibrillary tangles (NFTs).NFTs can be found in the somatodendritic compartment of neurons.

[0093] Alpha-synuclein (aSyn) is a neuronal protein found abundantly in the brain, primarily in the axon terminals of presynaptic neurons. Synucleinopathies are a class of neurodegenerative disorders associated with the abnormal accumulation of aSyn aggregates, including Parkinson's disease (PD), dementia with Lewy bodies (LBD), and multiple system atrophy (MSA).

[0094] TAR DNA-binding protein 43 (TDP43) is a 43-kDa protein that accounts for the majority of mutations associated with familial amyotrophic lateral sclerosis (ALS). Hyperphosphorylated, ubiquitinated, and truncated forms of TDP-43, known as pathological TDP43, are the primary disease protein associated with conditions such as ALS. ALS is a terminal neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. Misfolded TDP-43 has also been associated with limbic-predominant age-related TDP-43 encephalopathy (LATE), a form of dementia.

[0095] "Contacting" is used according to its ordinary and simple meaning to refer to the process of bringing at least two distinct species (e.g., chemical compounds, including biomolecules, or cells) into sufficient proximity for them to interact. The term "contacting" can include causing two molecular species to react or come into physical contact, where the two species can be, for example, compounds, biomolecules, proteins, or enzymes described herein. In some embodiments, contacting includes allowing a compound described herein to interact with a protein (e.g., Aβ protein or phosphorylated tau protein) or enzyme.

[0096] Therefore, according to some embodiments of the present disclosure, a method for determining whether a patient has a neurological disease or disorder is provided.The method involves detecting the presence of amyloid beta protein or phosphorylated tau protein, or their accumulated masses, in a patient's tissue or sample by contacting the patient's tissue or sample with a compound described herein.Contacting can be performed in vivo or ex vivo.Contacting can be performed by administering the compound to the patient, for example, by topical administration or intravenous administration.

[0097] In another embodiment, a method for preparing a patient for diagnosis of a neurological disease or disorder is provided, comprising administering a compound described herein to the patient and allowing it to bind to amyloid beta protein or phosphorylated tau protein, or accumulated masses thereof. The compound may be administered intravenously. Once the compound is administered to the patient, its binding to amyloid beta protein or phosphorylated tau protein, or accumulated masses thereof and / or binding of the parent compound may be detected using any method, including the methods described herein. In some embodiments, binding indicates that the patient may have a neurological disease or disorder.

[0098] Neurological Diseases and Disorders and Treatment Thereof Proteinopathies are a group of diseases caused by misfolded proteins. Neurodegenerative proteinopathies are characterized by the formation of misfolded protein aggregates, which cause cytotoxicity and contribute to the breakdown of cellular proteostasis. Misfolded or aggregated proteins can be detected by contacting them with the compounds described herein, and the contact causes the emission of a detectable signal when activated by light. Generally, the compounds, compositions, and methods described herein are useful for detecting misfolded or aggregated proteins such as amyloid beta (Aβ, including both isoforms Aβ40 and Aβ42), phosphorylated tau, alpha-synuclein (aSyn), and TAR DNA-binding protein 43 (TDP43).

[0099] In some embodiments, the present disclosure provides a method for determining the presence or absence of a neurological disease or disorder in a patient. In some embodiments, the method comprises administering to the patient an effective amount of a compound described herein or a pharmaceutical composition thereof. The compound may be a compound of Formula I. In some embodiments, a method for determining whether a patient has a neurological disease or disorder is provided, the method comprising administering to the patient a compound described herein or a pharmaceutical composition described herein. In some methods, the compound is administered intravenously. In some methods, the compound is administered to the patient's eye. In some embodiments, the neurological disease or disorder is a disease or disorder characterized by protein aggregation or protein misfolding.

[0100] Also provided herein is a method for determining whether a patient has a neurological disease or disorder, comprising detecting the presence of amyloid beta protein or phosphorylated tau protein, or accumulated masses thereof, in a patient's tissue or sample, wherein the detecting step comprises contacting the tissue or sample with a compound described herein. The compound may be a compound of Formula I or II. The contacting may be performed in vivo. The tissue may be ocular tissue. The sample may be a urine sample.

[0101] 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 disease, vascular dementia, Alzheimer's disease, cerebral amyloid angiopathy, frontotemporal dementia, limbic-predominant age-related TDP-43 encephalopathy, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, age-related macular degeneration, 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.In some embodiments, the neurological disease or disorder is Alzheimer's disease or traumatic brain injury (TBI).

[0102] The neurological disease or disorder may be a tauopathy. Tauopathies are a class of neurological disorders associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of tau, which can dissociate tau protein from microtubules and form insoluble aggregates. Aggregations of hyperphosphorylated tau protein are sometimes called double-helical filaments. The exact mechanism of tangle formation is not fully understood, and it remains controversial whether tangles are the primary causative factor in disease or play a more peripheral role. Tauopathies are found in many neurological disorders, such as posttraumatic degeneration, infection, metabolic disease, and motor neuron degeneration. The spatial distribution, temporal appearance, and structural changes of tau protein manifest differently among various neurological disorders. Patients with AD have hyperphosphorylated, twisted, and 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, likely due to the interaction between synuclein and tau proteins. Non-Alzheimer's tauopathies are sometimes lumped together as "Pick's complex" due to their association 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 as neurofibrillary tangles (NFTs).

[0103] In some embodiments, the neurological disease or disorder is selected from primary age-related tauopathy (PART), neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Ritiko-Bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis complex, pantothenate kinase-associated neurodegeneration, and lipofuscinosis.

[0104] 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 can be classified as a secondary tauopathy. Alzheimer's disease is characterized by symptoms of memory loss in the early stages of the disease. Neurofibrillary tangles were the initial descriptor of AD. When tau becomes hyperphosphorylated, the protein dissociates from axonal microtubules. Tau can then misfold and begin to aggregate, which can form neurofibrillary tangles (NFTs). When tau dissociates, microtubules also become destabilized, and the combination of neurofibrillary tangles and destabilized microtubules disrupts processes such as axonal transport and neurotransmission. The degree of NFT involvement in AD is defined by the Braak stage. Braak stages I and II are used when NFT involvement is primarily limited to the transitional entorhinal cortex of the brain; stages III and IV are used when limbic regions, such as the hippocampus, are involved; and stages V and VI are used 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 higher risk for developing AD. APOε4 appears to be less efficient than other isoforms at clearing Aε and may therefore correlate with higher amyloid burden, tau phosphorylation, synaptic toxicity, and decreased synaptic density. Having experienced a traumatic brain injury (TBI) is another risk factor for developing AD, and studies have shown that individuals who have experienced TBI have a significantly increased risk of AD.

[0105] As AD progresses, symptoms include confusion, long-term memory loss, aphasia, vocabulary loss, aggression, irritability, and / or mood swings. In more advanced stages of the disease, physical function is lost. Patients with Alzheimer's disease (AD) have demonstrated numerous characteristic neuropathies, such as increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disrupted 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 has Alzheimer's disease includes detecting the presence of phosphorylated tau protein in the patient's tissue or sample, and the detecting comprises contacting the phosphorylated tau protein with a compound described herein.

[0106] 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.

[0107] In some embodiments, the neurological disease or disorder is Parkinson's disease. In some embodiments, the neurological disease or disorder is Parkinsonism-related dementia. In some embodiments, the neurological disease or disorder is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, a 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 involves neuronal dysfunction. Neuronal dysfunction can include neuronal atrophy or other decline in effective neuronal function. For example, Alzheimer's disease is known to exhibit neuronal dysfunction, particularly in cortical neurons, such as hippocampal neurons and neurons in close proximity to the hippocampus.

[0108] In some embodiments, the neurological disease or disorder is traumatic axonal injury (TAI), traumatic brain injury (TBD), dementia (e.g., generalized 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, Ritiko-Bodig disease (Parkinson-Dementia Complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis complex, pantothenate kinase-associated neurodegeneration, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic grain disease (AGD), or corticobasal degeneration.

[0109] The neurological disease or disorder may be an injury-related condition, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). TBI is a chronic disease resulting from damage to the brain caused by external forces, such as a collision, blow, impact, rapid acceleration or deceleration, or projectile penetration. The injury resulting in TBI can result in a reduced or altered state of consciousness, resulting in temporary or permanent impairments in cognitive, sensorimotor, and psychosocial functioning. CTE is a progressive degenerative disease found in people who have suffered repeated brain trauma, including blows to the head that did not result in TBI symptoms. Physical manifestations of CTE include brain shrinkage, atrophy of the frontal and temporal lobes, enlargement of the ventricles, and atrophy of the hippocampus, thalamus, brainstem, and cerebellum. Individuals with CTE may experience symptoms of dementia, memory loss, aggression, confusion, depression, and suicidal ideation, which may occur several years after the injury.

[0110] The neurological disease or disorder can be a neurological disease or disorder of the eye, for example, glaucoma, ocular hypertension, macular degeneration, diabetic retinopathy, age-related macular degeneration (AMD) or retinitis pigmentosa.

[0111] In some embodiments of the method, the neurological disease or disorder is a prion disease. Prion diseases are fatal, contagious neurological disorders, the most notable of which is Creutzfeldt-Jakob disease, or CJD. CJD is sometimes called the "great mimicker" because it causes symptoms similar to those of many other neurological disorders. Common CJD symptoms include a variety of neurological and psychiatric indications, including behavioral changes, confusion, cognitive impairment, motor problems, and visual impairment. CJD is difficult to diagnose, and current practice relies on cerebrospinal fluid testing. Interestingly, recent reports have demonstrated the presence of prion proteins in postmortem retinal tissue from CJD patients.

[0112] Thus, provided are methods for detecting prion deposits in a patient. In certain embodiments, detection is performed in the retina. In certain embodiments, methods are provided for detecting prion deposits in the retina of a patient, who may or may not exhibit clinical symptoms of a disease or disorder associated with prion deposition, such as Creutzfeldt-Jakob disease (e.g., behavioral changes, confusion, cognitive impairment, movement problems, visual impairment, kyphosis, ataxia, toe walking, etc.).

[0113] Cerebral amyloid angiopathy (CAA) is an age-related disease characterized by amyloid deposition within the walls of cerebral blood vessels. These deposits occur in cortical and pial arteries, leading to an increased risk of spontaneous intracerebral hemorrhage, ischemic lesions, and progressive dementia in elderly populations. The diagnosis of CAA is often overlooked by physicians because the presenting symptoms resemble transient ischemic attacks or "ministrokes." Diagnosis can be further complicated by CAA being found in up to 90% of patients with Alzheimer's disease. Several amyloidogenic peptides can lead to CAA, but amyloid beta (Aβ) is by far the most common form. Aβ deposits have been detected within the walls of arterioles, capillaries, and arteries in brain tissue from humans with severe CAA. It has been established that the Aβ42 isoform is preferentially present in intraparenchymal plaques in patients with Alzheimer's disease, while the Aβ40 isoform is more densely present within cerebrovascular wall deposits in CAA. In some embodiments of the method, the neurological disease or disorder is cerebral amyloid angiopathy (CAA), an age-related disease characterized by amyloid deposits in the walls of cerebral blood vessels.

[0114] Therefore, in certain embodiments, a method for detecting Aβ40 in a patient is provided. In certain embodiments, the detection is performed in the retina. In certain embodiments, the detection distinguishes between the Aβ isoform (Aβ40) associated with CAA and the Aβ isoform (Aβ42) associated with Alzheimer's disease.

[0115] In some embodiments, methods are provided for detecting alpha-synuclein (aSyn) in a patient. Alpha-synuclein has been associated with various neurological conditions, such as Parkinson's disease and Lewy body dementia (LBD).

[0116] In some embodiments, methods are provided for detecting TAR DNA-binding protein 43 (TDP43) in a patient. Hyperphosphorylated, ubiquitinated, and truncated forms of TDP-43, known as pathological TDP43, are the primary disease protein associated with conditions such as amyotrophic lateral sclerosis (ALS).

[0117] In some embodiments, the neurological disease or disorder involves a protein that develops an amyloid-like morphology, and a disease or condition associated with the formation of abnormal protein structures, protein aggregation, or protein misfolding. Non-limiting examples of amyloid-based diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Down's syndrome, and spongiform encephalopathies such as bovine spongiform encephalopathy (mad cow disease), Kura, Creutzfeldt-Jakob disease, and fatal familial insomnia. In some cases, other amyloid-based diseases detected, treated, or prevented by the methods of the present disclosure include reactive systemic amyloidosis, senile systemic amyloidosis (SAA), familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), prion diseases, coronary artery disease, atherosclerosis, cerebral hemorrhage, AL amyloidosis, type 2 diabetes, diseases or conditions characterized by loss of cognitive memory abilities, such as mild cognitive impairment (MCI), dementia with Lewy bodies (LBD), hereditary cerebral hemorrhage with amyloidosis (Dutch type), and Parkinson-Dementia Complex of Guam. Other diseases based on or associated with amyloid-like proteins are progressive supranuclear palsy, multiple sclerosis, HIV-associated dementia, ALS (amyotrophic lateral sclerosis), inclusion body myositis (IBM), adult-onset diabetes; endocrine tumors, as well as other diseases such as amyloid-related eye diseases that target various tissues of the eye, visual cortex (e.g., cortical visual impairment); anterior chamber and optic nerve (e.g., glaucoma); lens (e.g., cataracts due to beta-amyloid deposits); vitreous (e.g., ocular amyloidosis); retina (e.g., primary retinal degeneration and macular degeneration, particularly age-related macular degeneration); optic nerve (e.g., optic nerve drusen, optic neuropathy, and optic neuritis); and cornea (e.g., lattice dystrophies).

[0118] Further examples of neurological diseases or disorders include Alexander disease, Alpers disease, depression, perinatal asphyxia, Parkinson's 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, cannabinoid leukemia, and encephalopathy syndrome). Lehman's disease, Cockayne's syndrome, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, dementia with Lewy bodies, Machado-Joseph's disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Pelizaeus-Merzbach disease, primary lateral sclerosis, prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute myelopathy of the spinal cord secondary to pernicious anemia Combined spinal cord degeneration, schizophrenia, spinocerebellar ataxia (various features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord deafness, 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 juvenile (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), and mitochondrial Parkinson's disease.

[0119] Once a patient's neurological disease or disorder is determined, certain procedures can be provided to treat or ameliorate the symptoms of the neurological disease or disorder, or 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 a diagnosis is made, the treating physician can also suggest further treatments known to practitioners, including those described herein.

[0120] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the severity of the disease or condition), b) ameliorating, slowing, or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, causing partial or complete remission of the disease or condition, enhancing the effectiveness of another drug therapy, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0121] "Prevention" or "preventing" means any treatment of a disease or condition that keeps the clinical symptoms of the disease or condition from developing. The compounds may, in some embodiments, be administered to patients (including humans) who are at risk or have a family history of the disease or condition.

[0122] "Patient" refers to an animal, e.g., a mammal (including a human), that has undergone or been the subject of diagnosis, treatment, observation, or experiment. The methods described herein may be useful in human and / or veterinary applications. In some embodiments, the patient is a mammal. In one embodiment, the patient is a human.

[0123] The term "effective amount" of the compound described herein, or its pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomeric mixture, prodrug or deuterated analogue, refers to an amount that is sufficient to detect amyloid beta protein or phosphorylated tau protein, or its accumulated mass, or to bring about a therapeutic benefit, such as symptomatic relief or slowing of disease progression, when administered to a patient or a patient sample.For example, an effective amount can be an amount that is sufficient to reduce the symptoms of a disease or condition of a neurological disease or disorder.The effective amount can 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 mode of administration, and can be easily determined by those skilled in the art.

[0124] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" refers to within a living individual, such as an animal or human. In this context, the methods described herein can be used on an individual. "Ex vivo" refers to outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including 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 dosages of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or to design protocols for in vivo use in the clinic. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. Selected compounds can be further characterized to determine safety or tolerated dosage in human or non-human patients. Such properties can be determined using methods commonly known to those skilled in the art.

[0125] Target protein detection The neurological diseases or disorders described herein are characterized by certain peptides, proteins, or protein aggregates, the detection of which is useful for diagnosis. These peptides, proteins, or their accumulated aggregates are collectively referred to as detectable target proteins, and may include, for example, amyloid beta protein (Aβ), alpha-synuclein (aSyn), TAR DNA-binding protein 43 (TDP43), or phosphorylated tau protein.

[0126] Provided herein are methods for diagnosing a neurological disease or disorder in a patient, comprising administering a compound described herein to the patient's tissue. The compound may be a compound of Formula I or II. The method may include detecting binding of the compound and / or the parent compound to a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or a deposit thereof. Administration may be intravenous. The method may include detecting binding of the compound to the detectable target protein. In some embodiments, the method further includes activating with light to emit a detectable signal. In some embodiments, the method includes comparing the signal to a control value, where an increase in the signal compared to the control value indicates the presence of the detectable target protein, and the control value is a signal in the absence of the detectable target protein. In some embodiments of the method, the detectable signal is a fluorescent or infrared signal. In some embodiments, the light is a laser.

[0127] In some embodiments, the present disclosure provides a method for detecting a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or accumulated mass thereof. The method includes contacting a compound described herein with a tissue or sample that potentially contains a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or accumulated mass thereof, wherein the compound binds to the detectable target protein. In some embodiments, the present disclosure provides a method for detecting the presence or absence of binding of a compound described herein, or its parent compound, to a detectable target protein, the method comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient. In some embodiments, the present disclosure provides a method for monitoring the response of a patient having a disease or condition characterized by the presence of a detectable target protein to treatment, the method comprising, after treatment, binding an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to the detectable target protein and detecting a signal generated in response to the binding, wherein a decrease in the signal compared to before treatment indicates that the patient is responding to the treatment. In some embodiments, the detectable target protein is an amyloid or amyloid-like protein, such as Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase. In some embodiments, the amyloid or amyloid-like protein is beta amyloid (1-42) (Aβ(1-42)). In some embodiments, the detectable target protein is phosphorylated tau protein. In some embodiments, the phosphorylated tau protein is 3-repeat tau or 4-repeat tau.

[0128] In some embodiments, detection is performed within about 1 second, about 5 seconds, about 1 minute, about 10 minutes, about 30 minutes, or about 60 minutes of contact of the compound with the detectable target protein or administration of the compound, hi some embodiments, detection is performed within about 1-5 minutes of contact of the compound or administration of the compound.

[0129] In situ detection of the binding of a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or its accumulated mass with a compound described herein can be facilitated using a preferably handheld or portable imaging device. The imaging device can include a lens and an image sensor, and optionally a laser light source. When a light source emits laser light into a tissue, such as the retina, if a detectable target protein accumulates there and binds to a compound described herein, the target protein can be easily detected and quantified by a lens and an image sensor that collects and detects a fluorescent signal. The imaging device can be any device capable of detecting light, such as a camera. The imaging device can include a confocal lens. The imaging device can be a retinal imaging device. The imaging device can include a fundus camera. Detection can include a confocal laser scanning microscope. Detection can be non-mydriatic. For an overview of retinal imaging technology, see, for example, MD Abramoff et al., Retinal Imaging and Image Analysis (2010), IEEE Rev Biomed Eng. 3:169-208.

[0130] Amyloid beta protein or phosphorylated tau protein may accumulate in the patient's eye. In some embodiments, contact causes the emission of a detectable signal when activated by light. The signal may be fluorescent or infrared.

[0131] Provided herein is a method for treating a neurological disease or disorder in a patient, comprising administering to the patient a compound described herein. The compound can be a compound of Formula I or II.

[0132] Administration and Pharmaceutical Compositions Also provided are pharmaceutical compositions of the compounds described herein for administration to patients. The compound may be a compound of Formula I or II. The compound may be administered in a single dose or multiple doses. The compound may be administered by various methods, including, for example, rectal, oral buccal, intranasal, and transdermal routes. In certain embodiments, the compound may be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant. In some embodiments, the compounds described herein are administered intravenously. Intravenous administration may be by bolus injection or continuous injection. Additional injection methods include intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intradermal, subcutaneous, intramuscular and intradermal, intracranial, intralesional, and intratumoral.

[0133] In some embodiments, the compounds described herein are administered to the eye. In some embodiments, the compounds are administered topically to the eye. In some embodiments, administration is parenteral, for example by injection. In some embodiments, administration is oral.

[0134] The compound may be effective over a wide dosage range. In some embodiments, the dosage is 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, or 5 to 40 mg per day. Exemplary dosages include 10 mg, 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1000 mg. In some embodiments, an effective amount of the compound corresponds to approximately 50 to 500 mg. Effective amounts may vary between individual patients. The exact dosage will depend on the route of administration, the form in which the compound is administered, the patient being treated, the patient's weight or surface area being treated, and the preferences and experience of the attending physician.

[0135] In some embodiments, the effective amount of the compound is about 0.01-1000 mg per dose. In some embodiments, the effective amount of the compound is 50-500 mg 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 mg, 0.1-500 mg, 0. ...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 mg, 0.1-500 mg, 0.1-600 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 mg, 0.1-500 mg, .1~700mg, 0.1~800mg, 0.1~900mg, 0.1~1000mg, 1~100mg, 1~200mg, 1~300mg, 1~400mg, 1~500mg, 1~600mg, 1~700mg, 1~800mg, 1~900mg, 100~200mg, 100~300mg, 100~400mg, 100~500mg, 100~600mg, 100~700mg, 100~800mg, 100~900mg, 100~1000mg, 200~300mg, 200~400mg, 200~500mg, 200~600mg, 200~700mg, 200~800mg, 200~900mg, 200~1000mg, 300~ 400mg, 300~500mg, 300~600mg, 300~700mg, 300~800mg, 300~900mg, 300~1000mg, 400~500mg, 400~600mg, 400~700mg , 400 to 800 mg, 400 to 900 mg, 400 to 1000 mg, 500 to 600 mg, 500 to 700 mg, 500 to 800 mg, 500 to 900 mg, 500 to 1000 mg, 600 to 700 mg, 600 to 800 mg, 600 to 900 mg, 600 to 1000 mg, 700 to 800 mg, 700 to 900 mg, 700 to 1000 mg, 800 to 900 mg, 800 to 1000 mg or about 900 to 1000 mg.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 mg, 300-400 mg, 300-500 mg, or 400-500 mg per dose.

[0136] In some embodiments, the compound is administered in a single dose. In some embodiments, the compound is administered in multiple doses.

[0137] In some embodiments, the compound is administered in a pharmaceutical composition comprising a liquid carrier, for example, for intravenous administration. In some embodiments, the volume of the pharmaceutical composition is about 10 μL to about 1000 mL. For example, the volume can be about 10 μL, 50 μL, 100 μL, 300 μL, 500 μL, 1 mL, 10 mL, 50 mL, 100 mL, 200 mL, 300 mL, 400 mL, 500 mL, 600 mL, 700 mL, 800 mL, 900 mL, or 1000 mL.

[0138] In some embodiments, the compound is administered as droplets. In some embodiments, the size of the administered droplets ranges from about 10 to 100 μL, about 20 to 50 μL, or about 50 to 80 μL. In some embodiments, the droplets are administered in a number of drops per administration, e.g., 1 to 3 drops per administration, 3 to 10 drops per administration, or 7 to 10 drops per administration. In one example, the formulations of the present disclosure are administered at about 1 drop per administration and 1 to 6 times per day.

[0139] In some embodiments, the compound described herein is formulated into pharmaceutical compositions.In some embodiments, pharmaceutical compositions are 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.Suitable formulation depends on the route of administration selected.Any pharmaceutically acceptable technology, carrier and excipient can 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, HA 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). In some embodiments, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable carrier.

[0140] Provided herein is a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable diluent, excipient or carrier.The compound can be the compound of formula I or II described herein.In some embodiments, the compound is administered as a pharmaceutical composition, in which one or more compounds are mixed with other active ingredients, such as in combination therapy.In some embodiments, the pharmaceutical composition comprises one or more compounds described herein.

[0141] 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. A pharmaceutical composition can facilitate administration of a compound to a patient. In some embodiments, to practice the methods of treatment or use provided herein, an effective amount of one or more compounds described herein is administered in a pharmaceutical composition to a patient having a disease or condition to be detected, diagnosed, or treated. In some embodiments, the patient is human. The effective amount may vary 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 alone or in combination with one or more diagnostic or therapeutic agents as components of a mixture.

[0142] For administration by injection, the compounds described herein can be dispersed in a pharmaceutically acceptable liquid vehicle. The pharmaceutically acceptable liquid vehicle can be any aqueous or non-aqueous vehicle known in the art. Examples of aqueous vehicles include saline solution, sugar solutions such as glucose or mannitol, and pharmaceutically acceptable buffered solutions. In some embodiments, the aqueous vehicle is a physiologically compatible buffer, such as Hank's solution, Ringer's solution, aqueous acetate buffer, aqueous citrate buffer, aqueous carbonate buffer, aqueous phosphate buffer, aqueous succinate buffer, aqueous lactate buffer, or saline buffer. Examples of non-aqueous vehicles include fixed vegetable oils, glycerin, polyethylene glycol, alcohol, and ethyl oleate. The vehicle may further include antimicrobial preservatives, antioxidants, tonicity agents, buffers, stabilizers, surfactants, and other components. The pharmaceutical composition may include a cyclodextrin, such as sulfobutyl ether β-cyclodextrin or hydroxypropyl β-cyclodextrin.

[0143] The pharmaceutical composition of the compound described herein can be for parenteral administration, for example, by injection.The compound for injection administration can be prepared, for example, as an aqueous or oily suspension or emulsion in injection vehicle.Injection vehicle can include castor oil (ricinus communis oil), castor oil (ethoxylated), sesame oil, soybean oil, corn oil, cottonseed oil or peanut oil, and elixir, mannitol, glucose, benzyl alcohol, PEG 400, ethylene glycol, polysorbate 20, diethylene glycol monoethyl ether, 10% aqueous poloxamer 188, glycerol, 10% aqueous poloxamer 407 or poloxamer 124.

[0144] In some embodiments, the pharmaceutical formulation comprises one or more surfactants. Surfactants are materials that are hydrophobic or amphiphilic (i.e., contain both hydrophilic and hydrophobic components or regions). Surfactants can be used to modify the surface properties of particles and change the way they disperse, emulsify, or suspend. In some embodiments, the surfactant comprises a lipid. Lipids that can be used include the following classes of lipids: fatty acids and derivatives, mono-, di-, and triglycerides, phospholipids, sphingolipids, cholesterol and steroid derivatives, terpenes, prostaglandins, and vitamins. Examples of fatty acids include lauric acid, physeteric acid, myristoleic acid, palmitoleic acid, petroselinic acid, and oleic acid, and their mono-, di-, and triglycerides. Such mono-, di-, and triglycerides include, for example, digalactosyl diglyceride, 1,2-dioleoyl-sn-glycerol, 1,2-dipalmitoyl-sn-3 succinylglycerol, and 1,3-dipalmitoyl-2-succinylglycerol. In some embodiments, the surfactant comprises a phospholipid. Phospholipids that can be used include phosphatidic acid, phosphatidylcholine containing both saturated and unsaturated lipids, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, lysophosphatidyl derivatives, cardiolipin, and β-acyl-y-alkylphospholipids. Steroids that can be used include cholesterol, cholesterol sulfate, cholesterol hemisuccinate, 6-(5-cholesterol-3β-yloxy)hexyl-6-amino-6-deoxy-1-thio-α-D-galactopyranoside, 6-(5-cholesten-3β-yloxy)hexyl-6-amino-6-deoxy]-1-thio-α-D-mannopyranoside, cholesteryl (4'-trimethylammonio)butanoate, and sodium deoxycholate (NaDOC). Surfactant products include Tween® 20, Tween® 80, and Neobee M-5.

[0145] Other surfactants include ethoxylated sorbitan esters, sorbitan esters, fatty acid salts, sugar esters, Pluronic®, Tetronic®, ethylene oxide, butylene oxide, propylene oxide, anionic surfactants, cationic surfactants, mono- and diacylglycerols, mono- and diacylethylene glycols, mono- and diacylsorbitols, mono- and diacylglycerol succinates, alkyl acylphosphatides, fatty alcohols, fatty amines and their salts, fatty ethers, fatty esters, fatty amides, fatty carbonates, cholesterol esters, cholesterol amides and cholesterol. ether, aluminum monostearate, ammonium lauryl sulfate, calcium stearate, dioctyl calcium sulfosuccinate, dioctyl potassium sulfosuccinate, dioctyl sodium sulfosuccinate, emulsifying wax, magnesium lauryl sulfate, potassium oleate, sodium castor oil, sodium cetostearyl sulfate, sodium lauryl ether sulfate, sodium lauryl sulfate, sodium lauryl sulfoacetate, sodium oleate, sodium stearate, sodium stearyl fumarate, sodium tetradecyl sulfate, zinc oleate, zinc stearate, benzalconium chloride, cetrimide, cetrimide bromide, and cetylpyridinium chloride.

[0146] Oral administration can be another route for administering the compounds described herein. Pharmaceutical compositions can be, for example, in the form of capsules or enteric-coated tablets. Thus, the compounds described herein can be diluted with excipients and / or carriers. When excipients serve as diluents, they can be in the form of solid, semi-solid, or liquid materials, and act as a vehicle, carrier, or medium for active ingredients. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of active compounds, soft and hard gelatin capsules, sterile solutions for injection, and sterile-packaged powders.

[0147] Some examples of suitable excipients, carriers, and vehicles include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone (PVP), cellulose, sterilized water, syrup, and methylcellulose.In addition, the formulation can include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0148] In some embodiments, the compound described herein is formulated for administration to the eye.In some embodiments, the formulation for eye is liquid (solution, suspension, powder for reconstitution, sol-gel system form), semi-solid (ointment and gel), solid (ocular insert) and intraocular dosage form (injection, irrigation solution and implant).

[0149] Provided herein are ophthalmic formulations comprising the compounds described herein and ophthalmologically acceptable components. The ophthalmic formulations can be administered in any form suitable for ocular drug administration, such as solutions, suspensions, ointments, gels, liposomal dispersions, colloidal microparticle suspensions, etc., or as ocular inserts, for example, optionally in biodegradable controlled-release polymer matrices.

[0150] A "pharmaceutically acceptable" or "ophthalmically acceptable" component means a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into the ophthalmic formulations of the present disclosure and topically administered to a patient's eye without causing undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation composition that the formulation contains. When the term "pharmaceutically acceptable" is used to refer to a component other than a pharmacologically active agent, it implies that the component has met the required standards of toxicity and manufacturing testing or is included in the inactive ingredient guide prepared by the U.S. Food and Drug Administration.

[0151] Ophthalmic preparations can be adapted to be administered topically to the eye in the form of suspension or emulsion.Ophthalmic preparations can comprise ophthalmologically acceptable carriers.Such carriers include, for example, water, water mixtures, 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 preparations can also comprise one or more excipients, such as emulsifiers, preservatives, wetting agents, viscosity-imparting agents. For example, ophthalmic formulations may contain polyethylene glycol 200, 300, 400, and 600, Carbowax 1,000, 1,500, 4,000, 6,000, and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts, thimerosal, methyl and propylparaben, benzyl alcohol, phenylethanol, buffers such as sodium borate, sodium acetate, gluconic acid buffer, and other agents such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, and ethylenediamine tetracetic acid. Ophthalmic formulations may be isotonic. Ophthalmic formulations may also contain surfactants or stabilizers. Surfactants include Carbopol®. Stabilizers include sodium bisulfite, sodium metabisulfate, and sodium thiosulfate.

[0152] The formulation may comprise an effective amount of a penetration enhancer that promotes the penetration of 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 measurably increase the penetration of one or more of the formulation components through membranes, tissues, and extracellular matrices, as just described. Suitable penetration enhancers include, for example, methylsulfonylmethane (MSM, also known as methylsulfone), a combination of MSM and dimethylsulfoxide (DMSO), or in less preferred embodiments, a combination of MSM with DMSO, with MSM being particularly preferred.

[0153] Kits and Packaging Provided herein is a kit comprising a compound described herein, an imaging device, and, optionally, suitable packaging. The imaging device may be a retinal imaging device. In some embodiments, the kit further comprises instructions for use.

[0154] The imaging device may include a lens(es) and an image sensor for detecting the emitted signal. In some embodiments, the imaging device detects the fluorescent signal. In some embodiments, the imaging device further includes a laser light source that can be used to activate the fluorescent signal. The imaging device may include a suitable retinal scanning device. Acronyms and Abbreviations Table Abbreviation Meaning Aβ amyloid beta BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) DIBAL-H Diisobutylaluminum hydride DMF Dimethylformamide Et Ethyl Me methyl Min PCC Pyridinium Chlorochromate THF tetrahydrofuran [Example]

[0155] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that function well in the practice of the present invention and can therefore be considered to constitute specific modes for carrying out the present invention. However, those skilled in the art should understand in light of the present disclosure that many changes can be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present invention.

[0156] General information: NMR spectra were recorded on a Bruker 300 MHz spectrometer. 1 H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruple, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained on a Waters ZQ2000 mass spectrometer using electrospray ionization.

[0157] Example 1 Synthesis of (E)-6-(2-(2-hydroxyethoxy)ethoxy)-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)hexanenitrile (1) [ka] In step 1, methyl 6-bromo-2-naphthaoate is coupled with pyrrolidine using palladium acetate / BINAP, CS2CO3 as the base, and toluene as the solvent. Refluxing for approximately 30 hours results in the formation of methyl 6-(piperidin-1-yl)-2-naphthoate. Reduction with lithium aluminum hydride in step 2, followed by oxidation with MnO2 in step 3, affords 6-(piperidin-1-yl)-2-naphthaldehyde. In step 4, coupling of 6-(piperidin-1-yl)-2-naphthaldehyde with 6-(2-(2-hydroxyethoxy)ethoxy)-3-oxohexanenitrile in THF using piperidine as the base for approximately 24 hours affords compound 1. 1 H NMR (600 MHz, CDCl3): δ 8.31-8.22 (m, 2H), 8.14 (dd, J=8.8, 1.8 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.32 (dd, J=9.2, 2.5 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 3.82-3.74 (m, 2H), 3.70 (dd, J=5.8, 3.4 Hz, 2H), 3.66-3.56 (m, 6H), 3.50-3.35 (m, 4H), 3.05 (t, J=7.1 Hz, 2H), 2.38 (t, J=6.3 Hz, 1H), 2.12-1.98 (m, 2H), 1.83-1.66 (m, 6H). LC-MS (m / z) = 459.1 [M+Na] +

[0158] Using this synthesis, similar compounds are prepared by substituting other heterocycles, such as optionally substituted piperidines, azetidines, aziridines, etc., for pyrrolidine in Step 1. Also, starting with a naphthalene in Step 1 with the bromo group in a different position, and thus adding a heterocycle to a different position on the naphthalene, gives other analogs. Also, similar compounds with different side chains are prepared by adding a different cyano compound in Step 4, such as the one shown below. [ka]

[0159] Thus, Example 1a was synthesized by the method provided above using 6,7-dihydroxy-3-oxoheptanenitrile in step 4 to give (E)-6,7-dihydroxy-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)heptanenitrile. [ka] 1 H NMR (600 MHz, CDCl3) δ 8.29 (s, 1H), 8.27 (s, 1H), 8.14 (dd, J = 8.8, 1.7 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 9.2, 2.4 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 3.82 (qd, J =8.3, 4.3 Hz, 1H), 3.77-3.69 (m, 1H), 3.57-3.53 (m, 1H), 3.48-3.43 (m, 4H), 3.15 (td, J = 6.8, 1.2 Hz, 2H), 2.49 (d, J = 4.8 Hz, 1H), 1.99-1.87 (m, 3H), 1.80-1.74 (m, 4H), 1.73-1.68 (m, 2H). LC / MS (m / z) = 379.1 [M+H]+

[0160] Example 2 Synthesis of (Z)-6-(2-(2-hydroxyethoxy)ethoxy)-3-oxo-2-(2,2,2-trifluoro-1-(6-(piperidin-1-yl)naphthalen-2-yl)ethylidene)hexanenitrile (2) and (E)-6-(2-(2-hydroxyethoxy)ethoxy)-2-((6-(2-methylpiperidin-1-yl)naphthalen-2-yl)methylene)-3-oxohexanenitrile (3) [ka] In step 1, methyl 6-bromo-2-naphthoate is reduced with DIBAL-H in THF, followed by oxidation with PCC in methylene chloride to give 6-bromo-2-naphthaldehyde. In step 2, coupling of methyl 6-bromo-2-naphthaldehyde with piperidine is carried out using palladium acetate / BINAP and CS2CO3 as the base and toluene as the solvent, followed by nucleophilic reaction with (trifluoromethyl)trimethylsilane and oxidation to give 2,2,2-trifluoro-1-(6-(piperidin-1-yl)naphthalen-2-yl)ethan-1-one. In step 4, 2,2,2-trifluoro-1-(6-(piperidin-1-yl)naphthalen-2-yl)ethan-1-one is coupled with 6-(2-(2-hydroxyethoxy)ethoxy)-3-oxohexanenitrile using piperidine as a base in THF to give compound 2.

[0161] Alternatively, in step 3, coupling of methyl 6-bromo-2-naphthaldehyde with 2-methylpiperidine is carried out using palladium acetate / BINAP and CS2CO3 as the base and toluene as the solvent to give 6-(2-methylpiperidin-1-yl)-2-naphthaldehyde. In step 5, coupling of 6-(2-methylpiperidin-1-yl)-2-naphthaldehyde with 6-(2-(2-hydroxyethoxy)ethoxy)-3-oxohexanenitrile using piperidine as the base in THF gives compound 3.

[0162] Similar compounds are prepared using this synthesis by substituting other bases, such as optionally substituted piperidines, azetidines, aziridines, etc., for pyrrolidine. Also, starting with a naphthalene in Step 1 with the bromo group in a different position, and thus adding a heterocycle to a different position on the naphthalene, gives other analogs. Also, similar compounds with different side chains are prepared by adding a different cyano compound in Step 4, such as the one shown below. [ka]

[0163] The following compound can be prepared according to the above procedure but using 8-bromo-2-naphthaldehyde as the starting material: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0164] Example 3 A representative compound of Formula I or II described herein is intravenously administered to a mouse model having a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or its accumulated mass. The mouse retina is removed and mounted on a slide. The retina is washed twice with PBS for 5 minutes. A 98% formic acid solution is added and left for 5 minutes for antigen retrieval. The sample is washed twice with distilled water for 5 minutes. The sample is equilibrated in 1x PBS for 15 minutes, then blocked in 10% goat / donkey serum (depending on the antibody) in 1x PBS for 1 hour. The sample is covered with foil and washed three times with 1x PBS for 5 minutes each. The sample is stained with DAPI (300nM or 100ng / mL) in the dark for 10 minutes, and then the tissue is washed 3x10 minutes with PBS. DAKO mounting medium for anti-fade is added, a cover slip is placed, and the tissue is kept covered with foil until imaging.

[0165] Fluorescence imaging studies of the samples were performed using a Leica DMI 4000B microscope (Leica, Germany) equipped with a TCS SPE camera and Leica 10, 20, and 40x objectives. 408, 488, and 568 nm lasers were used to visualize fluorescent probes for DAPI (blue, nuclear stain), a representative compound of Formula I (green), and hyperphosphorylated tau (red). Z-stack images were taken at 40x magnification with 0.5 μm increments to visualize all tissue layers. Hyperphosphorylated 3-repeat tau protein was detected in the retina, producing a detectable fluorescent signal, whereas immunostaining with 3-repeat tau antibodies was not detected in age-matched wild-type mice. In conclusion, this study demonstrates that the compounds of Formula I or II described herein can be used as diagnostic agents for detecting amyloid beta protein or hyperphosphorylated tau protein.

[0166] Example 4 In vivo imaging studies in tau transgenic mice This example was performed to determine whether compounds of Formula I or II described herein detect Aβ in the retina of a TBI mouse model.

[0167] Compound 1 and compound 1a were administered intravenously (15 mg / kg) to anesthetized mice (8-12 month old females), and real-time fluorescence images were collected using a Phoenix Micron IV fluorescent rodent retinal imaging camera at the following time points: 0, 5 seconds, 10 seconds, 30 seconds, 45 seconds, 10 minutes, and 24 hours.

[0168] Figure 1 shows in vivo retinal images of 3R Tau mice after IV injection of Compound 1 at 15 mg / kg. Figure 2 shows in vivo retinal images of 3R Tau mice after IV injection of Compound 1a at 15 mg / kg.

[0169] Both Compound 1 and Compound 1a were observed in the retinal vasculature immediately (1-2 minutes) after tail vein injection. After injection, hyperfluorescent signals (indicated by white arrows) were observed especially in the peripheral retina.

[0170] Alternatively or in addition to retinal scanning, retinal tissue is removed and stained with an anti-Aβ antibody (6E10). Blast-injured mice exhibit immunoreactivity to Aβ in retinal tissue, whereas uninjured mice exhibit no reactivity to 6E10. Compounds of Formula I or II fluorescently label deposits in the retina, which are visible upon fluorescence activation, but tissue from uninjured mice does not exhibit any fluorescence enhancement.

[0171] Example 5 In vitro binding study of compounds with amyloid beta The fluorescence properties and emission spectra of Compound 1 and Compound 1a with aggregated amyloidogenic proteins were characterized as follows.

[0172] Emission spectra for Compound 1 and Compound 1a were collected at the characteristic excitation wavelengths (450 nm and 488 nm) used in standard ocular imaging devices after incubation of the compounds with and without aggregated amyloidogenic protein. The fold increase in maximum emission (Compound + Aβ / Compound) was calculated for each test compound and is shown in Table 1.

[0173] methodology Amyloidogenic proteins (synthetic aggregated amyloid beta (Aβ), α-synuclein (ASYN), transthyretin (TTR), TAR DNA-binding protein 43 (TDP43), and phosphorylated tau (TAU)) were aggregated in vitro using the following procedure. The amyloidogenic proteins were removed from the freezer and allowed to warm to room temperature. Then, 1 mg of amyloidogenic protein was dissolved in 215 μL of ddHO for approximately 10–20 min at room temperature. 2 mL of ddHO was added to the resulting solution to obtain a 100 μM stock solution. A 100 μL aliquot was sampled and frozen (non-aggregated sample). The tubes were placed in a thermoshaker at 350 rpm for 3 days. Care was taken to avoid the formation of bubbles. Protein aggregation was confirmed by measuring binding to thioflavin T (ThT). The aggregated protein was then divided into 150 μL aliquots and stored at −80°C.

[0174] To determine the binding of synthetic aggregated amyloid beta (Aβ), α-synuclein (ASYN), transthyretin (TTR), TAR DNA-binding protein 43 (TDP43), and phosphorylated tau (TAU) to the test compounds described herein, fluorescence emission spectra were measured as follows: A Shimadzu fluorimeter was turned on and allowed to warm for approximately 60 minutes. The test compounds were then removed from the -20°C freezer and allowed to warm to room temperature. A 100 μM solution of aggregated Aβ was then removed from the -80°C freezer and also allowed to warm to room temperature. Next, a 250 μM solution of each test compound in DMSO was prepared. These were then used to prepare 4 μM solutions of each test compound in triplicate, with and without 5 μM aggregated Aβ in 1×PBS. Using a cuvette, the fluorescence emission spectra of each test compound + Aβ solution was measured, using the DMSO / PBS solution as a blank. Each sample was tested by excitation at 450 nm and 488 nm. Fluorescence emission spectra were then collected for each 4 μM solution of test compound alone. The resulting data was used to plot intensity versus wavelength for each emission scan. The fold increase in maximum emission (compound + Aβ / compound) was calculated for each test compound.

[0175] The enhancement fold and peak luminescence data are shown in Table 1. [Table 1]

[0176] Both Compound 1 and Compound 1a successfully bound to all amyloidogenic aggregates tested (Aβ, ASYN, TTR, TDP43, 3RTau, and 4RTau). The strength and efficiency of binding to specific aggregates, as well as the maximum peak emission, varied between compounds and excitation wavelengths (450 nm or 488 nm). These results suggest that Compound 1 and Compound 1a can be used to specifically target amyloidogenic aggregates.

[0177] Example 6 Binding of test compounds to amyloid beta in human tissues This example is performed to determine the utility of the compounds described herein to mark Aβ aggregation in the eye for non-invasive detection using standard ocular imaging equipment, thus facilitating the diagnosis and monitoring of Alzheimer's disease.

[0178] It is contemplated that the compounds described herein bind to Aβ deposits in human tissues and increase fluorescence in a manner similar to that observed in vitro.The compounds described herein are tested for their ability to bind to Aβ in retina and brain in human tissues with Alzheimer's disease and emit fluorescence.Slices from these tissues are co-stained with the compounds described herein and Aβ-specific antibodies using the protocol provided below.Immunofluorescence images are collected and analyzed to determine whether the signal from the compounds described herein corresponds to the amyloid deposit area defined by Aβ staining. Tissue Staining Protocol

[0179] Tissue sections are deparaffinized and hydrated as follows: Preheat specimens to 60° C. for 1 hour. Slides are placed in holders and treated with detergent xylene (paraffin solvent) and a graded series of EtOH as follows: i. 100% xylene - 5 min ii. 100% xylene - 5 minutes iii. 50% / 50% xylene / 100% EtOH - 3 min iv.100%EtOH - 3 minutes v. 95% EtOH - 3 min 7. 70% EtOH - 3 min vii.50%EtOH - 3 minutes viii. Water - 2 x 3 minutes

[0180] The antigens are retrieved by incubating in 99% formic acid for 5 minutes, followed by washing with distilled water for 5 minutes. This step is repeated twice. Next, 10 mM citrate buffer pH 6.0 is preheated to boiling.

[0181] The slides are placed in a staining chamber with heated citrate buffer for 20 minutes, then cooled in a water bath. The slides are then washed in distilled water for 5 minutes. This step is repeated twice.

[0182] The slides were equilibrated in 1x PBS for 15 minutes, then blocked in 5% normal goat serum in PBST for 1 hour at room temperature. The slides were incubated overnight at 4°C in the primary Aβ antibody 6E10 (2.5% NGS in PBST). The tissues were then washed 3x for 10 minutes in PBST wash buffer.

[0183] Slides are incubated in secondary antibody (1:500 in PBST) for 1 hour at room temperature, ensuring that samples are kept in the dark from this point onwards.

[0184] Then, tissue is washed with PBST for 3 times 10 minutes.Tissue is stained with the test compound (60 μM) described herein at room temperature for 30 minutes as follows.The test compound described herein is allowed to warm to room temperature (about 30 minutes), and then 5 mg of each test compound is dissolved in 3.75 mL of DMSO, and the resulting solution is kept in the dark.Then, 100 μ L of each compound solution is diluted with 5 mL of PBS to provide the dye solution for each test compound described herein.

[0185] The stained tissue is then washed 3x10 min with PBST. Nuclei are then stained with Hoechst (1 mg / mL in PBS, diluted 2:1000) for 10 min. The tissue is then washed a further 3x10 min with PBST. The tissue is mounted using Prolong Glass mounting medium and allowed to dry overnight. Finally, the edges are sealed with nail polish.

[0186] 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.

[0187] The present disclosure illustratively described herein may suitably be practiced without any element or elements not specifically disclosed herein, and without any limitation or limitations. Thus, for example, terms such as "comprising," "including," "containing," etc., are intended to be read broadly and without limitation. In addition, the terms and expressions used herein are used as terms of description, not as terms of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, recognizing that various modifications are possible within the scope of the present disclosure as claimed.

[0188] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0189] While the present disclosure has been described in conjunction with the above-described embodiments, it should be understood that the foregoing description and examples are intended to illustrate the present disclosure and not to limit 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.

Claims

1. formula 【Transformation 36】 or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein W １ is O,N(R １４ ), or C(R ４ ) ２ and R １４ represents hydrogen, alkyl, halomethyl having 1 to 3 halo groups, —COOH, —CONH ２ , substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １ is selected from hydrogen, halo, haloalkyl having 1 to 3 halo groups, or cyano; R ２ , R ３ , R ４ , R ５ , and R ６ are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, —CN, —C(O)R １Ａ , -C(O)OR １Ａ , —C(O)NR １Ａ R １Ｂ , -OR １Ａ , -NHC(O)NR １Ａ R １Ｂ , -NR １Ａ R １Ｂ , -NHNR １Ａ R １Ｂ , -NR １Ａ C(O)R １Ｂ , -NR １Ａ C(O)OR １Ｂ , -NR １Ａ OR １Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １Ａ and R １Ｂ are each independently hydrogen, halo, haloalkyl having 1 to 3 halo groups, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is —C(O)— or —SO ２ - and Y is CH ２ , NH, or S; WSG is a water-soluble group, however, When Z is —C(O)—, Y is not NH; In Formula I, Y is CH ２ and W １ is O, N (CH ３ ), or CH ２ If ２ is hydrogen and C １ ~ １０ Not alkyl, In Formula II, Y is CH ２ and W １ is O, N (CH ３ ), or CH ２ and R ３ , R ５ , R ６ is hydrogen, then R ２ is hydrogen and C １～１０ It is not alkyl.

2. formula 【Chemistry 37】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

3. formula 【Transformation 38】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

4. R １ The compound according to any one of claims 1 to 3, wherein is hydrogen.

5. R ２ is hydrogen, halo, -CF ３ , -CBr ３ , -CCI ３ , -CCl ３ , -CHF ２ , -CHBr ２ , -CHCl ２ , -CHI ２ , -CH ２ F, -CH ２ Br, —CH ２ Cl, —CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NHNH ２ , -NHC(O)NHNH ２ , substituted or unsubstituted C １ ~C ６ The compound of any one of claims 1 to 4, which is alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl.

6. R ２ is hydrogen or unsubstituted C １ ~C ４ The compound of any one of claims 1 to 5, which is alkyl.

7. R ２ The compound of any one of claims 1 to 6, wherein is unsubstituted methyl, unsubstituted ethyl, or unsubstituted propyl.

8. R ３ , R ４ , R ５ , and R ６ The compound of claim 1 , wherein is hydrogen.

9. formula 【Chemistry 39】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

10. formula 【Chemistry 40】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

11. R １ is hydrogen, halo, -CF ３ , -CBr ３ , -CCI ３ , -CCl ３ , -CHF ２ , -CHBr ２ , -CHCl ２ , -CHI ２ , -CH ２ F, -CH ２ Br, —CH ２ Cl, —CH ２ The compound according to claim 9 or claim 10, wherein the aryl group is —I, or —CN.

12. R １ But, -CF ３ or unsubstituted methyl.

13. R ２ , R ３ , R ４ , R ５ , and R ６ is hydrogen, halo, -CF ３ , -CBr ３ , -CCI ３ , -CCl ３ , -CHF ２ , -CHBr ２ , -CHCl ２ , -CHI ２ , -CH ２ F, -CH ２ Br, —CH ２ Cl, —CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , substituted or unsubstituted C １ ~C ６ The compound of any one of claims 9 to 12, which is alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl.

14. WSG, 【Chemistry 41】 14. The compound of any one of claims 1 to 13, selected from the group consisting of:

15. WSG, 【Chemistry 42】 wherein m is an integer having a value from 1 to 10, and each R １’ But independently, H. 【Chemistry 43】 wherein each X is independently O or S; Each R １１ are independently hydrogen, C １～１０ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are selected from 1 to 4 R ２１ or each XR １１ are independently -XP(X)(R １２ ) ２ may be Each R １２ are independently hydroxy, thiol, -XP(X)(R １３ ) ２ , C １～１０ Alkyl, —O—C １～１０ Alkyl, and —S—C １～１０ alkyl, Each R １３ are independently hydroxy, thiol, C １～１０ Alkyl, —O—C １～１０ Alkyl, and —S—C １～１０ alkyl, Each R ２１ are independently halo, hydroxy, thiol, -NO ２ , -N ３ , Cyano, C １～１０ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, C １～８ Haloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, —O—C １～１０ Alkyl, —O—C ２～６ Alkenyl, —O—C ２～６ Alkynyl, —O—C ３～１０ Cycloalkyl, —O—C １～８ Haloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —NH ２ , -NH(R ３１ ), -N(R ３１ ) ２ , —C(O)(R ３１ ), -C(O)O(R ３１ ), -C(O)OH, -C(O)NH ２ , -C(O)NH(R ３１ ), -C(O)N(R ３１ ) ２ , -NHC(O)(R ３１ ), -NHC(O)O(R ３１ ), -NHC(O)NH(R ３１ ), -S(R ３１ ), -NHS(O) ｙ (R ３１ ), -N(C １～１０ alkyl)S(O) ｙ (R ３１ ), -S(O) ｙ N (R ３１ ) ２ , -S(O)NH(R ３１ ), and -S(O) ｙ (R ３１ ), and each R ３１ are independently １～１０ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, C １～８ selected from haloalkyl, aryl, heteroaryl, and heterocyclyl; each y is independently 1 or 2. The compound according to any one of claims 1 to 13, selected from the group consisting of:

16. formula 【Chemistry 44】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

17. formula 【Chemistry 45】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

18. formula 【Chemistry 46】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

19. formula 【Chemistry 47】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

20. formula 【Chemistry 48】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

21. formula 【Chemistry 49】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

22. formula [Transformation 50] 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

23. formula 【Chemistry 51】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

24. formula 【Chemistry 52】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

25. formula 【Chemistry 53】 2. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt, tautomer, or prodrug thereof. 【Request Item 26】 【Chemistry 54-1】 【Chemistry 54-2】 【Chemistry 54-3】 【Chemistry 54-4】 【Chemistry 54-5】 【Chemistry 54-6】 【Chemistry 54-7】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

27. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.

28. 28. A method for determining whether a patient has a neurological disease or disorder, comprising administering to the patient a compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, or a pharmaceutical composition of claim 27.

29. 29. The method of claim 28, wherein the compound is administered intravenously.

30. 29. The method of claim 28, wherein the compound is administered to the eye of the patient.

31. 31. The method of any one of claims 28 to 30, further comprising detecting the presence or absence of binding of said compound or its parent compound to a detectable target protein.

32. 32. The method of claim 31 , wherein the detecting step comprises activating the patient's tissue to be investigated with light, thereby causing emission of a detectable signal, and detecting the detectable signal.

33. 33. The method of claim 32, wherein the detectable signal is a fluorescent signal.

34. 34. The method of any one of claims 28 to 33, wherein the neurological disease or disorder is Alzheimer's disease or traumatic brain injury (TBI).

35. 34. The method of any one of claims 28 to 33, 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.

36. 36. The method of claim 35, wherein the age-related disease or disorder is selected from Parkinson's disease, 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.

Images