N-Heterocyclyl-substituted 2-cyano-3-(naphthalen-2-yl)acrylamide derivatives as fluorophores for detecting amyloid and amyloid-like proteins for the diagnosis of neurodegenerative disorders

Abstract

Provided herein is the design and synthesis of novel molecular rotor fluorophores of formula I, useful for the detection of amyloid or amyloid-like proteins. TIFF2024525693000133.tif6289 fluorophores are designed to show enhanced fluorescence emission when associated with amyloid or amyloid-like proteins compared to unbound compounds.Also disclosed herein are compounds for use in methods for the diagnosis and treatment of diseases associated with amyloid or amyloid-like proteins, such as Alzheimer's disease or traumatic brain injury (TBI), Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis, Down's syndrome, traumatic brain injury, chronic traumatic encephalopathy, schizophrenia or depression.Experimental data is provided for in-vitro binding studies with amyloid beta.

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 / 222,380, filed July 15, 2021, the entirety of which is hereby incorporated by reference. [Background technology]

[0002] background Accumulation of amyloid plaques in the brain is a hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, Down's syndrome, and Creutzfeldt-Jakob disease (CJD). Approaches to clinically diagnose these diseases and monitor their progression include targeting amyloid deposits with small molecule imaging agents. Thus, fluorescence-based small molecule imaging of amyloid is a low-cost, available, non-radioactive technique for detecting amyloid deposits. Disclosed herein are fluorescent compounds that maintain their brightness, spectroscopic properties, and binding specificity with amyloid in neural tissue and exhibit excellent chemical / hydrolytic stability in physiologically relevant solutions. The enhanced stability of such compounds is useful for labeling amyloid deposits in living systems. Summary of the Invention [Means for solving the problem]

[0003] overview The present disclosure provides a compound of formula I [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof, wherein EDG is, [ka] and Each R 1 are independently halogen, -OR 2, -NR 3 R 4 , 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, and the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 9 where appropriate, R 2 , R 3 and R 4 are independently hydrogen, 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 R 9 where appropriate, R 5 is hydrogen or C 1~10 is alkyl, Each R 9 are independently halogen, -OR 6 , -NR 7 R 8 , C 1~10 Alkyl, C 1~10 Haloalkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, C 1~10 Heterocyclyl, C 6~10 Aryl, or C 1~10 is heteroaryl, R 6 , R 7 and R 8 are independently hydrogen or C 1~10 is alkyl, R 84 is hydrogen, halo, C 1~10 Alkyl, or C 1~10 is haloalkyl, EWG is an electron withdrawing group, WSG is a water soluble group, Z is C=O or SO 2 and Y is CH 2 , NH, or S; q is 0, 1, 2, 3, 4, 5, or 6; where Y is NH or S and R 84 When is hydrogen or methyl, EDG is attached to the 6-position of the naphthalene. [ka] isn't it].

[0004] The disclosure also provides a pharmaceutical composition comprising a compound of formula I as described herein, or a pharma- ceutically 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 as described herein, or a pharma- ceutically acceptable salt, tautomer, or prodrug thereof, or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Detailed Description definition The following description describes exemplary embodiments of the present technology, but it should be appreciated that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0006] 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.

[0007] A dash (e.g., "-" or "-") indicates a bond and may be a point of attachment for a substituent. For example, -C(O)NH 2is attached through a carbon atom. Chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. In structures, a wavy line drawn across a line indicates the point of attachment of a substituent or group.

[0008] 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.

[0009] Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments 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 description of "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.

[0010] "Alkyl," alone 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., C 1 ~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, n-octyl, etc.

[0011] "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).

[0012] "Alkynyl" refers to an alkynyl 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.

[0013] "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 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl.

[0014] "Cyano" refers to -CN.

[0015] "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 having 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 3~10 cycloalkyl), 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.

[0016] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0017] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more hydrogen atoms have been replaced by a halogen. For example, if an alkyl residue is substituted with more than one halogen, the haloalkyl may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, respectively, which may or may not be the same halogen. Examples of haloalkyl include difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0018] "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 may be optionally oxidized and N may be optionally quaternized. The heteroatom(s), i.e., N, O, S, P and Si, may 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 may be consecutive in the chain. Examples of heteroalkyl include -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH-N(CH 3 )-CH 3 , O-CH 3, and -O-CH 2 -CH 3 These include, but are not limited to:

[0019] "Heteroaryl" refers to aromatic groups, 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 3-20 ring atoms (i.e., 3-20 membered heteroaryl), 3-12 ring atoms (i.e., 3-12 membered heteroaryl), or 5-10 ring atoms (i.e., 5-10 membered heteroaryl), and 1-5 heteroatoms independently selected from N, O, and S. Heteroaryl does not encompass or overlap with aryl as defined above. Heteroaryl groups 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, 5-furyl, 6-furyl, 7-furyl, 8-furyl, 9-furyl, 10-furyl, 11-furyl, 12-furyl, 13-furyl, 14-furyl, 15-furyl, 16-furyl, 17-furyl, 18-furyl, 19-furyl, 20-furyl, 21-furyl, 22-furyl, 23-furyl, 24-furyl, 25-furyl, 26-furyl, 27-furyl, 28-furyl, 29 ...30-furyl, 3 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.

[0020] 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:

[0021] "Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to a double-bonded O, for example, written as (=O) or (O). When tautomeric forms of the compounds exist, the hydroxyl and oxo groups are interchangeable.

[0022] "Thiol" refers to -SH.

[0023] Each of the above terms (eg, "alkyl," "heteroalkyl," "aryl" and "heteroaryl") can include both substituted and unsubstituted forms of the indicated radical.

[0024] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0025] 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 any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0026] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers, and carbonyl-containing compounds can exist in equilibrium with enol tautomers. Regardless of which tautomer is shown and regardless of 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.

[0027] Also, any formula or structure given herein is intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure illustrated by the formula given herein, except that one or more atoms are replaced by an atom having a 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, e.g. 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 Various isotopically labeled compounds of the present disclosure include, but are not limited to, I. 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.

[0028] The present disclosure also includes deuterated analogs of compounds of formula I, for example, where one to n hydrogens (n ​​being the number of hydrogens in the molecule) attached to a carbon atom are replaced by deuterium. Such compounds may exhibit increased resistance to metabolism when administered to a mammal, particularly a human, and may be useful for extending the half-life of any compound of formula I. See, for example, 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 by deuterium.

[0029] Deuterium-labeled or substituted compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can confer certain advantages resulting from higher metabolic stability, such as extended in vivo half-life, reduced dosage requirements and / or improved therapeutic index. 18F-labeled compounds can be useful for PET or SPECT studies.The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations, by using readily available isotopically labeled reagents instead of nonisotopically labeled reagents.In this context, it is understood that deuterium is considered as a substituent in the compounds described herein.

[0030] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. Any atom not specifically designated as a particular isotope in the compounds of the present disclosure is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, any atom specifically designated as deuterium (D) in the compounds of the present disclosure is meant to represent deuterium.

[0031] 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.

[0032] Also provided are pharma- ceutically 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.

[0033] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be 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 basic 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 salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkylamines (i.e., HN(alkyl) 2 ), trialkylamines (i.e., N(alkyl) 3 ), alkenylamines (i.e., NH 2 (alkenyl)), dialkenylamines (i.e., HN(alkenyl) 2 ), trialkenylamines (i.e., N(alkenyl) 3 ), mono-, di- or tri-cycloalkylamines (i.e., NH 2(cycloalkyl), HN(cycloalkyl) 2 , N(cycloalkyl) 3 ), mono-, di- or tri-arylamines (i.e., NH 2 (aryl), HN(aryl) 2 , N(aryl) 3 ), or salts of alkylamines, alkenylamines, cycloalkylamines and / or arylamine mixtures. 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.

[0034] 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 substituents provided herein, or combinations thereof. Polymers or similar indefinite structures arrived at by defining a substituent with further substituents added indefinitely (e.g., substituted aryls with substituted alkyls, which are themselves substituted with substituted aryl groups, which are further substituted with substituted heteroalkyl groups, etc.) are not intended to be encompassed herein.

[0035] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, and absorption delaying agents, etc. 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 composition is contemplated. Supplementary active ingredients can also be incorporated into the composition.

[0036] A "solvate" is formed by the interaction of a solvent with a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0037] "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, prodrugs are covalently modified analogs or latent forms of the biologically active parent compound.

[0038] "Water-soluble group" refers to any group that alters the water solubility of a compound of formula I. Examples include, but are not limited to, sugars, polyethylene glycols, polypropylene glycols, copolymers of polyethylene glycols and polypropylene glycols, or alkoxy derivatives thereof. Other examples include the compounds of formula [ka] [In the formula, n is an integer of 1 to 50, and R 86 , 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, C 1~10 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

[0039] The present disclosure provides compounds useful for the detection and treatment of neurological diseases and disorders.

[0040] In some embodiments, the present disclosure provides a compound represented by formula I [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof, wherein EDG is, [ka] and Each R 1 are independently halogen, -OR 2 , -NR 3 R 4 , 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, and the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 9 where appropriate, R 2 , R 3 and R 4 are independently hydrogen, 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 R 9 where appropriate, Each R 5 is hydrogen or C 1~10 is alkyl, Each R 9 are independently halogen, -OR 6 , -NR 7 R8 , C 1~10 Alkyl, C 1~10 Haloalkyl, C 1~10 Heteroalkyl, C 3~10 Cycloalkyl, C 1~10 Heterocyclyl, C 6~10 Aryl, or C 1~10 is heteroaryl, R 6 , R 7 and R 8 are independently hydrogen or C 1~10 is alkyl, R 84 is hydrogen, halo, C 1~10 Alkyl, or C 1~10 is haloalkyl, EWG is an electron withdrawing group, WSG is a water soluble group, Z is C=O or SO 2 and Y is CH 2 , NH, or S; q is 0, 1, 2, 3, 4, 5, or 6; where Y is NH or S and R 84 When is hydrogen or methyl, EDG is attached to the 6-position of naphthalene. [ka] isn't it].

[0041] In some embodiments, the compound is [ka] isn't it.

[0042] In some embodiments, the disclosure provides a compound of formula I as described herein, wherein q is 0. In some embodiments, q is 1, 2, 3, 4, 5, or 6.

[0043] In some embodiments, the present disclosure provides a method for the preparation of a compound comprising: 84 In some embodiments, compounds of formula I as described herein are provided, wherein R is hydrogen.84 Halo, C 1 ~C 10 Alkyl, or C 1~10 In some embodiments, R is selected from the group consisting of haloalkyl. 84 is Cl, Br, I, F, methyl, ethyl, propyl, or CF 3 It is.

[0044] In some embodiments, the present disclosure provides that the EWG is selected from the group consisting of F, Cl, Br, -CH=O, NO 2 , -CF 3 , -CCl 3 , -SO 3 In some embodiments, the compound of formula I described herein is selected from the group consisting of: -CN, -CN, and -CN.

[0045] In some embodiments, the disclosure provides a compound of formula I as described herein, wherein Z is C=O. In some embodiments, Y is NH. In some embodiments, Y is CH 2 It is.

[0046] In some embodiments, the present disclosure provides a method for the preparation of a compound comprising: 5 is hydrogen.

[0047] In some embodiments, the present disclosure provides a method for the preparation of a compound comprising: 5 C 1~10 In some embodiments, R is an alkyl group. 5 is C 1~4 It is an alkyl.

[0048] In some embodiments, the present disclosure provides a WSG comprising: [ka] The present invention provides a compound of formula I as described herein, selected from the group consisting of:

[0049] 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, [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, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are each 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, -X(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, -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, C6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -OC 1~10 Alkyl, -OC 2~6 Alkenyl, -OC 2~6 Alkynyl, -OC 3~10 Cycloalkyl, -OC 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 ), 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 of formula I described herein is selected from the group consisting of:

[0050] In some embodiments, the present disclosure provides a compound of formula IA′ [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0051] In some embodiments, the present disclosure provides a compound of formula IB' [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0052] In some embodiments, the present disclosure provides a compound represented by formula IA [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0053] In some embodiments, the present disclosure provides a compound of formula IB [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0054] In some embodiments, the present disclosure provides a compound of formula IC [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0055] In some embodiments, the present disclosure provides a method for the preparation of a compound of formula ID [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0056] In some embodiments, the present disclosure provides a compound of formula IE, IF, IG, IH, II, IJ, or IK [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0057] In some embodiments, the present disclosure provides a compound of formula IE' [ka] The present invention provides a compound of the formula:

[0058] In some embodiments of formula IE′, R 84 is not hydrogen. In some embodiments of IE', EDG is [ka] In some embodiments, R 5 is other than hydrogen.

[0059] In some embodiments, the present disclosure provides a compound of formula IG' [ka] The present invention provides a compound of the formula:

[0060] In some embodiments of formula IG′, R 84 is not hydrogen. In some embodiments of IG', EDG is [ka] In some embodiments, R 5 is other than hydrogen.

[0061] In some embodiments, the present disclosure provides a compound of formula IH′ [ka] The present invention provides a compound of the formula:

[0062] In some embodiments of formula IH′, R 84 is hydrogen. In some embodiments, R 84 is C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0063] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0064] In some embodiments, the present disclosure provides a compound represented by formula IIA [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0065] In some embodiments, the present disclosure provides a compound represented by formula IIB [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0066] In some embodiments, the present disclosure provides a compound represented by formula IIC [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0067] In some embodiments, the present disclosure provides a method for the preparation of a compound of formula IID [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0068] In some embodiments, the present disclosure provides a compound represented by formula IIE, IIF, IIG, IIH, III, IIJ, or IIK. [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0069] In some embodiments, the present disclosure provides a compound represented by formula IIE' [ka] The present invention provides a compound of the formula:

[0070] In some embodiments of formula IIE′, R 84 is not hydrogen. In some embodiments of IIE', EDG is [ka] In some embodiments, R 5 is other than hydrogen.

[0071] In some embodiments, the present disclosure provides a compound of formula IIG' [ka] The present invention provides a compound of the formula:

[0072] In some embodiments of formula IIG′, R 84 is not hydrogen. In some embodiments of IIG', EDG is [ka] In some embodiments, R 5 is other than hydrogen.

[0073] In some embodiments, the present disclosure provides a compound of formula IIH' [ka] The present invention provides a compound of the formula:

[0074] In some embodiments of Formula IIH′, R 84 is hydrogen. In some embodiments, R 84 is C 1~4 Alkyl or C 1~4 It is haloalkyl.

[0075] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, tautomer or prodrug thereof.

[0076] The ketone compounds of formula IIA are contemplated to have increased fluorescence at excitation wavelengths of 450 nm and / or 488 nm and to produce fewer metabolites that may cause adverse effects. General synthesis

[0077] The compounds of the present disclosure can be prepared using the methods disclosed herein and their routine modifications that become clear in light of the present disclosure of the present specification and methods known in the art.In addition to the teachings of the present specification, conventional well-known synthetic methods may also be used.The synthesis of the exemplary compounds of formula (I), for example, the compounds having the structure described by formula (I) or the compounds disclosed herein, or pharma-ceutically acceptable salts thereof, can be carried out as known in the art, as described in the examples.

[0078] Exemplary embodiments of compounds according to the present disclosure can be synthesized using the reaction schemes and / or examples below. In view of the description herein, it is apparent that the schemes can be modified by substituting materials with other materials having similar structures to accordingly result in different products. The description of the synthesis follows below, providing examples of how steps can be modified to result in desired products. Labels of groups (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 embodiments or fragments thereof.

[0079] 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 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 required 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.

[0080] 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 supplements (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 thEdition, 2001), as well as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0081] Scheme 1 shows an exemplary synthetic route for the synthesis of compounds provided herein (eg, compounds of Formula I). Scheme I [ka]

[0082] Compound A, a halo-substituted naphthalene, is reacted under suitable reaction conditions, for example, in a solvent such as toluene, with a palladium catalyst and a base, for example Cs 2 CO 3 Compound B is coupled under suitable reaction conditions to give compound C, an EDG-substituted naphthalene. Compound D is obtained by reduction of the ester of compound C using a metal hydride reagent under suitable reaction conditions, for example in a solvent such as THF. 2 Compound E (R 84 is H). Compound E 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 (R 84 Compound E (R is H) can be obtained by reaction with a suitable alkyl magnesium halide under suitable reaction conditions in a solvent such as THF. 84 is H) to give compound K (R 84 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 (R 84 is alkyl).

[0083] Alternatively, the EDG group can be added to the naphthalene after aldehyde formation, as shown in Scheme II below. Scheme II [ka]

[0084] Compound A, a halo-substituted naphthalene, is reduced under suitable reaction conditions, such as a metal hydride agent in a solvent such as THF, to give compound G. Compound H (R 84 is H). Under suitable reaction conditions, for example in a solvent such as toluene, a palladium catalyst and a base such as Cs 2 CO 3 Compound H is coupled with compound B to obtain compound M (R 84 is H). Under suitable reaction conditions, in a solvent such as THF, a suitable trifluoromethyl compound, such as (CF 3 )SiMe 3 Compound H(R 84 is H) to give compound N(R 84 CF 3 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 compound I (R 84 CF 3 Alternatively, compound H(R 84 is H) to give compound J (R 84 is alkyl). Compound J is coupled with compound B under suitable reaction conditions to give compound K. Compound K can be obtained by coupling with a palladium catalyst and a base, such as Cs, in a solvent such as toluene under suitable reaction conditions. 2 CO 3 Compound K is coupled with compound F below to give compound I (R 84 is alkyl).

[0085] Prodrugs of compounds of formula I can be prepared by the methods disclosed in WO2020 / 093008, see, for example, Scheme III below. Scheme III [ka]

[0086] In Scheme III, compound O, an exemplary compound of formula I, 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. Detectable target proteins

[0087] The compounds described herein may be useful for detecting or treating a neurological disease or disorder. In this regard, the compounds described herein may be prodrugs.

[0088] 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 accumulation masses, which are described herein as detectable proteins. Detectable proteins or their accumulation masses can include, for example, amyloid beta protein or phosphorylated tau protein. Amyloid beta protein or phosphorylated tau protein can be detected by contacting with the compounds described herein. In general, the compounds and methods described herein are useful for detecting amyloid beta protein or phosphorylated tau protein, or its accumulation masses, in patient tissue or sample. Such presence of amyloid beta protein or phosphorylated tau protein can be detected using a compound that can bind to amyloid beta protein or phosphorylated tau protein and then detect the binding.

[0089] 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 believed 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 believed to result from 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 believed to be involved in the pathogenesis of neurological diseases. Aβ is also believed to be toxic to neuronal cells.

[0090] 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.

[0091] "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 intraneuronal transport of cargo. Tau can also participate in signaling pathways by interacting with actin through its acidic N-terminus, which protrudes from microtubules for neurite outgrowth and stabilization during brain development. Tau proteins provided herein can include any isoform, or any combination of isoforms. MAPT transcripts are differentially expressed in the nervous system depending on the maturation stage of neurons and the type of neurons. MAPT gene mutations have been associated with several neurological disorders, e.g., 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 about 50 amino acids inserted into that 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.

[0092] The human tau gene is located at position 17q21 on the long arm of chromosome 17. The gene is believed to contain 16 exons, including exon 21 as part of the promoter. The tau primary transcript contains 13 exons, with exons 4A, 6, and 8 not transcribed in humans. Exons 21 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive, and exons 2, 3, and 10 are alternatively spliced, resulting in six different mRNAs that are translated into six different 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 (R1-R4) repeat regions in the carboxy-terminal portion. The fourth microtubule binding domain is encoded by exon 10. Six tau protein isoforms are known to exist in human brain tissue: (2+3+10+) isoform (having 441 amino acids), (2+3+10-) isoform (having 410 amino acids), (2+3-10+) isoform (having 412 amino acids), (2+3-10-) isoform (having 381 amino acids), (2-3-10+) isoform (having 383 amino acids), and (2-3-10-) isoform (having 352 amino acids). The tau may be a mutant tau. The mutation may be a 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.

[0093] "Phosphorylated tau protein" or "phosphorylated tau" is a tau protein in which at least one amino acid residue is modified by a phosphate group. Tau is believed to contain as many as 85 amino acid residues that are compatible with phosphorylation. Generally, the phosphate group is a post-translational modification and can be attached at 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. The 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. The 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 tangle (NFT).NFT can be found in the soma-dendritic compartment of neurons.

[0094] "Contacting" is used according to its ordinary and simple meaning and refers to the process of bringing at least two distinct species (e.g., chemical compounds, including biological molecules, or cells) into sufficient proximity for them to interact. The term "contacting" can include reacting or physically touching two molecular species, where the two species can be, for example, compounds, biological molecules, proteins, or enzymes described herein. In some embodiments, contacting includes interacting a compound described herein with a protein (e.g., Aβ protein or phosphorylated tau protein) or enzyme.

[0095] Thus, according to some embodiments of the present disclosure, a method is provided for determining whether a patient has a neurological disease or disorder.The method entails detecting the presence of amyloid beta protein or phosphorylated tau protein, or its accumulated mass, in a patient's tissue or sample by contacting the patient's tissue or sample with a compound as described herein.The contacting can be performed in vivo or ex vivo.The contacting can be performed by administering the compound to the patient, for example, by topical administration or intravenous administration.

[0096] In another embodiment, a method is provided for preparing a patient for diagnosis of a neurological disease or disorder, comprising administering a compound described herein to the patient and binding to amyloid beta protein or phosphorylated tau protein, or its accumulated mass. The compound can be administered intravenously. Once the compound is administered to the patient, its binding to amyloid beta protein or phosphorylated tau protein, or its accumulated mass, and / or the binding of the parent compound can be detected using any method, including the methods described herein. In some embodiments, the binding indicates that the patient may have a neurological disease or disorder. Neurological Diseases and Disorders and Treatment Thereof

[0097] In some embodiments, the 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 can 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 embodiments of the method, the compound is administered intravenously. In some embodiments of the method, the compound is administered to the eye of the patient. In some embodiments, the neurological disease or disorder is a disease or disorder characterized by protein aggregation or protein misfolding.

[0098] 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 can be a compound of formula I. The contacting can be performed in vivo. The tissue can be an eye tissue. The sample can be a urine sample.

[0099] 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, and amyotrophic lateral sclerosis, the genetic disease or disorder is Down's syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the psychiatric disease or disorder is selected from schizophrenia and depression. The neurological disease or disorder can be a tauopathy. In some embodiments, the neurological disease or disorder is Alzheimer's disease or traumatic brain injury (TBI).

[0100] The neurological disease or disorder may be a tauopathy. Tauopathies are a class of neurological disorders associated with 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 forms of 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 a primary causative factor in disease or play a more peripheral role. Tauopathies are found in many neurological disorders, such as post-traumatic degeneration, infection, metabolic disease, and motor neuron degeneration. The spatial distribution, temporal appearance, and structural changes of tau protein appear differently among various neurological disorders. AD patients have hyperphosphorylated, twisted, non-periodic 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 of synuclein with 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 has many similarities to tauopathies, including tau hyperphosphorylation and aggregation as neurofibrillary tangles (NFTs).

[0101] 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 microtubules in axons. Tau can then become misfolded and begin to aggregate, which can lead to the formation of neurofibrillary tangles (NFTs). When tau dissociates, it also destabilizes microtubules, 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 localized to the transitional entorhinal cortex of the brain, stages III and IV are used when limbic regions, e.g., 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 of developing AD. APOε4 appears to be less efficient than other isoforms at clearing Aε and therefore may correlate with higher amyloid burden, tau phosphorylation, synaptic toxicity, and reduced synaptic density. Having experienced traumatic brain injury (TBI) is another risk factor for developing AD, and studies have shown that those who have experienced TBI have a significantly increased risk of AD.

[0102] As AD progresses, symptoms include confusion, long-term memory loss, aphasia, vocabulary loss, invasion, irritability and / or mood swings. In more advanced stages of the disease, bodily functions are lost. Patients with Alzheimer's disease (AD) have demonstrated many characteristic neuropathies, such as increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. AD-related disorders include senile dementia of the AD type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-associated memory impairment (AAMI). In some embodiments, determining whether a patient has Alzheimer's disease comprises detecting the presence of phosphorylated tau protein in the patient's tissue or sample, and detecting comprises contacting phosphorylated tau protein with a compound described herein.

[0103] 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.

[0104] In some embodiments, the neurological disease or disorder is Parkinson's disease. In some embodiments, the neurological disease or disorder is Parkinson-dementia. In some embodiments, the neurological disease or disorder is related to (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the patient with a neurological disease or disorder has suffered a traumatic brain injury before, during, or after the onset of the neurological disease or disorder. In some embodiments, the neurological disease or disorder comprises neuronal dysfunction. Neuronal dysfunction may include atrophy of neurons or other decline in effective function of neurons. For example, Alzheimer's disease is known to exhibit neuronal dysfunction, particularly in cortical neurons, such as hippocampal neurons and neurons in close proximity to the hippocampus.

[0105] 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), senile dementia with predominantly neurofibrillary tangles, 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, pantothenate kinase-associated neurodegeneration, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic grain disease (AGD), or corticobasal degeneration.

[0106] 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 an external force, such as a collision, blow, impact, rapid acceleration or deceleration, or projectile penetration. The injury resulting in TBI may 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 humans who have suffered repeated brain trauma, including blows to the head, that did not result in TBI symptoms. Physical aspects of CTE include brain shrinkage, atrophy of the frontal and temporal lobes, enlargement of the ventricles, atrophy of the hippocampus, thalamus, brainstem, and cerebellum. Individuals with CTE may have symptoms of dementia, memory loss, aggression, confusion, depression, and suicidal ideation, which may occur years after the injury.

[0107] The neurological disease or disorder may be an ocular neurological disease or disorder, for example, glaucoma, ocular hypertension, macular degeneration, diabetic retinopathy, age-related macular degeneration (AMD) or retinitis pigmentosa.

[0108] Further examples of neurological diseases or disorders include Alexander disease, Alper's 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 encephalopathy (CAN), and cerebrovascular accidents. Strössler-Scheinker syndrome, Cockayne's disease, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Pelizaeus-Merzbach disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, subacute myelopathy of the spinal cord secondary to pernicious anemia Associated spinal degeneration, schizophrenia, spinocerebellar ataxia (variable features, mixed), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord laryngeal stenosis, 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.

[0109] 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.

[0110] "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition); b) ameliorating, slowing, or halting the onset of one or more clinical symptoms associated with a 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) relieving the disease, i.e., causing regression of clinical symptoms (e.g., reversing the pathology, causing partial or complete remission of the disease or condition, enhancing the effect of another drug therapy, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0111] "Prevention" or "preventing" refers to 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.

[0112] "Patient" refers to an animal, e.g., a mammal (including a human), that has undergone or is 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.

[0113] The term "effective amount" of the compound described herein, or its pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue, means an amount sufficient to detect amyloid beta protein or phosphorylated tau protein, or its accumulated mass, or to provide 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 may be an amount sufficient to reduce the symptoms of a disease or condition of a neurological disease or disorder.An effective amount may vary depending on the patient and the disease or condition to be treated, the patient's weight and age, the severity of the disease or condition, and the mode of administration, and they can be easily determined by those skilled in the art.

[0114] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein may be used on an individual. "Ex vivo" means 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 may 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 may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine dosages of the disclosed compounds that are optimal for a given indication, cell type, individual, and other parameters. Information gathered from such use may be used for experimental purposes or to set up 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 one of skill in the art. Selected compounds can be further characterized to determine safety or tolerated dosages in human or non-human patients. Such properties can be determined using methods commonly known to those of skill in the art. Target Protein Detection

[0115] Provided herein is a method for diagnosing a neurological disease or disorder in a patient, comprising administering a compound described herein to a tissue of the patient. The compound can be a compound of formula I. The method can include detecting the binding of the compound and / or the binding of the parent compound to a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or a mass of accumulation thereof. The administration can be intravenous. The method can include detecting the 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.

[0116] 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 an accumulation mass thereof. The method includes contacting a compound described herein with a tissue or sample that may potentially contain a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or an accumulation mass thereof, where 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 with a detectable target protein, comprising administering a compound described herein or a pharma- ceutically 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 a treatment, comprising binding an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof to the detectable target protein after the treatment, and detecting a signal generated in response to the binding, where a decrease in the signal compared to before the 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.

[0117] 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.

[0118] In situ detection of the binding of the compounds described herein with a detectable target protein, such as amyloid beta protein or phosphorylated tau protein, or their accumulated masses, can be facilitated using an imaging device, preferably handheld or portable. The imaging device can include a lens and an image sensor, and optionally a laser light source. When the light source emits laser light into a tissue, such as the retina, if the detectable target protein is accumulated there and bound to the compounds described herein, the target protein can be easily detected and quantified by the lens and image sensor that collects and senses the fluorescent signal. The imaging device can be any device that can detect 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.

[0119] 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 a fluorescent or infrared signal.

[0120] 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 may be a compound of formula I. Administration and Pharmaceutical Compositions

[0121] Also provided is a pharmaceutical composition of the compound described herein for administration to a patient. The compound can be a compound of formula I. The compound can be administered in either a single dose or multiple doses. The compound can be administered by various methods, including, for example, rectal, intraoral buccal, intranasal and transdermal routes. In certain embodiments, the compound can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant. In some embodiments, the compound described herein is administered intravenously. Intravenous administration can be a bolus or continuous injection. Additional injection methods include intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intradermal, subcutaneous, intramuscular and intradermal, intracranial, intralesional, and intratumoral.

[0122] 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.

[0123] The compounds may be effective over a wide dosage range. In some embodiments, the dosage is 0.01-1000 mg, 0.5-100 mg, 1-50 mg, or 5-40 mg per day. Exemplary dosage amounts 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 about 50-500 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 weight or surface area of ​​the patient being treated, and the preferences and experience of the attending physician.

[0124] 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, 0.1-500 mg, 0.1-600 mg, 0 .1~700mg, 0.1~800mg, 0.1~900mg, 0.1~1000mg, 1~100mg, 1~200mg, 1~300mg, 1~400mg, 1~500mg, 1~600mg, 1~700mg, 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 , 400-800mg, 400-900mg, 400-1000mg, 500-600mg, 500-700mg, 500-800mg, 500-900mg, 500-1000mg, 600-700mg, 600-800mg, 600-900mg, 600-1000mg, 700-800mg, 700-900mg, 700-1000mg, 800-900mg, 800-1000mg or about 900-1000mg.In some embodiments, the effective amount is about 50-100 mg, 50-400 mg, 50-500 mg, 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500 mg, 300-400 mg, 300-500 mg, or 400-500 mg per dose.

[0125] In some embodiments, the compound is administered in a single dose. In some embodiments, the compound is administered in multiple doses.

[0126] 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.

[0127] In some embodiments, the compound is administered as droplets. In some embodiments, the size of the droplets administered ranges from about 10-100 μL, about 20-50 μL, or about 50-80 μL. In some embodiments, the droplets are administered in a few drops per administration, for example, 1-3 drops per administration, 3-10 drops per administration, or 7-10 drops per administration. In one example, the formulations of the present disclosure are administered about 1 drop per administration and 1-6 times per day.

[0128] In some embodiments, the compound described herein is formulated into pharmaceutical composition.In some embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compound into medicament-usable preparations.The appropriate formulation depends on the route of administration selected.Any pharmaceutically acceptable technology, carrier and excipient can be used as suitable for formulating the pharmaceutical composition 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 that includes a compound described herein and a pharma- ceutically acceptable carrier.

[0129] Provided herein is a pharmaceutical composition comprising the compound described herein and pharma- ceutical acceptable diluent, excipient or carrier.The compound can be the compound of formula I 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.

[0130] Pharmaceutical composition, as used herein, refers to a mixture of the compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition can facilitate administration of the compound to a patient. In some embodiments, to carry out 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 a 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.

[0131] For administration by injection, the compounds described herein can be dispersed in a pharma- ceutically acceptable liquid vehicle. The pharma- ceutically acceptable liquid vehicle can be any aqueous or non-aqueous vehicle known in the art. Examples of aqueous vehicles include saline solution, sugar, such as glucose or mannitol solution, and pharma- ceutically 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, isotonicity agents, buffers, stabilizers, surfactants, and other components. The pharmaceutical composition may include a cyclodextrin, for example, sulfobutyl ether β-cyclodextrin or hydroxypropyl β-cyclodextrin.

[0132] The pharmaceutical composition of the compound described herein can be for parenteral administration, for example, by injection.The compound for administration by injection can be prepared, for example, as an aqueous or oily suspension or emulsion in injection vehicle.Injection vehicle can include castor oil (ricinus communis), 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.

[0133] 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 with both saturated and unsaturated lipids, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, lysophosphatidyl derivatives, cardiolipin, and β-acyl-y-alkyl phospholipids. Steroids that may 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.

[0134] Other surfactants include ethoxylated sorbitan esters, sorbitan esters, fatty acid salts, sugar esters, Pluronics, Tetronics, 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 acyl phosphatides, fatty alcohols, fatty amines and their salts, fatty ethers, fatty esters, fatty amides, fatty carbonates, cholesterol esters, cholesterol amides and cholesterol ethers, 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 oleate, sodium lauryl sulfate ... 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.

[0135] Oral administration may be another route for administration of the compounds described herein. The pharmaceutical composition may be in the form of, for example, capsules or enteric coated tablets. Thus, the compounds described herein may be diluted by excipients and / or with carriers. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material, and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile solutions for injection, and sterile packaged powders.

[0136] Some examples of suitable excipients, carriers and vehicles include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, 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 hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0137] In some embodiments, the compound described herein is formulated for administration to the eye.In some embodiments, the formulation for the eye is liquid (solution, suspension, powder for reconstitution, sol-gel system), semi-solid (ointment and gel), solid (ocular insert) and intraocular dosage form (injection, irrigation solution and implant).

[0138] Provided herein is an ophthalmic formulation comprising the compound described herein and an ophthalmologically acceptable component.Ophthalmic formulation can be administered in any form suitable for drug administration to eye, such as solution, suspension, ointment, gel, liposomal dispersion, colloidal microparticle suspension, etc., or in ocular insert, such as a biodegradable controlled release polymer matrix if necessary.

[0139] A "pharmacologically acceptable" or "ophthalmically acceptable" component means a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into an ophthalmic formulation of the present disclosure and administered topically 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. The term "pharmacologically acceptable," when used to refer to a component other than a pharmacologically active agent, implies that the component has met the necessary standards of toxicity and manufacturing testing or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0140] Ophthalmic formulations can be adapted to be administered topically to the eye in the form of suspension or emulsion.Ophthalmic formulations can include ophthalmologically acceptable carriers.Such carriers include, for example, water, mixtures of water, such as phosphate buffer, boric acid, sodium chloride and sodium borate, and water-miscible solvents, such as lower alcohols, aryl alcohols, polyalkylene glycols, carboxymethylcellulose, polyvinylpyrrolidone and isopropyl myristate.Ophthalmic formulations can also include one or more excipients, such as emulsifiers, preservatives, wetting agents, viscosity-imparting agents. For example, the ophthalmic formulation may contain polyethylene glycol 200, 300, 400 and 600, carbowax 1,000, 1,500, 4,000, 6,000 and 10,000, antimicrobial components such as quaternary ammonium compounds, phenylmercuric salts, thimerosal, methyl and propyl paraben, benzyl alcohol, phenylethanol, buffers such as sodium borate, sodium acetate, gluconic acid buffers, and other agents such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol and ethylenediamine tetracetic acid. The ophthalmic formulation may be isotonic. The ophthalmic formulation may also contain surfactants or stabilizers. Surfactants include Carbopol®. Stabilizers include sodium bisulfite, sodium metabisulfate and sodium thiosulfate.

[0141] The formulation may include an effective amount of a penetration enhancer that enhances the penetration of the formulation components through cell membranes, tissues, and extracellular matrices, including the cornea. An "effective amount" of a penetration enhancer refers to a concentration sufficient to 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 a less preferred embodiment of MSM in combination with DMSO, with MSM being particularly preferred. Kits and Packaging

[0142] Provided herein is a kit that includes the compound described herein, an imaging device, and optionally suitable packaging materials.The imaging device can be a retinal imaging device.In some embodiments, the kit further includes instructions for use.

[0143] 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 EXAMPLES

[0144] 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 work well in the implementation of the present invention, and therefore can be considered as constituting specific modes for the implementation of the present invention. However, those skilled in the art should understand in light of this 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.

[0145] Example 1 Synthesis of (E)-2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-3-(6-(pyrrolidin-1-yl)naphthalen-2-yl)acrylamide (1) [ka] In step 1, the coupling of methyl 6-bromo-2-naphthaoate with pyrrolidine was carried out using palladium acetate / BINAP and CS as the base. 2 CO 3 and toluene as the solvent. After refluxing for about 30 hours, methyl 6-(pyrrolidin-1-yl)-2-naphthoate is formed. In step 2, reduction with lithium aluminum hydride is followed in step 3 by MnO 2 In step 4, 6-(pyrrolidin-1-yl)-2-naphthaldehyde is coupled with 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide in THF using piperidine as a base for about 24 hours to give compound 1.

[0146] Similar compounds are prepared using this synthesis by substituting other heterocycles, such as optionally substituted piperidines, azetidines, aziridines, etc., in place of the pyrrolidine in step 1. Other analogs are also obtained by 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. Similar compounds with different side chains are also prepared by adding a different cyano compound in step 4, such as the one shown below. [ka]

[0147] Example 2 Synthesis of 2-cyano-4,4,4-trifluoro-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-3-(6-(pyrrolidin-1-yl)naphthalen-2-yl)but-2-enamide (2) and 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-3-(6-(2-methylpyrrolidin-1-yl)naphthalen-2-yl)acrylamide (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, the coupling of methyl 6-bromo-2-naphthaldehyde with pyrrolidine is carried out using palladium acetate / BINAP and CS as the base. 2 CO 3and toluene as a solvent, followed by nucleophilic reaction with (trifluoromethyl)trimethylsilane and oxidation to give 2,2,2-trifluoro-1-(6-(pyrrolidin-1-yl)naphthalen-2-yl)ethan-1-one. In step 4, 2,2,2-trifluoro-1-(6-(pyrrolidin-1-yl)naphthalen-2-yl)ethan-1-one is coupled with 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide using piperidine as base in THF to give compound 2.

[0148] Alternatively, in step 3, the coupling of methyl 6-bromo-2-naphthaldehyde with 2-methylpyrrolidine can be carried out using palladium acetate / BINAP and CS as the base. 2 CO 3 and toluene as a solvent to give 6-(2-methylpyrrolidin-1-yl)-2-naphthaldehyde. In step 5, 6-(2-methylpyrrolidin-1-yl)-2-naphthaldehyde is coupled with 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide in THF using piperidine as a base to give compound 3.

[0149] Similar compounds are prepared using this synthesis by substituting other bases in place of pyrrolidine, such as optionally substituted piperidine, azetidine, aziridine, etc. 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]

[0150] Example 2A Synthesis of (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide (4) [ka] In step 1, the coupling of methyl 6-bromo-2-naphthoate with piperidine was carried out using palladium acetate / BINAP and CS as the base. 2 CO 3 The reaction was completed using toluene as the solvent and refluxed for about 30 hours to form methyl 6-(piperidin-1-yl)-2-naphthoate. In step 2, methyl 6-(piperidin-1-yl)-2-naphthoate was reduced with lithium aluminum hydride, followed in step 3 by the reduction of the resulting product with MnO 2 Oxidation with ethyl acetate gave 6-(piperidin-1-yl)-2-naphthaldehyde.

[0151] In step 4, to a round bottom flask containing a solution of 957.3 mg of 6-(piperidin-1-yl)-2-naphthaldehyde (4.0 mmol, 1.0 equiv.) and 759.2 mg of 2-cyano-N-(2,3-dihydroxypropyl)acetamide (4.8 mmol, 1.2 equiv.) in 16.0 mL of anhydrous THF was added 0.079 mL of piperidine (0.8 mmol, 0.2 equiv.) and the resulting mixture was refluxed overnight. The reaction was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography to give compound 4.

[0152] 1H NMR (600 MHz, DMSO) δ 8.26 (d, J = 1.2 Hz, 1H), 8.23 ​​(s, 1H), 8.14 (t, J = 5.6 Hz, 1H), 8.03 (dd, J = 8.8, 1.8 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 9.2, 2.5 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 4.88 (d, J = 5.0 Hz, 1H), 4.62 (t, J = 5.8 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.42 - 3.34 (m, 7H), 3.21 - 3.16 (m, 1H), 1.69 - 1.61 (m, 6H).m / z:380(M+H + ).

[0153] Example 2B Synthesis of (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(pyrrolidin-1-yl)naphthalen-2-yl)acrylamide (5) [ka] In step 1, methyl 6-bromo-2-naphthoate is reduced with lithium aluminum hydride, followed in step 2 by the reduction of the resulting product with MnO 2 Oxidation with 5-methyl-2-naphthaldehyde gave 6-bromo-2-naphthaldehyde.

[0154] In step 3, 705.2 mg of 6-bromo-2-naphthaldehyde (3.0 mmol, 1.0 equiv.), 0.322 mL of pyrrolidine (3.9 mmol, 1.3 equiv.), and Pd(OAc) were added to 30 mL of dry, degassed toluene. 2 (0.15 mmol, 0.05 equiv.) 33.7 mg, BINAP (0.15 mmol, 0.05 equiv.) 93.4 mg, and Cs 2 CO 3(4.5 mmol, 1.5 equiv.) were added sequentially. The reaction was stirred at 100° C. for 20 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, and added Na 2 SO 4 The organic solvent was evaporated under vacuum and the resulting residue was purified by flash column chromatography to give 6-(pyrrolidin-1-yl)-2-naphthaldehyde.

[0155] In step 4, to a round-bottom flask containing a solution of 450.6 mg of 6-(pyrrolidin-1-yl)-2-naphthaldehyde (2.0 mmol, 1.0 equiv.) and 379.6 mg of 2-cyano-N-(2,3-dihydroxypropyl)acetamide (2.4 mmol, 1.2 equiv.) in 8.0 mL of anhydrous THF, 0.04 mL of piperidine (0.4 mmol, 0.2 equiv.) was added and the resulting mixture was stirred at 50° C. overnight. The crude reaction mixture was concentrated under reduced pressure and the resulting residue was suspended in ethyl acetate and stirred vigorously for 2 hours at room temperature. The mixture was then filtered and the filtrate was washed twice with ethyl acetate to give compound 5.

[0156] 1 H NMR (600 MHz, DMSO) δ 8.24 (d, J = 1.3 Hz, 1H), 8.20 (s, 1H), 8.07 (t, J = 5.6 Hz, 1H), 8.02 (dd, J = 8.8, 1.8 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 9.0, 2.4 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 4.87 (d, J = 5.0 Hz, 1H), 4.62 (t, J = 5.8 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.46 - 3.33 (m, 7H), 3.22 - 3.13 (m, 1H), 2.12 - 1.90 (m, 4H).m / z:366(M+H + ).

[0157] Example 2C Synthesis of (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(1-(piperidin-1-yl)naphthalen-2-yl)acrylamide (6) [ka] In step 1, 2350.8 mg of 1-bromo-2-naphthaldehyde (10.0 mmol), 1.3 mL of piperidine (13.0 mmol, 1.3 equiv.), and Pd(OAc) were added to 30 mL of dry, degassed toluene. 2 (0.5 mmol, 0.05 equiv.) 112.3 mg, BINAP (0.5 mmol, 0.05 equiv.) 311.3 mg, and Cs 2 CO 3 (15.0 mmol, 1.5 equiv.) were added in sequence. The reaction mixture was stirred at 100° C. for 20 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, and added with Na 2 SO 4 The organic solvent was evaporated in vacuo to give a residue which was purified by flash column chromatography to give 1-(piperidin-1-yl)-2-naphthaldehyde. 1 H NMR (600 MHz, CDCl 3 ) δ 10.67 (d, J = 0.7 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.02 - 7.77 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.61 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.57 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 3.49 - 3.47 (m, 4H), 1.94 - 1.69 (m, 6H).

[0158] In step 2, 9.393 g of 3-aminopropane-1,2-diol (100 mmol, 1.0 equiv.) was added to 9.0 mL of methyl 2-cyanoacetate (100 mmol, 1.0 equiv.) in a round-bottom flask and the mixture was stirred at room temperature for 3 hours. Then, 50 mL of diethyl ether was added and the resulting mixture was kept stirring vigorously for 30 minutes. The round-bottom flask was then placed in a dry ice box for 30 minutes and then left at room temperature for another 30 minutes, at which point a precipitate was observed. The resulting precipitate was filtered and washed with diethyl ether to give 2-cyano-N-(2,3-dihydroxypropyl)acetamide.

[0159] In step 3, to a solution of 478.6 mg of 1-(piperidin-1-yl)-2-naphthaldehyde (2.0 mmol, 1.0 equiv.) and 379.6 mg of 2-cyano-N-(2,3-dihydroxypropyl)acetamide (2.4 mmol, 1.2 equiv.) in 8.0 mL of anhydrous THF, 0.04 mL of piperidine (0.4 mmol, 0.2 equiv.) was added, and the resulting mixture was refluxed overnight. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by flash column chromatography to give compound 6.

[0160] 1 H NMR (600 MHz, DMSO) δ 8.67 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.21 (t, J = 5.5 Hz, 1H), 8.00 - 7.94 (m, 1H), 7.84 (dd, J = 66.6, 8.7 Hz, 2H), 7.64-7.55 (m, 2H), 4.88 (d, J = 5.0 Hz, 1H), 4.65 (t, J = 5.7 Hz, 1H), 3.66 (dq, J = 10.7, 5.4 Hz, 1H), 3.45 - 3.18 (m, 8H), 1.77 - 1.63 (m, 6H).m / z:380(M+H + ).

[0161] Example 2D Synthesis of (E)-3-(1-(azetidin-1-yl)naphthalen-2-yl)-2-cyano-N-(2,3-dihydroxypropyl)acrylamide (7) [ka] Compound 7 was synthesized using a method similar to that described for the synthesis of compound 6, replacing piperidine in step 1 with azetidine.

[0162] 1 H NMR (600 MHz, DMSO) δ 8.28 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.93 (t, J = 5.5 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.59 - 7.51 (m, 1H) 7.40 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H) 7.20 (d, J = 8.7 Hz, 1H), 4.87 (d, J = 5.0 Hz, 1H), 4.62 (t, J = 5.8 Hz, 1H), 4.40 (t, J = 7.6 Hz, 4H), 3.62 (dq, J = 10.6, 5.3 Hz, 1H) 3.41 - 3.27 (m, 3H), 3.21 - 3.12 (m, 1H), 2.43 - 2.33 (m, 2H).m / z:352(M+H + ).

[0163] Compounds substituted with electron donating groups at the 8-position of the naphthalene can be prepared by using the starting material 8-bromo-2-naphthaldehyde using the synthetic methods described in Examples 2A-2D.

[0164] Example 2E Synthesis of (S,E)-6,7-dihydroxy-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)heptanenitrile (8) [ka] In step 1, a solution of 1000 mg of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (8.612 mmol, 1.0 equiv.), 12.7 mL of 2,2-dimethoxypropane (103.345 mmol, 12.0 equiv.), and 163.8 mg of p-toluenesulfonic acid monohydrate (0.861 mmol, 0.1 equiv.) in 12.9 mL of methanol was stirred at room temperature for 24 h. The reaction mixture was quenched with 30 mL of water and the resulting aqueous phase was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine and diluted with MgSO 4 Drying at 40° C. and evaporation gave crude methyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propanoate, which was used in the next step without further purification.

[0165] In step 2, to a solution of 941.1 mg of methyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)propanoate (5.0 mmol, 1.0 equiv.) and 0.787 mL of acetonitrile (15.0 mmol, 3.0 equiv.) in 10.0 mL of anhydrous THF, 400.0 mg of NaH (60% suspension in mineral oil, 10.0 mmol, 2.0 equiv.) was added under nitrogen and the resulting mixture was refluxed for 2 h. The reaction mixture was then cooled to 0 °C, quenched with 2 M aqueous HCl until the pH was neutral, and extracted with ethyl acetate. The organic extract was washed with brine and diluted with MgSO 4 It was dried at 40° C., filtered and the solvent was evaporated in vacuo. The crude material was purified by flash chromatography to give 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-oxopentanenitrile.

[0166] In step 3, to a solution of 844.5 mg of 6-(piperidin-1-yl)-2-naphthaldehyde (3.529 mmol, 1.0 equiv.) and 696.0 mg of 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-oxopentanenitrile (3.529 mmol, 1.0 equiv.) in 50 mL of anhydrous THF, 69 μL of piperidine (0.698 mmol, 0.198 equiv.) was added and the resulting mixture was stirred overnight at 70° C. The solvent was removed to give (E)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)pentanenitrile.

[0167] In step 4, 586.0 mg of (E)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)pentanenitrile (1.4 mmol, 1.0 equiv.) was treated with 20 mL of acetic acid and 5.0 mL of water at 50° C. to give compound 8.

[0168] 1 H NMR (600 MHz, CDCl 3 ) 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 m / z:379(M+H) + ).

[0169] Example 2F Synthesis of (E)-6-(2-(2-hydroxyethoxy)ethoxy)-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)hexanenitrile (9) [ka] In step 1, 19.625 g of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (100 mmol, 2.5 equiv.) was added dropwise to a stirred ice-cold suspension of 4.0 g of NaH (100 mmol, 2.5 equiv.) in 120 mL of THF. The resulting mixture was kept stirring at 50° C. for 2 h. After cooling to 0° C., a solution of 6.680 g of 4-bromobutanoic acid (40 mmol, 1.0 equiv.) in 50 mL of THF was added dropwise. The resulting mixture was stirred at 70° C. for 24 h. The reaction was then quenched with water (300 mL). The aqueous phase was washed with ether (2×30 mL) and acidified to pH 1 with 2 M HCl. The aqueous phase was then extracted with ether (3×300 mL). The combined organic extracts were washed with brine and diluted with Na 2 SO 4 The extract was dried at 4° C., filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 4-(2-(2-(benzyloxy)ethoxy)ethoxy)butanoic acid.

[0170] In step 2, to a stirred solution of 2.0 g of 4-(2-(2-(benzyloxy)ethoxy)ethoxy)butanoic acid (7.084 mmol, 1.0 equiv.) and 0.625 mL of methyl cyanoacetate (7.084 mmol, 1.0 equiv.) in 20 mL of anhydrous DMF under argon at 0° C., 3.0 mL of triethylamine (21.251 mmol, 3.0 equiv.) was added. The reaction mixture was stirred at 0° C. for 15 min, followed by the addition of 1.3 mL of diethyl pyrocarbonate (8.501 mmol, 1.2 equiv.). The resulting mixture was then stirred at 20° C. for 24 h, followed by quenching with brine and adjusting the pH to 5 by the addition of dilute HCl at 0° C. The mixture was extracted with dichloromethane, washed with brine, and purified by filtration using NaCl. 2 SO4 and concentrated to give methyl 6-(2-(2-(benzyloxy)ethoxy)ethoxy)-2-cyano-3-oxohexanoate.

[0171] In step 3, a stirred solution of 1.3 g of methyl 6-(2-(2-(benzyloxy)ethoxy)ethoxy)-2-cyano-3-oxohexanoate (4 mmol) in 12 mL of DMSO and 3 mL of water was heated to 130° C. for 45 min under an argon atmosphere. 200 mL of ethyl acetate was added to the mixture, followed by washing with brine and then Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give a residue which was purified by column chromatography (petroleum ether:ethyl acetate, 3:1) to give 6-(2-(2-(benzyloxy)ethoxy)ethoxy)-3-oxohexanenitrile.

[0172] In step 4, anhydrous FeCl in 10.0 mL of anhydrous dichloromethane 3 To a stirred suspension of 1,062.3 mg of 6-(2-(2-(benzyloxy)ethoxy)ethoxy)-3-oxohexanenitrile (6.549 mmol, 4.0 equiv.) was added a solution of 500 mg of 6-(2-(2-(benzyloxy)ethoxy)ethoxy)-3-oxohexanenitrile (1.637 mmol, 1.0 equiv.) in 15 mL of anhydrous dichloromethane at 0 °C under an argon atmosphere. The reaction mixture was stirred at 5 °C for 3-5 h, then quenched with water, extracted with dichloromethane, and purified by filtration with NaCl. e SO 4 Drying at 40° C. and concentration gave 6-(2-(2-hydroxyethoxy)ethoxy)-3-oxohexanenitrile.

[0173] In step 5, to a solution of 391.8 mg of 6-(piperidin-1-yl)-2-naphthaldehyde (1.637 mmol, 1.0 equiv.) and 352.4 mg of 6-(2-(2-hydroxyethoxy)ethoxy)-3-oxohexanenitrile (1.637 mmol, 1.0 equiv.) in 25 mL of anhydrous THF, 32 μL of piperidine (0.324 mmol, 0.198 equiv.) was added and the resulting mixture was stirred overnight at 70° C. The solvent was removed to give (E)-6-(2-(2-hydroxyethoxy)ethoxy)-3-oxo-2-((6-(piperidin-1-yl)naphthalen-2-yl)methylene)hexanenitrile.

[0174] 1 H NMR (600 MHz, CDCl 3 ) 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).m / z:459(M+Na + ).

[0175] Example 2G Synthesis of (E)-3-(6-(azetidin-1-yl)naphthalen-2-yl)-2-cyano-N-(2,3-dihydroxypropyl)acrylamide (10) [ka] In step 1, 364.8 mg of azetidine hydrochloride (3.9 mmol, 1.3 equiv.) and Cs were added to a round-bottom flask containing 30 mL of dry, degassed toluene. 2 CO 3 (12.5 mmol, 2.5 equiv.) was added sequentially and the resulting reaction mixture was stirred vigorously under argon for 1 h. The reaction mixture was then charged with 705.2 mg of 6-bromo-2-naphthaldehyde (3.0 mmol, 1.0 equiv.), 93.4 mg of BINAP (0.15 mmol, 0.05 equiv.), and Pd(OAc) 2 (0.15 mmol, 0.05 equiv.) 33.7 mg was added. The resulting reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, and added with Na 2 SO 4 The organic solvent was evaporated under vacuum and the resulting residue was purified by flash column chromatography to give 6-(azetidin-1-yl)-2-naphthaldehyde.

[0176] In step 2, 6-(azetidin-1-yl)-2-naphthaldehyde was coupled with 2-cyano-N-(2,3-dihydroxypropyl)acetamide using piperidine as a base in THF to give compound 10.

[0177] 1H NMR (600 MHz, DMSO) δ 8.26 (d, J = 1.3 Hz, 1H), 8.21 (s, 1H), 8.12 (t, J = 5.6 Hz, 1H), 8.03 (dd, J = 8.8, 1.8 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.3 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 4.88 (d, J = 5.0 Hz, 1H), 4.63 (t, J = 5.8 Hz, 1H), 4.02 (t, J = 7.3 Hz, 4H), 3.64 (dq, J = 15.8, 5.3 Hz, 1H), 3.42 - 3.34 (m, 3H), 3.21 - 3.14 (m, 1H), 2.43 - 2.36 (m, 2H).m / z:352(M+H + ).

[0178] 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] [ka]

[0179] Example 3 Model mice with detectable target proteins, such as amyloid beta protein or phosphorylated tau protein, or their accumulated masses, are intravenously administered with a representative compound of formula I described herein. The mouse retinas are removed and mounted on slides. The retinas are washed twice for 5 minutes with PBS. A 98% formic acid solution is added and left for 5 minutes for antigen retrieval. The samples are washed twice for 5 minutes with distilled water. The samples are equilibrated for 15 minutes in 1×PBS, then blocked for 1 hour in 10% goat / donkey serum (depending on the antibody) in 1×PBST. The samples are covered with foil and washed three times for 5 minutes each with 1×PBS. The samples are stained with DAPI (300 nM or 100 ng / mL) in the dark for 10 minutes, then the tissue is washed 3×10 minutes with PBS. DAKO mounting medium is added to prevent fading, a cover slip is placed, and the foil is kept covered until imaging.

[0180] Fluorescence imaging studies of samples are performed on 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 are used to visualize fluorescent probes for DAPI (blue, nuclear stain), representative compound of formula I (green) and hyperphosphorylated tau (red). Z-stack images are taken at 40x with 0.5 μm increments to visualize all layers of tissue. In the retina, hyperphosphorylated 3-repeat tau protein is detected, which produces detectable fluorescent signals, whereas immunostaining with 3-repeat tau antibody is not detected in age-matched wild-type mice. In conclusion, this study shows that the compound of formula I described herein can be used as a diagnostic agent to detect amyloid beta protein or hyperphosphorylated tau protein.

[0181] Example 4 This example is performed to determine whether compounds of Formula I described herein detect Aβ in the retina of a TBI mouse model.

[0182] Representative compounds of Formula I are administered intravenously to blast model and non-injured mice 24 hours after injury. Mouse retinas are scanned by scanning laser ophthalmoscopy (SLO). Images are generated that show the presence of Aβ plaques.

[0183] Alternatively or in addition to retinal scanning, retinal tissue is removed and stained with anti-Aβ antibody (6E10). Blast-injured mice show immunoreactivity to Aβ in retinal tissue, whereas uninjured mice show no reactivity to 6E10. Compounds of formula I fluorescently label deposits in the retina and are visible upon fluorescence activation, whereas tissue from uninjured mice does not show any fluorescence enhancement.

[0184] Example 5 In vitro binding study of compounds with amyloid beta The fluorescent properties and emission spectra of the compounds described herein were characterized using aggregated amyloid beta (Aβ1-42) as follows.

[0185] Emission spectra for the compounds described herein 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 Aβ. The fold increase in maximum emission (compound + Aβ / compound) was calculated for each test compound. Table 1 shows the results. methodology

[0186] The Aβ1-42 peptide was aggregated in vitro using the following procedure: Aβ42(HFIP) was removed from the freezer and allowed to warm to room temperature. 1 mg of Aβ42 was then added to ddHO. 2 The mixture was dissolved in 215 μL of HO at room temperature for about 10 to 20 minutes. The resulting solution was added to ddHO. 2 2 mL of O was added to obtain a 100 μM stock solution. A 100 μL aliquot was sampled and frozen (non-aggregated sample). The tube was placed in a thermoshaker at 350 rpm for 3 days. Care was taken to avoid air bubbles. Aβ aggregation was confirmed by measuring binding to Thioflavin T (ThT). The aggregated Aβ1-42 peptide was then divided into 150 μL aliquots and stored at −80° C.

[0187] Fluorescence emission spectra were measured to determine the binding of Aβ to the test compounds described herein as follows: The 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. The 100 μM solution of aggregated Aβ was then removed from the -80°C freezer and also allowed to warm to room temperature. A solution of 250 μM of each test compound in DMSO was then 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. A cuvette was used to measure the fluorescence emission spectrum of each test compound+Aβ solution, using the DMSO / PBS solution as a blank. Each sample was tested with excitation at 450 nm and 488 nm. A fluorescence emission spectrum was 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 maximal light emission (compound+Aβ / compound) was calculated for each test compound and is shown in Table 1. [Table 1]

[0188] The control is the same as compound 10 except that it has piperidine instead of azetidine. It is contemplated that compounds having piperidine as the EDG may be more prone to protonation at physiological pH than smaller rings such as azetidine, and therefore will give a smaller fold enhancement when measured at a particular wavelength.

[0189] 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.

[0190] It is contemplated that the compounds described herein bind to Aβ deposits in human tissue and increase fluorescence in a manner similar to that observed in vitro.The compounds described herein are tested for their ability to bind to and fluoresce with retinal and brain Aβ in human tissues with Alzheimer's disease.Slices from these tissues are co-stained with the compounds described herein and antibodies specific for Aβ 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

[0191] Tissue sections are deparaffinized and hydrated as follows: Samples are pre-heated at 60° C. for 1 hour. Slides are placed in holders and processed through detergents xylene (paraffin solvent) and a graded series of EtOH as follows. i. 100% xylene - 5 min ii. 100% xylene - 5 min iii. 50% / 50% xylene / 100% EtOH - 3 min iv.100%EtOH - 3 minutes v. 95% EtOH - 3 min vi. 70% EtOH - 3 min vii.50%EtOH - 3 minutes viii. Water - 2 x 3 minutes

[0192] The antigens are retrieved by incubation 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.

[0193] 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.

[0194] Slides are equilibrated in 1x PBS for 15 min, then blocked in 5% normal goat serum in PBST for 1 h at room temperature. Slides are incubated overnight at 4°C in Aβ primary antibody 6E10 (2.5% NGS in PBST). Tissues are then washed 3x 10 min in PBST wash buffer.

[0195] Slides are incubated in secondary antibody (1:500 in PBST) for 1 hour at room temperature, making sure that samples are kept in the dark from this point onwards.

[0196] Tissue is then washed with PBST for 3x10 minutes. Tissue is stained with test compounds (60μM) as described herein for 30 minutes at room temperature as follows. Test compounds as described herein are allowed to warm to room temperature (approximately 30 minutes), then 5mg of each test compound is dissolved in 3.75mL of DMSO, and the resulting solution is kept in the dark. Next, 100μL of each compound solution is diluted with 5mL of PBS to provide dye solutions for each test compound as described herein.

[0197] The stained tissue is then washed 3x10 min in PBST. Nuclei are then stained with Hoechst (2:1000 dilution from 1 mg / mL in PBS) for 10 min. The tissue is then further washed 3x10 min in PBST. The tissue is mounted using Prolong Glass mounting medium and allowed to dry overnight. Finally, the edges are sealed with nail polish.

[0198] 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.

[0199] The present disclosure illustratively described herein may be suitably practiced without any one or more elements not specifically disclosed herein, and without any one or more limitations. Thus, for example, terms such as "comprising", "including", "containing" and the like are 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, and it is recognized that various modifications are possible within the scope of the present disclosure as claimed.

[0200] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, as if each was individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

[0201] 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. A compound of formula I, or a pharmaceutically acceptable salt, tautomer or prodrug thereof [wherein, 【Chemical Formula 90】 EDG is EWG is an electron withdrawing group, 【Chemical Formula 91】 WSG is a water soluble group, Each R １ is, independently, halogen, -OR ２ , -NR ３ R ４ , 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, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R ９ and R ２ 、R ３ and R ４ are, independently, hydrogen, 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, and each of them, excluding hydrogen, is optionally substituted with one or more R ９ ; R ５ is hydrogen or C １～１０ alkyl, and Each R ９ is, independently, halogen, -OR ６ , -NR ７ R ８ , C １～１０ alkyl, C １～１０ haloalkyl, C １～１０ heteroalkyl, C ３～１０ cycloalkyl, C １～１０ heterocyclyl, C ６～１０ aryl, or C １～１０ heteroaryl, and R ６ 、 R ７ and R ８ are, independently, hydrogen or C １～１０ alkyl, R ８４ is hydrogen, halo, C １～１０ alkyl, or C １～１０ haloalkyl, and q is 0, 1, 2, 3, 4, 5, or 6, is not]. Z is C=O or SO ２ wherein Y is CH ２ , NH, or S,

2. However, when Y is NH or S and R ８４ is hydrogen or methyl, EDG is bonded to the 6-position of naphthalene 【Chemical Formula 92】 The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein q is 0.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein q is 1, 2, 3, 4, 5, or 6.

4.

5.

6. R ８４ The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein R is hydrogen.

7. R ８４ is halo, C １ -C １０ alkyl, or C １～１０ haloalkyl, and is a compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

8. R ８４ is Cl, Br, I, F, methyl, ethyl, propyl, or CF ３ The compound according to claim 5, or a pharmaceutically acceptable salt, tautomer or prodrug thereof. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein EWG is -CN. The EWG is selected from the group consisting of F, Cl, Br, -CH=O, NO ２ , -CF ３ , -CCl ３ , -SO ３ , and -CN, the compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein Z is C=O.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein Y is NH.

11.

12.

13. R ５ The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein R is hydrogen. WSG is R ５ is C １～１０ The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein R is C alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, selected from the group consisting of [wherein m is an integer having a value of 1 to 10].

14. 【Chemical Formula 93】 WSG is The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, selected from the group consisting of [wherein each X is independently O or S, each y is independently 1 or 2] 【Chemical Formula 94】 selected from the group consisting of, wherein m is an integer having a value of 1 to 10, and each R １’ is, independently, 【Chemical Formula 95】

15. Each R １１ is independently selected from 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 the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 4 R ２１ groups, or each XR １１ is independently -XP(X)(R １２ ) ２ and may be Each R １２ is independently selected from 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 is independently selected from hydroxy, thiol, C １～１０ alkyl, -O-C １～１０ alkyl, and -S-C １～１０ alkyl, Each R ２１ is, 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 is selected from Each R ３１ is independently selected from C １～１０ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, C １～８ haloalkyl, aryl, heteroaryl, and heterocyclyl, The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula IA

16. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula IB

17. 【Chemical Formula 96】 The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula IC

18. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula ID 【Chemical 97】

19. The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula IE, IF, IG, IH, II, IJ or IK

20. 【Chemical Formula 98】 The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, having formula IL ​ ​ 【Chemical Formula 99】 ​ ​ ​ 【Chemical 100】 ​

20. 【Fig. 101】 【Chemical 102】 【Chemical Formula 103】 【Chemical 104】 【Chemical 105】 【Chemical 106】 【Chemical 107】 【Chemical 108】 【Chemical 109】 【Chemical 110】 【Chemical 111】 【Chemical 112】 【Chemical 113】 【Chemical 114】 【Chemical 115】 【Chemical 116】 【Chemical 117】 【Chemical 118】 【Chemical 119】 【Chemical 120】 【Chemical 121】 【Chemical 122】 【Chemical 123】 【Chemical 124】 【Chemical 125】 【Chemical 126】 【Chemical 127】 【Chemical 128】 【Chemical 129】 【Chemical 130】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt, tautomer or prodrug thereof.

21. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.

22. For use in a method for determining whether a patient has a neurological disease or disorder, a composition comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, tautomer or prodrug thereof, or the pharmaceutical composition according to claim 21, wherein the method comprises administering the composition to the patient.

23. The composition according to claim 22, wherein the composition is administered intravenously.

24. The composition according to claim 22, wherein the composition is administered to the eyes of the patient.

25. The composition according to claim 22, wherein the method further comprises detecting the presence or absence of binding of the compound or its parent compound to a detectable target protein.

26. The composition according to claim 25, wherein the detection comprises activating tissue of the patient to be investigated by light, thereby generating the emission of a detectable signal, and detecting the detectable signal.

27. The composition according to claim 26, wherein the detectable signal is a fluorescence signal.

28. The composition according to claim 22, wherein the neurological disease or disorder is Alzheimer's disease or traumatic brain injury (TBI).

29. The composition according to claim 22, wherein the neurological disease or disorder is selected from age-related diseases or disorders, genetic diseases or disorders, injury-related diseases or disorders, and mental diseases or disorders.

30. The composition according to claim 29, 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 syndrome, the injury-related disease or disorder is selected from traumatic brain injury and chronic traumatic encephalopathy, and the mental disease or disorder is selected from schizophrenia and depression.

Images