Method for detecting neurological diseases by binding to phosphorylated TAU protein

Abstract

Provided herein are methods and compositions for determining whether a patient has a neurological disease or disorder comprising detecting the presence of phosphorylated tau protein in a tissue of the patient, wherein the detecting comprises contacting the phosphorylated tau protein with a compound described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application Serial No. 62 / 902,265, filed September 18, 2019, which is incorporated herein by reference in its entirety. Background Art

[0003] Neurological diseases are diseases of the brain, spinal cord, and peripheral nervous system. In terms of epidemiology and individual morbidity, the greatest societal cost is caused by neurological diseases. The most prominent of these neurological diseases are Alzheimer's disease and Parkinson's disease. Other neurological diseases include age-related conditions (e.g., Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis), genetic syndromes (e.g., Down syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic encephalopathy), and conditions that are generally considered to be purely psychiatric in nature, such as schizophrenia and depression.

[0004] Microtubule-associated protein tau (MAPT) is a class of proteins that stabilize microtubules during assembly and disassembly. MAPT transcripts are expressed differently in the nervous system, depending on the stage of neuronal maturation and the type of neuron. MAPT gene mutations have been associated with a variety of neurological disorders, such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortical basal degeneration, and progressive supranuclear palsy. Compared to normal brains, Tau proteins in the diseased brains of patients with Alzheimer's disease, for example, may be abnormally phosphorylated. Therefore, materials and methods for detecting phosphorylated tau proteins are needed. Summary of the Invention

[0005] In some embodiments, a method for determining whether a patient has a neurological disease or condition is provided, comprising detecting the presence of phosphorylated tau protein in a tissue of the patient, wherein the detecting comprises contacting the phosphorylated tau protein with a compound described herein. The compound can be a compound of Formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is Compound 1, 2, 3, 4, or 5.

[0006] In some embodiments, neurological disease or illness are selected from age-related diseases or illness, genetic disease or illness, the disease or illness relevant to injury and mental illness or illness. In some embodiments, the disease or illness relevant to age is selected from Parkinson's dementia, vascular dementia and amyotrophic lateral sclerosis, wherein genetic disease or illness is Down syndrome, wherein the disease or illness relevant to injury is selected from traumatic brain injury and chronic traumatic encephalopathy, and wherein mental illness or illness is selected from schizophrenia and depression. Nervous system disease or illness can be Alzheimer's disease or chronic traumatic encephalopathy (CTE). Neurological disease or illness can be tauopathy.

[0007] In some embodiments, a method for preparing a patient for diagnosis of a neurological disease or condition is provided, comprising administering a compound described herein to the patient. The compound can be a compound of Formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is Compound 1, 2, 3, 4, or 5. In some embodiments, administration is intravenous administration or placement in the retina of the eye. In some embodiments, administration is topical administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figures 1A-1C The results show that 3RTau mice of different ages were stained with 3RTau Ab, compound 5 and DAPI at 3 months ( Figure 1A )、6 months( Figure 1B ) and 12 months ( Figure 1C ) retinal sections.

[0009] Figures 2A-2B Illustration of retinal sections of 3RTau mice (12 months) stained with 3RTau Ab, compound 5 and DAPI ( Figure 2A ) and wild-type mouse (12 months) retinal sections stained with 3RTau Ab, compound 5 and DAPI ( Figure 2B ).

[0010] Figure 3 Illustrated are retinal sections of 3RTau mice (12 months) stained with 3RTau Ab, compound 5, and DAPI. DETAILED DESCRIPTION

[0011] definition

[0012] The following description sets forth exemplary embodiments of the present disclosure. However, it should be appreciated that the description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0013] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0014] The term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched chain, or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include divalent and polyvalent groups, having the specified number of carbon atoms (i.e., C1-C 10 represents one to ten carbons). Examples of saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0015] The term "heteroalkyl," by itself or in combination with another term, refers, unless otherwise stated, to a stable straight, branched, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl radical or at the position at which the alkyl radical is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Two or more heteroatoms may also be consecutive.

[0016] Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, refer to cyclic forms of "alkyl" and "heteroalkyl," respectively. Additionally, for heterocycloalkyl groups, a heteroatom may occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyl groups include, but are not limited to, tetrahydropyran, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl. Examples of heterocycloalkyl groups include, but are not limited to, glucose, mannose, allose, altrose, gulose, idose, galactose, and talose. Examples of heterocycloalkyl groups include, but are not limited to:

[0017] wait.

[0018] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is intended to include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0019] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused ring aryl) or covalently linked. A fused ring aryl refers to multiple rings fused together, wherein at least one of the fused rings is an aryl ring.

[0020] The term "heteroaryl" refers to an aromatic group (or ring) comprising one to four heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together, wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule via 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, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above mentioned aryl and heteroaryl ring systems are selected from the group consisting of the acceptable substituents described below.

[0021] "Arylene" and "heteroarylene" by themselves or as part of another substituent refer to a divalent radical derived from aryl and heteroaryl, respectively.

[0022] For the sake of brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is meant to include those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).

[0023] Each of the above terms (eg, "alkyl," "heteroalkyl," "aryl," and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each radical are provided below.

[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] Certain commonly used alternative chemical names may be used. For example, divalent radicals (such as divalent "alkyl", divalent "aryl", etc.) may also be referred to as "alkylene" or "alkylenyl", "arylene" or "arylenyl", respectively. In addition, unless otherwise expressly stated, when a combination of groups is referred to herein as one group (e.g., aralkyl), the last-mentioned group includes the atom through which it is attached to the rest of the molecule.

[0026] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. Additionally, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may be substituted with a group other than hydrogen or may not be substituted.

[0027] These compounds of part exist in the form of tautomers.Tautomers are balanced with each other.For example, the compound containing amides can exist with the imidic acid (imidic acid) tautomer balance.No matter which tautomer is shown, and no matter how the equilibrium property between the tautomers is, those of ordinary skill in the art will interpret the compound as both comprising the amide tautomer and the imidic acid tautomer.Therefore, the compound containing amides will be interpreted as comprising its imidic acid tautomer.Similarly, the compound containing imidic acid will be interpreted as comprising their amide tautomers.

[0028] Any chemical formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of these compounds. Isotopically labeled compounds have structures depicted by the chemical formulas given herein, except that one or more atoms are replaced by atoms 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, such as, but not limited to: 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, and125 I. Various isotopically labeled compounds of the present disclosure are compounds into which a radioactive isotope (e.g. 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radioisotope therapy of patients.

[0029] The present disclosure also includes "deuterated analogs" of compounds of Formula I, wherein 1 to n hydrogens attached to the carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased metabolic resistance and, therefore, can be used to increase the half-life of any compound of Formula I when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized using methods well known in the art, for example, by using a starting material in which one or more hydrogens have been replaced by deuterium.

[0030] Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Due to higher metabolic stability, such as longer in vivo half-life, reduced dosage requirements and / or an increase in therapeutic index, substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages. 18 F-labeled compounds can be used for PET or SPECT studies. Isotopically labeled compounds and prodrugs thereof disclosed herein can generally be prepared by following the procedures disclosed in the following schemes or in the following examples and preparations, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0031] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0032] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0033] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0034] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, specifically a pharmaceutically acceptable addition salt, can be prepared according to conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-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, for example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), Di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl), N(cycloalkyl), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl), N(aryl), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0035] The term "substituted" refers to any one or more hydrogen atoms on a designated atom or group being replaced by one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, assorted alkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thioketone or a combination thereof. By limiting the polymer obtained by infinitely attaching a substituent with a further substituent or a similar indefinite structure (for example, a substituted aryl with a substituted alkyl, a substituted alkyl itself being substituted by a substituted aryl, which is further substituted by a substituted assorted alkyl, etc.) it is not intended to be included herein. Unless otherwise indicated, the maximum number of serial substitutions in the compounds described herein is three. For example, the serial substitution of a substituted aryl by two other substituted aryls is limited to (aryl substituted by (substituted aryl)) substituted aryl. Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., methyl substituted by 5 fluorines or heteroaryl having two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituent of the group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, the substituents including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted by halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl (each of which is substituted). In other embodiments, the substituents can be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl (each of which is unsubstituted).

[0036] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0037] A "solvate" is formed by the interaction of a solvent with a compound. Also provided are solvates of salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0038] Phosphorylated Tau protein

[0039] Neurological diseases, including neurodegenerative diseases and injury-related diseases, are associated with the release and / or accumulation of phosphorylated tau protein. Phosphorylated tau protein can be detected by contact with a compound as described herein, wherein the contact causes the emission of a detectable signal after being activated by light. Generally, the compositions and methods described herein can be used to detect phosphorylated tau protein in any tissue of a patient. However, phosphorylated tau protein may accumulate in the patient's retina. As shown in the experimental examples, the presence of phosphorylated tau protein in the retina can be detected using a compound that binds to phosphorylated tau protein, and the binding can then be detected by means such as laser-activated retinal fluorescence scanning.

[0040] "Microtubule-associated protein tau," "MAPT," "tau protein," or "tau" is a class 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 protein is important in the stabilization and assembly of microtubules and, in turn, affects the intraneuronal transport of cargo. Tau may also participate in signaling pathways through the interaction of its acidic N-terminus with actin, thereby protruding from microtubules to promote neurite growth and stabilization during neural development. The tau protein provided herein may include any isoform or any combination of isoforms. MAPT transcripts are differentially expressed in the nervous system, depending on the stage of neuronal maturation and neuronal type. Mutations in the MAPT gene have been associated with a variety of neurological disorders, such as Alzheimer's disease, Pick's disease, frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy. Tau proteins may or may not contain post-translational modifications. The tau protein family is characterized by an N-terminal segment shared by all members, a sequence of ~50 amino acids inserted in the N-terminal segment that is developmentally regulated in the brain, a characteristic tandem repeat region consisting of 3 or 4 tandem repeats of 31-32 amino acids, and a C-terminal tail.

[0041] The human tau gene is located at position 17q21 on the long arm of chromosome 17. It is generally believed that the gene contains 16 exons, of which exon 21 is part of the promoter. The primary tau transcript contains 13 exons, and exons 4A, 6, and 8 are not transcribed in humans. Exons 21 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, and 13 are constitutive, and exons 2, 3, and 10 are spliced, resulting in six different mRNAs that are translated into six different tau isoforms. These isoforms differ in the presence or absence of one or two 29-amino acid repeats (ON, 1N, or 2N) encoded by exons 2 and 3 in the amino-terminal region, or three microtubule-binding repeats (R1, R3, and R4), or four repeat regions (R1-R4) in the carboxyl-terminal region. The fourth microtubule-binding domain is encoded by exon 10. Six tau protein isoforms are known to exist in human brain tissue: the (2+3+10+) isoform (having 441 amino acids), the (2+3+10-) isoform (having 410 amino acids), the (2+3+10-) isoform (having 412 amino acids), the (2+3-10-) isoform (having 381 amino acids), the (2-3-10+) isoform (having 383 amino acids), and the (2-3-10-) isoform (having 352 amino acids). The tau may be a mutant tau. The mutation may be an FTDP-17 mutation. Examples of mutations include: G272V, N279K, N296, P201L, P301S, G303V, S305N, L315R, S320F, P332L, V337M, E342V, S352L, K369I, G389R, R5H, R5L, K257T, I260V, L266V, G272V, delK280, N296H, N296N, delN296, P301L, P301S, K317M, G335V, Q336R, R406W, and R427M.

[0042] "Phosphorylated tau protein" or "phospho-tau" is a tau protein having at least one amino acid residue modified by a phosphate group. Tau is generally believed to include up to 85 amino acid residues compatible with phosphorylation. Typically, the phosphate group is a post-translational modification and can be attached to the side chain of the amino acid residue. The phosphorylated amino acid residue can be, for example, a serine (S), a threonine (T), or a tyrosine (Y) residue, or a combination thereof. The phosphorylated tau protein can include 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 include at least 3 moles of phosphate per mole of protein. The phosphorylated tau protein may include 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. Phosphorylated tau protein can include phosphorylated Ser422. Phosphorylated tau protein as provided herein can be deposited or can be undeposited. Phosphorylated tau protein as provided herein can be soluble. Tau protein or phosphorylated tau protein can be a three-repeat tau, a four-repeat tau or a combination thereof. In some embodiments, tau protein or phosphorylated tau protein can include a mixture of three repeat tau and four repeat tau, wherein four repeat tau is more common. In some embodiments, tau protein or phosphorylated tau protein can include a mixture of three repeat tau and four repeat tau, wherein three repeat tau is more common. Phosphorylated tau protein can be fibrillar, for example, as neurofibrillary tangles (NFTs). NFTs can be found in the dendritic compartments of neurons.

[0043] Therefore, according to some embodiments of the present disclosure, a method for determining whether a patient suffers from a neurological disease or condition is provided. The method requires contacting the patient's tissue with a compound described herein to detect the presence of phosphorylated tau protein in the patient's tissue. The contact can be in vivo or in vitro. The contact can be administered to the patient, for example, topically or intravenously. It is expected that accumulation of phosphorylated tau protein may occur in the retina of the eye. Therefore, the detection can be directed to phosphorylated tau protein in the retina.

[0044] In another embodiment, a method of preparing a patient for diagnosis of a neurological disease or condition is provided, the method comprising administering to the patient a compound that specifically binds to phosphorylated tau protein. The compound can be administered to the patient's eye. Once the compound is administered to the patient, its binding to phosphorylated tau protein can be detected by any method, including those described herein, and the binding indicates accumulation of phosphorylated tau protein, which is an indication of the neurological disease or condition.

[0045] Phospho-tau binding compounds

[0046] The present disclosure further provides a compound capable of binding to phosphorylated tau. In one embodiment, the compound can be selected from those described in WO 2011 / 072257, WO 2015 / 143185 or WO 2017 / 004560, which are incorporated herein by reference in their entirety.

[0047] In one embodiment, the compound may be selected from the compounds described in WO 2015 / 143185, which are described below.

[0048] In some embodiments, the present disclosure provides a compound of Formula I, or a salt or solvate thereof:

[0049]

[0050] in

[0051] EDG is an electron donating group;

[0052] Each Ar is independently C1-C 14 Arylene or C1-C 14 heteroarylene, each optionally substituted with one or more R1;

[0053] Each R1 is independently halogen, -OR2, -NR3R4, C 1- C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C10 Arylene or C1-C 10 heteroarylene;

[0054] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally substituted with one or more R5;

[0055] R2, R3 and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene, each of which, excluding hydrogen, is optionally substituted with one or more R5;

[0056] Each R5 is independently halogen, -OR6, -NR7R8, C 1- C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene;

[0057] R6, R7, R8 and R 84 are independently hydrogen or C1-C 10 alkyl;

[0058] R 84 is hydrogen or C1-C 10 alkyl;

[0059] EWG is an electron-withdrawing group;

[0060] WSG is a water-soluble group;

[0061] X is C=O or SO2 or X and R 84 Combine to form a pyridyl group;

[0062] Y is NH or S;

[0063] Each x is independently an integer from 0 to 10;

[0064] Each w is independently an integer from 1 to 5;

[0065] Each y is independently an integer from 0 to 10; and

[0066] z is an integer from 1 to 10.

[0067] In some embodiments, the present disclosure provides a compound of Formula II, or a salt or solvate thereof:

[0068]

[0069] in

[0070] EDG is an electron donating group;

[0071] Ar2 and each Ar1 are independently C1-C 14 Arylene or C1-C 14 heteroarylene;

[0072] Each optionally represented by one or more R 41 replace;

[0073] Each R 41 are independently halogen, -CN, -OR 42 、-NR 43 R 44 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene

[0074] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 45 replace;

[0075] R 42 、R 43 and R 44 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene, each of which, except hydrogen, is optionally replaced by one or more R 45 replace;

[0076] Each R 45 are independently halogen, -OR 46 、-NR 47 R 48 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10heteroarylene; and

[0077] R 46 、R 47 and R 48 are independently hydrogen or C1-C 10 alkyl;

[0078] EWG is an electron-withdrawing group;

[0079] Y is absent, O, NH or S;

[0080] WSG is hydrogen or water-soluble group;

[0081] x is an integer from 0 to 10;

[0082] y is an integer between 0 and 10; and

[0083] z is an integer from 1 to 10.

[0084] In some embodiments, R 84 In some embodiments, R 84 It is C1-C 10 In some embodiments, R 84 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, heptyl or decyl. In some embodiments, R 84 It's methyl.

[0085] As is known in the art, the substituent EDG is an electron donor group. In some embodiments, EDG is any atom or functional group that is capable of donating some of its electron density to a conjugated π system, thereby making the π system more nucleophilic.

[0086] In some embodiments,

[0087] EDG is -OR9, -NR 10 R 11 、-SR 12 、-PR 13 R 14 、-NR 15 C(O)R 16 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0088] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 17 replace;

[0089] Each R 17 are independently halogen, -OR 18 、-NR 19 R 20 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene;

[0090] R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 18 、R 19 and R 20 Each of which is independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0091] Each of these, except hydrogen, is optionally replaced by one or more R 21 substituted, and wherein R 10 and R 11 optionally linked together to form optionally R 21 substituted heterocycloalkyl or heteroaryl;

[0092] Each R 21 are independently halogen, -OR 22 、-NR 23 R 24 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 heteroarylene,

[0093] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 25 replace;

[0094] R 22 、R 23 and R 24 Each of which is independently hydrogen or C1-C 10 alkyl; and

[0095] Each R 25 Independently C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene.

[0096] In some embodiments, the EDG is selected from:

[0097]

[0098] In some embodiments, EDG is In some embodiments, EDG is

[0099] EWG is an electron withdrawing group. In some embodiments, an electron withdrawing group as used herein is any atom or group that is capable of withdrawing electron density from adjacent atoms toward itself through resonance or inductive effects.

[0100] In some embodiments,

[0101] EWG is selected from halogen, -CN, -NO2, -SO3H, -CR 26 R 27 R 28 、-COR 29 or -COOR 30 ;

[0102] Each R 26 、R 27 and R 28 are independently hydrogen or halogen;

[0103] R 29 Halogen, hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0104] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 31replace;

[0105] R 30 is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0106] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 32 Replacement; and

[0107] Each R 31 and R 32 Independently C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene.

[0108] In some embodiments, EWG is selected from -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3, and -CN. In some embodiments, EWG is F, Cl, or Br. In some embodiments, EWG is -CN.

[0109] WSG is a water-soluble group. In some embodiments, the WSG group is used to change the solubility of the compound in an aqueous system.

[0110] In some embodiments,

[0111] WSG is hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0112] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 33 replace;

[0113] Each R 33 are independently halogen, -OR 34 、-NR 35 R 36、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0114] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 37 replace;

[0115] Each R 34 、R 35 and R 36 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 heteroarylene,

[0116] wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 37 replace;

[0117] Each R 37 are independently halogen, -OR 38 、-NR 39 R 40 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, -(C 1- C6 alkyl)(C1-C 10 Heterocycloalkylene), C1-C 10 Arylene or C1-C 10 heteroarylene; and

[0118] R 38 、R 39 and R 40 Each of which is independently hydrogen or C1-C 10 alkyl.

[0119] In some embodiments, WSG is

[0120] In some embodiments, the WSG is polyethylene glycol, polypropylene glycol, a copolymer of polyethylene glycol and polypropylene glycol, or an alkoxy derivative thereof.

[0121] In some embodiments, WSG is Where n is an integer from 1 to 50, R 81 is hydrogen, C1-C 10 Alkyl, C1-C 10 Alkenyl or C1-C 10 Alkynyl, wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 In some embodiments, R 81 In some embodiments, R 81 In some embodiments, R 81 In some embodiments, R 81 In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, n is an integer having a value of 2-10, 1-10, 1-20, 1-30, 1-40, 1-50, 10-20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50, 30-40, 30-50, or 40-50. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is 3 or 6.

[0122] In some embodiments, WSG is

[0123] In some embodiments, WSG is

[0124] In some embodiments, WSG is

[0125] Each R 82 are independently hydrogen or C1-C 10 alkyl.

[0126] In some embodiments, each R 82 are independently hydrogen, methyl, ethyl, propyl or butyl.

[0127] In some embodiments, WSG is

[0128]

[0129] In some embodiments, WSG is

[0130]

[0131] In some embodiments, WSG is

[0132] Each R 83 is hydrogen or C1-C 10 In some embodiments, each R 83 are independently hydrogen, methyl, ethyl, propyl or butyl.

[0133] In some embodiments, WSG is

[0134]

[0135] In some embodiments, WSG is

[0136]

[0137] In some embodiments, WSG is -(C1-C 10 Alkylene)-R 33 -R 37 In some embodiments, WSG is -(C1-C 10 Alkylene)-R 33 -R 37 And R 33 C1-C 10 In some embodiments, WSG is -(C1-C 10 alkyl)-R 33 -R 37 , R 33 C1-C 10 heteroarylene, and R 37 -(C1-C6 alkyl)(C1-C 10) In some embodiments, WSG is -CH2-R 33 -R 37 In some embodiments, WSG is -CH2-R 33 -R 37 And R 33 is triazole, imidazole or pyrazole. In some embodiments, WSG is -CH2-R 33 -R 37 And R 33In some embodiments, WSG is -CH2-R 33 -R 37 And R 33 In some embodiments, WSG is -CH2-R 33 -R 37 And R 33 In some embodiments, WSG is -CH2-R 33 -R 37 , R 33 is 1,2,3-triazole, and R 37 -(C1-C6 alkyl)(C1-C 10 is heterocycloalkyl). In some embodiments, WSG is -CH2-R 33 -R 37 , R 33 is 1,2,3-triazole, and R 37 -(C1 alkyl)(C1-C 10 In some embodiments, WSG is -CH2-R 33 -R 37 , R 33 is 1,2,3-triazole, R 37 -(C1 alkyl)(C1-C 10 Heterocycloalkyl), and C1-C 10 Heterocycloalkyl is a tetrahydropyran derivative.

[0138] In some embodiments, WSG is Each R 87 is hydrogen, C1-C 10 Alkyl or -C(=O)C1-C 10 In some embodiments, each R 87 R is independently hydrogen, methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. 87 is independently hydrogen or methyl. 87 is independently methyl or acetate.

[0139] In some embodiments, WSG is

[0140] In some embodiments, WSG is

[0141] In some embodiments, WSG is -(C1-C 10 heteroalkyl)-R 33 -R 37 In some embodiments, WSG is -(C1-C10 heteroalkyl)-R 33 -R 37 And R 33 C1-C 10 In some embodiments, WSG is -(C1-C 10 heteroalkyl)-R 33 -R 37 And R 33 C1-C 10 heteroarylene, and R 37 -(C1-C6 alkyl)(C1-C 10 heterocycloalkyl).

[0142] In some embodiments, WSG is and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In some embodiments, p is an integer with a value of 2-10, 1-10, 1-20, 1-30, 1-40, 1-50, 10-20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50, 30-40, 30-50, or 40-50. In some embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 3 or 6. In some embodiments, p is 3.

[0143] In some embodiments, WSG is And R 33 C1-C 10 In some embodiments, R 33 In some embodiments, R 33 is triazole, imidazole or pyrazole. In some embodiments, R 33 In some embodiments, R 33 In some embodiments, R 33 In some embodiments, R 33 is 1,2,3-triazole, and p is 3. In some embodiments, R 33 is 1,2,3-triazole, and R 37 -(C1-C6 alkyl)(C1-C 10 In some embodiments, R 33 is 1,2,3-triazole, and R37 -(C1 alkyl)(C1-C 10 In some embodiments, R 33 is 1,2,3-triazole, R 37 is a tetrahydropyran derivative. In some embodiments, R 33 is 1,2,3-triazole, and R 37 for

[0144] In some embodiments, WSG is R 33 is 1,2,3-triazole, R 37 for p is 3.

[0145] In some embodiments, WSG is Each R 87 is hydrogen, C1-C 10 Alkyl or -C(=O)C1-C 10 In some embodiments, each R 87 R is independently hydrogen, methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. 87 is independently hydrogen or methyl. 87 is independently methyl or acetate.

[0146] In some embodiments, WSG is

[0147] In some embodiments, WSG is

[0148] In some embodiments, X is C=O or SO2. In some embodiments, X is C=O. In some embodiments, X is SO2.

[0149] In some embodiments, Y is NH or S. In some embodiments, Y is NH. In some embodiments, Y is S.

[0150] The variable w in Formula I is an integer from 1 to 5. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5.

[0151] The variable x in Formula I is an integer from 0 to 10. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0152] The variable y in Formula I is an integer from 0 to 10. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10.

[0153] The variable z in Formula I is an integer from 1 to 10. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0154] In some embodiments, x is 0, w is 1, y is 0, z is 1, X is C=O, and Y is NH.

[0155] In some embodiments, x is 0, w is 1, y is 0, z is 1, X is SO2, and Y is NH.

[0156] In some embodiments, x is 0, w is 2, y is 0, z is 1, X is C=O, and Y is NH.

[0157] In some embodiments, x is 0, w is 2, y is 0, z is 1, X is SO2, and Y is NH.

[0158] In some embodiments, the present disclosure provides a compound of Formula Ia, or a salt or solvate thereof: Among them, EDG, Ar, R 84 , x, w, y, z, EWG and WSG are defined as described above.

[0159] In some embodiments, the present disclosure provides a compound of Formula Ib, or a salt or solvate thereof: Among them, EDG, Ar, R84 , x, w, y, z, EWG and WSG are defined as described above.

[0160] In some embodiments, the present disclosure provides a compound of Formula Ic, or a salt or solvate thereof: Among them, EDG, Ar, R 84 , X, Y, EWG and WSG are defined as described above.

[0161] In some embodiments, the present disclosure provides a compound of Formula Ic, or a salt or solvate thereof:

[0162]

[0163] in

[0164] EDG is:

[0165] a) a heterocycloalkyl group of not more than 10 carbon atoms, optionally substituted by one or more R 17 replace; or

[0166] b)-NR 10 R 11 ;

[0167] Each R 17 are independently halogen, -OR 18 、-NR 19 R 20 、C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons;

[0168] R 10 、R 11 、R 18 、R 19 and R 20 Each of which is independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons, each of which is optionally replaced by one or more R 21 replace;

[0169] R 21 Each of is independently halogen, -OR 22 、-NR 23 R 24 、C1-C 10 Alkyl, C1-C10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene group is optionally replaced by one or more R 25 replace;

[0170] R 22 、R 23 and R 24 Each of which is independently hydrogen or C1-C 10 alkyl; and

[0171] Each R 25 Independently C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons;

[0172] Ar is an arylene group of up to 14 carbon atoms or a heteroarylene group of up to 14 carbon atoms, each optionally substituted with one or more R1;

[0173] Each of R1 is independently halogen, -OR2, -NR3R4, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionally substituted with one or more R5;

[0174] R2, R3 and R4 are independently hydrogen, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons, each of which is optionally substituted with one or more R5, excluding hydrogen;

[0175] Each R5 is independently halogen, -OR6, -NR7R8, C1-C 10 Alkyl, C1-C 10 heteroalkyl, cycloalkyl of up to 10 carbons, heterocycloalkyl of up to 10 carbons, arylene of up to 10 carbons, or heteroarylene of up to 10 carbons;

[0176] R6, R7, R8 and R 84 are independently hydrogen or C1-C 10 alkyl;

[0177] EWG is selected from -F, -Cl, -Br, -CH=O, NO2, -CF3, -CCl3, -SO3H and -CN;

[0178] WSG is:

[0179] i)

[0180]

[0181] ii) polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, or alkoxy derivatives thereof;

[0182] iii)

[0183]

[0184] Where n is an integer from 1 to 50 and R 81 is hydrogen, C1-C 10 Alkyl, C1-C 10 Alkenyl or C1-C 10 Alkynyl, wherein the alkyl, alkenyl or alkynyl group is optionally substituted by one or more C1-C 10 Alkyl, C1-C 10 substituted with heteroalkyl, cycloalkyl of up to 10 carbon atoms, heterocycloalkyl of up to 10 carbon atoms, arylene of up to 10 carbon atoms, or heteroarylene of up to 10 carbon atoms;

[0185] iv)

[0186]

[0187] v)

[0188]

[0189] vi)

[0190] -(C1-C 10 alkyl)-R 33 -R 37 ,in:

[0191] R 33 is a heteroarylene group of not more than 10 carbons; and

[0192] R 37 is -(C1-C6 alkyl)(heterocycloalkyl of not more than 10 carbons);

[0193] vii)

[0194]

[0195] viii)

[0196] –(C1-C 10 heteroalkyl)-R 33 -R 37 ,in:

[0197] R 33 is a heteroarylene group of not more than 10 carbons; and

[0198] R 37 is -(C1-C6 alkyl)(heterocycloalkyl of not more than 10 carbons); or

[0199] ix)

[0200]

[0201] X is C=O or SO2 or X and R 84 Combine to form a pyridyl group;

[0202] Y is NH or S.

[0203] In some embodiments, the present disclosure provides a compound of Formula Id, or a salt or solvate thereof: Among them, EDG, R 84 , Ar, EWG and WSG are as defined above. In some embodiments, the present disclosure provides a compound of Formula le or a salt or solvate thereof: Among them, EDG, R 84 , Ar, EWG and WSG are as defined above. In some embodiments, the compound is selected from:

[0204]

[0205] wherein n is an integer with a value of 1 to 50. In some embodiments, n is an integer with a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0206] In some embodiments, n is an integer with a value of 2-10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0207] In some embodiments, the compound is selected from:

[0208]

[0209]

[0210] In some embodiments, the compound is selected from:

[0211]

[0212] In some embodiments, the compound is selected from:

[0213]

[0214] wherein p is an integer with a value of 1 to 50. In some embodiments, p is an integer with a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer with a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0215] In some embodiments, the compound is selected from: wherein n is an integer with a value of 1 to 50. In some embodiments, n is an integer with a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0216] In some embodiments, n is an integer with a value of 2-10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0217] In some embodiments, the compound is selected from:

[0218] In some embodiments, the compound is selected from:

[0219]

[0220] In some embodiments, the compound is selected from:

[0221]

[0222] In some embodiments, the compound is selected from:

[0223]

[0224] In some embodiments, the compound is selected from:

[0225] wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0226] In some embodiments, the compound is selected from: wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0227] In some embodiments, the compound is selected from: wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0228] In some embodiments, the compound is selected from: wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0229] In some embodiments, the compound is selected from: wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0230] In some embodiments, the compound is selected from: wherein n is an integer having a value of 1 to 50. In some embodiments, n is an integer having a value of 1 to 10, for example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is an integer having a value of 2 to 10, for example, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0231] In some embodiments, the compound is selected from:

[0232]

[0233] In some embodiments, the compound is selected from:

[0234]

[0235] In some embodiments, the compound is selected from:

[0236] In some embodiments, the compound is selected from:

[0237]

[0238] In some embodiments, the compound is selected from:

[0239]

[0240] In some embodiments, the compound is selected from:

[0241]

[0242] In some embodiments, the compound is selected from:

[0243]

[0244] In some embodiments, the compound is selected from:

[0245]

[0246] In some embodiments, the compound is selected from:

[0247]

[0248] In some embodiments, the compound is selected from:

[0249]

[0250] In some embodiments, the compound is selected from:

[0251]

[0252] In some embodiments, the compound is selected from:

[0253]

[0254] In some embodiments, the compound is selected from:

[0255]

[0256] In some embodiments, the compound is selected from:

[0257] In some embodiments, the compound is selected from:

[0258]

[0259] In some embodiments, the compound is selected from:

[0260]

[0261] In some embodiments, the compound is selected from:

[0262]

[0263] In some embodiments, the compound is selected from:

[0264]

[0265] In some embodiments, the compound is:

[0266]

[0267] In some embodiments, the compound is (E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0268] In some embodiments, the compound is:

[0269]

[0270] In some embodiments, the compound is (E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide.

[0271] In some embodiments, the compound is:

[0272]

[0273] In some embodiments, the compound is (E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0274] In some embodiments, the compound is:

[0275]

[0276] In some embodiments, the compound is (E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide.

[0277] In some embodiments, the compound is:

[0278]

[0279] In some embodiments, the compound is (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

[0280] In some embodiments, the compound is:

[0281]

[0282] In some embodiments, the compound is (E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethylenesulfonamide.

[0283] In some embodiments, the compound is:

[0284]

[0285] In some embodiments, the compound is (E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0286] In some embodiments, the compound is:

[0287]

[0288] In some embodiments, the compound is (E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

[0289] In some embodiments, the compound is:

[0290]

[0291] In some embodiments, the compound is (E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0292] In some embodiments, the compound is:

[0293]

[0294] In some embodiments, the compound is (E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

[0295] In some embodiments, the compound is:

[0296]

[0297] In some embodiments, the compound is (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide. In some embodiments, the compound is (Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

[0298] In some embodiments, the compound is:

[0299]

[0300] In some embodiments, the compound is (E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide. In some embodiments, the compound is (Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

[0301] In some embodiments, the compound is:

[0302]

[0303] In some embodiments, the compound is (R,E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide. In some embodiments, the compound is (R,Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

[0304] In some embodiments, the compound is:

[0305]

[0306] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

[0307] In some embodiments, the compound is:

[0308]

[0309] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

[0310] In some embodiments, the compound is:

[0311]

[0312] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

[0313] In some embodiments, the compound is:

[0314]

[0315] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

[0316] In some embodiments, the compound is:

[0317]

[0318] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

[0319] In some embodiments, the compound is:

[0320]

[0321] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

[0322] In some embodiments, the compound is:

[0323]

[0324] In some embodiments, the compound is (E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide. In some embodiments, the compound is (Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

[0325] In some embodiments, the compound is

[0326] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 23.

[0327] In some embodiments, the compound is

[0328] In some embodiments, the compound is a pharmaceutically acceptable salt or solvate of Compound 24.

[0329] In some embodiments, the compound is

[0330]

[0331] In some embodiments, the compound is

[0332]

[0333] In some embodiments, the compound is

[0334]

[0335] In some embodiments, each Ar1 is independently substituted or unsubstituted naphthylene or substituted or unsubstituted phenylene. In some embodiments, Ar2 is substituted or unsubstituted naphthylene or substituted or unsubstituted phenylene. In some embodiments, Ar2 is substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl or substituted or unsubstituted pyridazinyl. In some embodiments, Ar2 is substituted or unsubstituted pyridyl.

[0336] In some embodiments, the substituent EDG in Formula II can be an electron donating group. In some embodiments, EDG is any electron donating group known in the art. In some embodiments, any atom or functional group can donate some of its electron density to the conjugated pi system by resonance or induced electron withdrawal, thereby making the pi system more nucleophilic. In some embodiments, EDG is -OR 49 、-NR 50 R 51 、-SR 52 、-PR 53 R 54 、-NR 55 C(O)R 56 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 57 Replace; wherein each R 57 are independently halogen, -OR 58 、-NR 59 R 60 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene; R 49 、R 50 、R 51 、R 52 、R 53 、R 54 、R 55 、R 56 、R 58 、R 59 and R 60 Each of which is independently hydrogen, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene, each of which, excluding hydrogen, is optionally replaced by one or more R 61 substituted, and wherein R 50 and R51 optionally linked together to form optionally R 61 substituted heterocycloalkyl or heteroaryl; each R 61 are independently halogen, -OR 62 、-NR 63 R 64 、C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene, or C1-C 10 Heteroarylene, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene or heteroarylene is optionally replaced by one or more R 65 Replacement; R 62 、R 63 and R 64 Each of which is independently hydrogen or C1-C 10 alkyl; and each R 65 Independently C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Cycloalkyl, C1-C 10 Heterocycloalkyl, C1-C 10 Arylene or C1-C 10 Heteroarylene.

[0337] In some embodiments, Y is absent, O, NH, or S. In some embodiments, Y is absent (i.e., Y is a bond). In some embodiments, Y is O. In some embodiments, Y is NH. In some embodiments, Y is S.

[0338] The variable x in Formula II is an integer from 0 to 10. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.

[0339] The variable y in Formula II is an integer from 0 to 10. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, y is 10.

[0340] The variable z in Formula II is an integer from 1 to 10. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0341] In some embodiments, x is 0, y is 0, z is 1, and Y is O.

[0342] In some embodiments, x is 0, y is 0, z is 1, and Y is S.

[0343] In some embodiments, x is 0, y is 0, z is 1, and Y is NH.

[0344] In some embodiments, x is 0, y is 0, z is 1, and Y is absent.

[0345] In some embodiments, x is 0, y is 0, z is 2, and Y is O.

[0346] In some embodiments, x is 0, y is 0, z is 2, and Y is S.

[0347] In some embodiments, x is 0, y is 0, z is 2, and Y is NH.

[0348] In some embodiments, x is 0, y is 0, z is 2, and Y is absent.

[0349] In one aspect, the present disclosure provides compounds of Formula IIa: wherein EDG, Ar1, Ar2, Y, EWG and WSG are as defined in Formula II above.

[0350] In one aspect, the present disclosure provides compounds of Formula IIb: wherein EDG, Ar1, Ar2, Y, EWG and WSG are as defined in Formula II above.

[0351] In some embodiments, the compound according to Formula II is selected from:

[0352] wherein n is an integer with a value of 0 to 50. In some embodiments, n is an integer with a value of 0 to 10, for example, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0353] In some embodiments, the compound is selected from:

[0354]

[0355] In some embodiments, the compound is selected from:

[0356] where R 85 is H or CN.

[0357] In some embodiments, the compound is selected from: where R 85 is H or CN, R 86 for wherein n is an integer with a value of 0 to 50. In some embodiments, n is an integer with a value of 0 to 10, for example, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0358] In some embodiments, the compound is selected from:

[0359]

[0360] where R 85 is H or CN and R 86 For H.

[0361] In some embodiments, the compound is selected from:

[0362]

[0363] where R 85 is H or CN and R 86 for wherein n is an integer with a value of 0 to 50. In some embodiments, n is an integer with a value of 0 to 10, for example, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0364] In some embodiments, the compound is:

[0365]

[0366] In some embodiments, the compound is 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

[0367] In some embodiments, the compound is:

[0368]

[0369] In some embodiments, the compound is 4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

[0370] In some embodiments, the compound is selected from the group consisting of:

[0371]

[0372]

[0373] or a salt or solvate thereof.

[0374] Neurological diseases and disorders and their treatment

[0375] Provided herein is a method for determining whether a patient suffers from a neurological disease or condition, comprising detecting the presence of phosphorylated tau protein in a patient's tissue, wherein the detection comprises contacting phosphorylated tau protein with a compound described herein. The compound may be a compound of Formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is a compound of Formula Ic. In some embodiments, the compound is compound 1, 2, 3, 4, or 5. The contact may be in vivo contact. The tissue may be ocular tissue. In some embodiments, the neurological disease or condition is selected from age-related diseases or conditions, genetic diseases or conditions, diseases or conditions related to injury, and mental illnesses or conditions. In some embodiments, age-related diseases or conditions are selected from Parkinson's dementia, vascular dementia, and amyotrophic lateral sclerosis, wherein the genetic disease or condition is Down syndrome, wherein the disease or condition related to injury is selected from traumatic brain injury and chronic traumatic encephalopathy, and wherein the mental illness or condition is selected from schizophrenia and depression. The neurological disease or condition may be tauopathy. In some embodiments, the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE).

[0376] A neurological disease or condition may be a tauopathy. Tauopathy is a class of neurological diseases associated with pathological deposits of tau protein in neurofibrillary or gliofibril tangles in the human brain. Tangles can form through hyperphosphorylation of tau, which causes tau to dissociate from microtubules and form insoluble deposits. Deposits of hyperphosphorylated tau are also referred to as paired helical fibrils. The exact mechanism of tangle formation is not fully understood, and there is controversy as to whether tangles are the primary pathogenic factor or play a more peripheral role. Tauopathies have been identified in numerous neurological diseases, such as post-traumatic degeneration, infection, metabolic disease, and motor neuron degeneration. Tau protein spatial distribution, temporal appearance, and structural changes vary across various neurological diseases. Patients with AD have twisted, hyperphosphorylated, and aperiodic tau filaments, while patients with progressive supranuclear palsy and frontotemporal dementia (FTD) often have only straight tau filaments. Taupathies often overlap with synucleinopathies, likely due to interactions between synuclein and tau. Non-Alzheimer's diseases are sometimes grouped together with "Pick's syndrome" due to their association with frontotemporal dementia or frontotemporal lobar degeneration. A hallmark of tau hyperphosphorylation is tau pS422. Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) and shares many similarities with tauopathies, including tau hyperphosphorylation and deposits such as neurofibrillary tangles (NFTs).

[0377] The neuronal disease or disorder can be a neurodegenerative disease or disorder. In some embodiments, the neurological disease or disorder is Alzheimer's disease. AD is considered a secondary tauopathy. Alzheimer's disease is characterized by symptoms of amnesia in the early stages of the disease. Neurofibrillary tangles are an early description of Alzheimer's disease. When tau becomes hyperphosphorylated, the protein detaches from the microtubules of the axons. Then, tau becomes misfolded and begins to deposit, which may form neurofibrillary tangles (NFTs). Microtubules are also unstable when tau is detached, and the combination of neurofibrillary tangles and unstable microtubules leads to the disruption of processes such as axonal transport and neural communication. The extent of NFT involvement in Alzheimer's disease is defined by the Braak stage. When NFT involvement is primarily confined to the transluminal region of the brain, Braak stages I and II are used. When limbic areas such as the hippocampus are involved, stages III and IV are entered; when widespread involvement of the neocortex is shown, stages V and VI are entered. Due to the presence of senile plaques, Alzheimer's disease is also classified as an amyloidosis. In addition, some Apoε4 carriers are at greater risk for developing Alzheimer's disease. It is generally believed that APOε4 is not as effective as other isoforms in clearing Aε and is therefore associated with greater 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 developing AD.

[0378] As the disease progresses, symptoms include confusion, long-term memory loss, paraphasia, vocabulary loss, aggressiveness, irritability and / or mood swings. In the more advanced stages of the disease, there is loss of physical function. Patients with Alzheimer's disease (AD) show 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 conditions include: Alzheimer's disease type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-associated memory impairment (AAMI). In some embodiments, determining whether a patient suffers from Alzheimer's disease includes detecting the presence of phosphorylated tau protein in the patient's tissue, wherein the detection includes contacting the phosphorylated tau protein with a compound described herein.

[0379] In some embodiments, the neurological disease or condition is frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS). In some embodiments, the neurological disease or condition is frontotemporal dementia. In some embodiments, the neurological disease or condition comprises memory loss. In some embodiments, the neurological disease or condition is age-related memory loss. In some embodiments, the neurological disease or condition is type A FTLD-TDP. In some embodiments, the neurological disease or condition is type B FTLD-TDP. In some embodiments, the neurological disease or condition is type C FTLD-TDP. In some embodiments, the neurological disease or condition is type D FTLD-TDP.

[0380] In some embodiments, neurological disease or illness are Parkinson's disease. In some embodiments, neurological disease or illness are Parkinson's dementia. In some embodiments, the neurological disease or illness are relevant to the accumulation of amyloid plaques (for example, characterized by it). In some embodiments, the patient suffering from neurological disease or illness has suffered traumatic brain injury before, during or after neuronal disease attack. In some embodiments, neurological disease or illness include neuronal damage. Impaired neurons can include other reductions of the effective function of atrophy or neuron. For example, known Alzheimer's disease shows as impaired neurons, especially cortical neurons, such as hippocampal neurons and neurons near hippocampus are impaired.

[0381] In some embodiments, the neurological disease or disorder is traumatic axonal injury (TAI), traumatic encephalopathy (TBD), dementia (e.g., common dementia), frontal lobe dementia, Parkinson's disease with association with chromosome 17 (FTDP-17), primary age-related tauopathy (PART), Alzheimer's disease with predominant neurofibrillary tangles, progressive supranuclear palsy (PSP), corticobasal degeneration, Lytico-Bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, encephalomyelitis, poliomyelitis, encephalomyelitis, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic grain disease (AGD), or corticobasal degeneration.

[0382] The neurological disease or disorder can be an injury-related disease, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). Traumatic brain injury (TBI) is a chronic disease defined as damage to the brain caused by an external force, such as a bump, blow, jolt, rapid acceleration or deceleration, or projectile penetration. The injury that causes TBI can lead to a state of diminished or altered consciousness, resulting in temporary or permanent impairment of cognitive, sensorimotor, and psychosocial function. CTE is a progressive degenerative disease found in people who have suffered repetitive brain trauma, including blows to the head that do not result in TBI symptoms. The physical aspects of CTE include: brain atrophy, shrinkage of the frontal and temporal lobes, enlargement of the ventricles, and shrinkage of the hippocampus, thalamus, brainstem, and cerebellum. Individuals with CTE may have symptoms of dementia, memory loss, aggression, confusion, depression, and suicidal thoughts, which may occur many years after the injury.

[0383] The neurological disease or disorder can be of the eye, such as glaucoma, ocular hypertension, macular degeneration, diabetic retinopathy, age-related macular degeneration (AMD), or retinitis pigmentosa.

[0384] Examples of neuronal diseases that can be treated with the compounds or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, depression, perinatal asphyxia, Parkinson's disease dementia ("PD dementia"), amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Battens disease), spongiform encephalopathies (e.g., bovine spongiform encephalopathy (mad cow disease), Kuru disease, Creutzfeldt-Jakob disease, fatal familial insomnia, Canavan disease, Cockayne syndrome, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, and schizophrenia. disease), HIV-related dementia, Kennedy's disease, Krabbe's disease,Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, 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 Lewy bodies (PARK3), Parkinson's disease 4, autosomal dominant Lewy bodies (PARK4), Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive early-onset (PARK2), Parkinson's disease 7, autosomal recessive early-onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), and mitochondrial Parkinson's disease.

[0385] After a neurological disease or condition is diagnosed in a patient, certain procedures can be provided to treat or ameliorate the symptoms of the neurological disease or condition, or to slow or prevent its progression. Once a neurological disease or condition is diagnosed, the progression of the disease can also be monitored using the methods described herein. Once diagnosed, the attending physician can also recommend other treatments as described herein.

[0386] "Treatment" or "treatment" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) ameliorating, slowing, or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis); and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, partially or completely resolving the disease or condition, enhancing the efficacy of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0387] "Prevention" or "preventing" refers to the treatment of any disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compound can be administered to a subject (including a human) who is at risk for or has a family history of the disease or condition.

[0388] "Patient" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the patient is a mammal. In one embodiment, the patient is a human.

[0389] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, refers to an amount sufficient to effect treatment, provide a therapeutic benefit, such as improvement in symptoms or slowing of disease progression, when administered to a patient. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition of a neurological disease or disorder. The therapeutically effective amount can vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and the therapeutic effectiveness can be readily determined by one of ordinary skill in the art.

[0390] The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means in a living individual, such as an animal or human. In this article, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, which include fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this article, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, for a given indication, cell type, individual, and other parameters, the compounds and compositions described herein can be used in vitro to determine the optimal administration regimen and / or dosage of the compounds of the present invention. The information collected from such use can be used for experimental purposes or in the clinic to set up an in vivo treatment regimen. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. The selected compounds can be further characterized to examine safe or tolerated doses in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

[0391] Detection of phosphorylated tau

[0392] Provided herein are methods for diagnosing a neurological disease or condition, comprising administering a compound described herein to a patient's tissue. The compound may be a compound of Formula I, II, Ia, Ib, Ic, Id, or Ie. In some embodiments, the compound is a compound of Formula Ic. In some embodiments, the compound is Compound 1, 2, 3, 4, or 5. The method may include detecting the binding of the compound to phosphorylated tau protein. The binding may cause emission of a detectable signal upon photoactivation. The signal may be a fluorescent or infrared signal. Administration may be intravenous or directed to the retina of the eye.

[0393] Detection of phosphorylated tau protein can be performed using a probe that can selectively bind to phosphorylated tau, which is referred to herein as a phosphorylated tau probe. The probe comprises a compound described herein.

[0394] In one embodiment, a phosphorylated tau probe, such as a compound described herein, when bound to phosphorylated tau can be detected by the fluorescent signal it emits when activated by a laser. Examples of phosphorylated tau binding compounds are described herein.

[0395] Retinal imaging devices, preferably handheld or portable, can be used to facilitate in situ detection of binding of phosphorylated tau binding probes, such as the compounds described herein, to phosphorylated tau protein in the patient's retina. The retinal imaging device can include a lens and an image sensor, and optionally a laser light source. When the light source emits laser light toward the retina, if phosphorylated tau accumulates on the retina and binds to the phosphorylated tau binding probe, such as the compounds described herein, the accumulation can be easily detected and quantified by the lens and image sensor that collect and sense the fluorescent signal.

[0396] The method for determining whether a patient has a neurological disease or condition can be performed in any manner described herein. In some embodiments, the contact causes emission of a detectable signal when activated by light. In some embodiments, the detectable signal is a fluorescent signal. In some embodiments, the phosphorylated tau protein comprises at least three moles of phosphate per mole of protein. In some embodiments, the phosphorylated tau protein is tri-repeat tau, tetra-repeat tau, or a combination thereof.

[0397] Administration and pharmaceutical compositions

[0398] In some embodiments, the compounds described herein are administered to the eye. In some embodiments, the pharmaceutical compositions of the present disclosure administered to the eye are delivered to the retina, the intraocular space, the ocular surface, interconnected nerves, the conjunctiva, the lacrimal glands, or the meibomian glands. In certain embodiments, the compounds are administered topically to the eye. In some embodiments, the compounds are administered as eye drops. Administration can be topical.

[0399] The compounds may also be formulated for intravenous and subcutaneous use, without limitation. Intravenous administration may be by bolus administration or continuous infusion.

[0400] The compound may be effective over a wide dosage range. In some embodiments, in the case of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day are examples of dosages used. An exemplary dosage is 10 to 30 mg per day. In dosages for adolescents, the dosage may be equal to or less than the adult dosage. In some embodiments, the effective amount of the compound is equivalent to about 50-500 mg of the compound per adult patient. The exact dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0401] In some embodiments, the effective amount of the compound is equivalent to about 0.01-1000 mg of the compound per dose per human patient. In some embodiments, the effective dose of the compound is 50-500 mg per dose per human patient. In some embodiments, the effective amount corresponds to 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, 0.1-60 0mg, 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, 1 00-900mg, 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, 400-60 900-1000 mg. In some embodiments, the effective amount corresponds to about 50-100 mg, 50-400 mg, 50-500 mg, 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500, 300-400 mg, 300-500 mg, or 400-500 mg per adult per dose.

[0402] In some embodiments, the compound is administered in a single dose. In some embodiments, the compound is administered in multiple doses. In some embodiments, the administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In some embodiments, the administration is about once a month, once every two weeks, once a week, or every other day. In another case, the compound and another agent are administered together from about once a day to about 6 times a day. In some embodiments, the administration of the compound and the agent continues for less than about 7 days. In another case, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some embodiments, continuous administration can be achieved and maintained for as long as necessary.

[0403] In some embodiments, the compound is administered one to ten times, one to four times, or once a day. In some embodiments, the compound is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In some embodiments, the compound is administered in the form of drops. In some embodiments, the size of the drops administered is in the range of about 10-100 μL, about 10-90 μL, about 10-80 μL, about 10-70 μL, about 10-60 μL, about 10-50 μL, about 10-40 μL, about 10-30 μL, about 20-100 μL, about 20-90 μL, about 20-80 μL, about 20-70 μL, about 20-60 μL, about 20-50 μL, about 20-40 μL, or about 20-30 μL. An example of the present disclosure administers drops in the range of about 10 to about 30 μL. One example of the present disclosure applies drops in the range of about 10 to about 100 μL. One example of the present disclosure applies drops in the range of about 20 to about 50 μL. One example of the present disclosure applies drops in the range of about 20 to about 40 μL. One example of the present disclosure applies drops in the range of about 10 to about 60 μL. In some embodiments, the ophthalmic preparation of the present disclosure is applied in a few drops at a time, for example, 1-3 drops at a time, 1-3 drops at a time, 1-4 drops at a time, 1-5 drops at a time, 1-6 drops at a time, 1-7 drops at a time, 1-8 drops at a time, 1-9 drops at a time, 1-10 drops at a time, 3-4 drops at a time, 3-5 drops at a time, 3-6 drops at a time, 3-7 drops at a time, 3-8 drops at a time, 3-9 drops at a time, 3-10 drops at a time, 5-6 drops at a time, 5-7 drops at a time, 5-8 drops at a time, 5-9 drops at a time, 5-10 drops at a time, 7-8 drops at a time, 7-9 drops at a time or 9-10 drops at a time. In one embodiment, the formulation of the present disclosure is administered about one drop at a time and 1-6 times per day.

[0404] Pharmaceutical compositions / preparations

[0405] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In some cases, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that assist in processing the active compound into a pharmaceutically acceptable formulation. The correct formulation depends on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients suitable for formulating the pharmaceutical compositions described herein are used: Remington: The Science and Practice of Pharmacy, 19th Edition (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, 7th Edition (Lippincott Williams & Wilkins 1999).

[0406] The pharmaceutical compositions provided herein comprise the probes described herein and a pharmaceutically acceptable diluent, excipient, or carrier. In some cases, such as in combination therapy, the compounds described herein are administered as pharmaceutical compositions in which one or more compounds are mixed with other active ingredients. In certain instances, pharmaceutical compositions include one or more compounds described herein.

[0407] As used herein, pharmaceutical composition refers to a mixture of a compound described herein and other chemical ingredients (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). In some cases, the pharmaceutical composition promotes the administration of the compound to an organism. In some embodiments for practicing the methods of treatment or uses provided herein, a therapeutically effective amount of one or more compounds described herein provided herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease or condition to be detected, diagnosed or treated. In certain cases, the mammal is a human being. In some cases, the therapeutically effective amount depends on the severity of the disease, the patient's age and relative health status, the effectiveness of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of the mixture.

[0408] In some embodiments, one or more compounds are formulated in an aqueous solution. In certain instances, by way of example only, the aqueous solution is selected from a physiologically compatible buffer such as Hank's solution, Ringer's solution, acetate buffered aqueous solution, citrate buffered aqueous solution, carbonate buffered aqueous solution, phosphate buffered aqueous solution, or physiological saline buffer.

[0409] In some cases, the compounds described herein are formulated for ophthalmic administration. In some cases, ophthalmic formulations are liquids (in the form of solutions, suspensions, reconstituted powders, sol-to-gel systems), semisolids (ointments and gels), solids (ophthalmic formulations), and intraocular dosage forms (injections, irrigants, and implants).

[0410] Provided herein are ophthalmic formulations comprising a compound described herein and an ophthalmologically acceptable component. The ophthalmic formulations can be administered in any form suitable for ophthalmic pharmaceutical administration, for example, as a solution, suspension, ointment, gel, liposomal dispersion, colloidal microparticle suspension, or the like, or in an ocular insert, for example, in an optionally biodegradable controlled release polymer matrix.

[0411] A "pharmaceutically acceptable" or "ophthalmologically acceptable" component is one that is not biologically or otherwise undesirable, i.e., the component can be incorporated into the ophthalmic formulations of the present invention and topically administered to the patient's eye without causing any undesirable biological effect or interacting in a deleterious manner with any other components of the formulation composition. When the term "pharmaceutically acceptable" is used to refer to a component other than a pharmacologically active agent, it means that the component has met the required standards of toxicology and manufacturing testing, or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0412] Ophthalmic preparations can be suitable for topical administration to the eye in the form of a suspension or emulsion. Ophthalmic preparations can include an ophthalmologically acceptable carrier. Such carriers include, for example, water; aqueous mixtures such as phosphate buffer, boric acid, sodium chloride, and sodium borate; and water-miscible solvents such as lower alcohols, aryl alcohols, polyalkylene glycols, carboxymethylcellulose, polyvinylpyrrolidone, and isopropyl myristate. Ophthalmic preparations can also include one or more excipients, such as emulsifiers, preservatives, wetting agents, and thickening agents. For example, ophthalmic preparations may include polyethylene glycol 200, 300, 400, and 600; polyethylene glycol 1,000, 1,500, 4,000, 6,000, and 10,000; antimicrobial ingredients such as quaternary ammonium compounds, phenylmercuric salts, thimerosal, methyl and propyl parabens, benzyl alcohol, phenylethyl alcohol; buffers such as sodium borate, sodium acetate, gluconate buffers; and other agents such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitate, sodium dioctylsulfosuccinate, monothioglycerol, thiosorbitol, and ethylenediaminetetraacetic acid. The ophthalmic preparations may be isotonic. The ophthalmic preparations may also include surfactants or stabilizers. Surfactants include Stabilizers include sodium bisulfite, sodium metabisulfite, and sodium thiosulfate.

[0413] The formulation may contain an effective amount of a penetration enhancer that promotes penetration of the formulation components across cell membranes, tissues, and extracellular matrices (including the cornea). An "effective amount" of a penetration enhancer means an amount sufficient to provide a measurable increase in the concentration of one or more formulation components through membranes, tissues, and extracellular matrices, as just described. Suitable penetration enhancers include, for example, methylsulfonylmethane (MSM; also known as methyl sulfone), a combination of MSM and dimethylsulfoxide (DMSO), or, in a less preferred embodiment, a combination of MSM and DMSO, with MSM being particularly preferred.

[0414] Kits and Packaging

[0415] Also provided herein are kits and packages comprising a compound of the invention, a retinal imaging device, and optionally suitable packaging. In one embodiment, the kit further comprises instructions for use.

[0416] The retinal imaging device can include a lens and an image sensor (thereby forming a suitable retinal scanner) for detecting the emitted signal. In some embodiments, the retinal imaging device detects a fluorescent signal. In some embodiments, the retinal imaging device also includes a laser light source, which can be used to activate the fluorescent signal.

[0417] Example

[0418] The following examples are included herein to disclose specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the disclosed technology in the ensuing examples represents the technology that plays a role well in the practice of the present disclosure, and therefore can be considered to constitute the specific mode of its implementation. However, it will be appreciated by those skilled in the art that, without departing from the spirit and scope of the present disclosure, according to content disclosed in the present invention, many changes can be made to disclosed specific embodiments and still identical or similar results can be obtained.

[0419] Example 1: Tau protein retinal staining

[0420] The retinas of mice with triple tau ("3RTau") of different ages (3 months, 6 months, and 12 months) were mounted on slides. The retinas were washed twice with PBS for 5 minutes. A 98% formic acid solution was added for 5 minutes to recover the antigen. The samples were washed twice with distilled water for 5 minutes each. The samples were equilibrated in 1× PBS for 15 minutes and then blocked with 10× goat / donkey serum in 1× PBST (depending on the antibody) for 1 hour. The samples were then incubated with a triple tau antibody containing 10% goat serum in 1x PBST at 4°C overnight and then rinsed 3 times with 1x PBST for 5 minutes each. The samples were incubated with a secondary antibody (AlexaFluor 568 Anti mouse) in 1x PBST for 1 hour, then covered with foil and then rinsed 3 times with 1x PBST for 5 minutes each. The samples were stained with compound 5 working solution at room temperature for 30 minutes, covered with foil, and washed 3 times with 1× PBS for 5 minutes each. The samples were stained with DAPI (300 nM or 100 ng / mL) for 10 minutes in the dark, and the tissues were then washed 3×10 minutes with PBS. Anti-fade DAKO mounting medium was added, coverslipped, and kept under foil until imaging. Images were acquired using a Leica confocal microscope.

[0421] Hyperphosphorylated 3RTau was detected in the retinas of 3RTau transgenic mice at different ages. Figure 1A 、 1BFigures 1 and 1C show the appearance of fluorescent aggregates (approximately 5-10 μm in diameter) in retinal sections of 12-month-old 3RTau mice, which are absent in control retinal sections. As expected, immunofluorescence with 3RTau antibodies showed the presence of accumulated tau aggregates in the blood vessels and neurons of 3RTau mice. The merged image shows the colocalization of compound 5 with 3RTau antibodies in neuronal cell bodies. Analysis of statistical tests using Image J to assess the degree of colocalization and relationship showed that the Pearson correlation coefficient (PCC) was 0.67 for 3RTau mice and 0.04 for control mice (PCC measures the correlation between the pixel values ​​of the two reporter channels, where -1 = complete anti-colocalization; 0 = non-colocalization; 1 = complete colocalization).

[0422] Immunoreactivity with 3RTau Ab increased in the retina with age. 3Rtau staining was robust in 12-month-old transgenic mice compared to 6- and 3-month-old transgenic mice. 3Rtau immunoreactivity in the retina co-localized with compound 5. Co-localization of compound 5 and 3RTau antibody was observed by immunostaining, confirming specificity for tau. Interestingly, at 3 months, tau aggregates were observed closer to the optic disc, while at 12 months, the increase in tau was more prevalent in the retinal periphery. No immunostaining with 3RTau Ab was detected in wild-type mice of comparable age. In conclusion, this study suggests that compound 5 has the potential to be used as a diagnostic agent for the detection of hyperphosphorylated tau in the retina. Shown Figure 1A 、 1B The results of 1C and 1C provide evidence that the compounds described herein have the potential to diagnose Alzheimer's disease and other tauopathies and to monitor disease progression.

[0423] Example 2: Imaging

[0424] Fluorescence imaging studies were performed on a Leica DMI4000B microscope (Leica, Germany) equipped with a TCS SPE camera and Leica 10, 20, and 40X objectives. The following lasers were used to visualize fluorescent probes related to DAPI (blue, nuclear stain), compound 5 (green), and 3RTau (red): 408, 488, and 568 nm. Z-stack images were taken at 40X in 0.5 μm increments to visualize the entire thickness of the tissue.

[0425] Figure 1A 、 1B and 1C illustrate the 3RTau cells of mice of different ages at 3 months ( Figure 1A )、6 months( Figure 1B ) and 12 months ( Figure 1C) retinal sections.

[0426] Figure 2A and 2B Illustration of retinal sections of 3RTau mice (12 months) stained with 3RTau Ab, compound 5 and DAPI ( Figure 2A ) and wild-type mouse (12 months) retinal sections stained with 3RTau Ab, compound 5 and DAPI ( Figure 2B ).

[0427] Figure 3 Illustrated are retinal sections of 3RTau mice (12 months) stained with 3RTau Ab, compound 5, and DAPI.

[0428] Example 3: Synthesis

[0429] Synthesis of compound 23

[0430]

[0431] Synthesis of (6-bromonaphthalen-2-yl)methanol (27)

[0432] Under N2, at 0 ℃, to LiAlH4(8.2g, 217mmol in 500mL THF) solution) in 6-bromo-2-naphthoic acid methyl ester (26) (50.0g, 189mmol) in 500mL anhydrous THF was added dropwise.The reaction mixture was stirred at 0 ℃ for 1 hour.After utilizing TLC to monitor the reaction, the mixture was treated with H2O, 15%NaOH, H2O (1:1:3, v / v / v).After filtering, the filtrate was concentrated and extracted with EA, dried with NaSO4.The crude product was purified from (PE:EA=3:1) to obtain the title compound.

[0433] Synthesis of 6-bromo-2-naphthaldehyde (28)

[0434] In a suspension of (6-bromonaphthalene-2-yl)methanol (27) (42.0 g, 177 mmol) and silica gel (76.4 g) in DCM (500 mL), PCC (76.4 g, 354 mmol) was added. The reactant was stirred at RT (room temperature, 25 ± 5 ° C) for 1.5 hours. After completion, it was filtered through a pad of silica and concentrated under reduced pressure to obtain the title compound.

[0435] Synthesis of 6-(piperidin-1-yl)-2-naphthaldehyde (29)

[0436] In dry and degassed toluene (300 mL), Pd (OAc) 2 (1.5 g, 6.3 mmol), BINAP (4.4 g, 7.1 mmol), 6-bromo-2-naphthaldehyde (28) (30.0 g, 127.8 mmol), Cs 2 CO 3 (60.0 g, 183.9 mmol) and piperidine (12.7 g, 149.5 mmol) were added. The reactants were stirred at 115 ° C for 8 hours. After cooling, the mixture was filtered and washed with EA, then concentrated to one-third of the volume, and 200 ml of 6N hydrochloric acid was added thereto with sufficient stirring. The aqueous phase was separated, extracted three times with DCM, then adjusted to alkalinity with 5N NaOH, and extracted with EA. The organic phase was concentrated to give the crude product, which was further purified by silica gel chromatography (PE: EA = 20: 1 to 2: 1) to obtain the title compound.

[0437] Synthesis of 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide (31)

[0438] In a pear-shaped flask, 30 (6.0 g, 40 mmol) was added to methyl 2-cyanoacetate (4.0 g, 40 mmol) under stirring. The mixture was stirred at room temperature overnight and then concentrated to a crude material. The crude material was used directly in the next step.

[0439] Synthesis of (E)-2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide (Compound 23)

[0440] To a solution of 6-(piperidin-1-yl)-2-naphthaldehyde (29) (7.0 g, 29.3 mmol) and 2-cyano-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)acetamide (31) (7.9 g, 36.5 mmol) in anhydrous THF (250 mL) was added piperidine (0.5 g, 5.9 mmol), and the resulting mixture was refluxed for 12 hours. The reaction mixture was then concentrated under reduced pressure to a crude material, which was purified by silica gel chromatography to give the title compound. Exact weight 437.23; m / e 437.23 (100%), 438.23 (28.9%), 439.24 (4.7%); elemental analysis (C 25 H 31 N3O4): C 68.63%, H 7.14%, N 9.60%, O14.63%.

[0441] Synthesis of compound 24

[0442]

[0443] Synthesis of 33

[0444] At zero degrees, 1.6 g (3 mM) of tetrabenzyl pyrophosphate prepared using Merck organic synthesis was added to 1 g (2.3 mM) of compound 23 in 15 mL of THF to give a deep red solution. Sodium hydride (100 mg, 2.5 mM, 60% in oil) was added. After 15 minutes, the mixture was warmed to room temperature and solids began to precipitate. DMF (5 mL) was added and stirred at RT for 1 hour. Water (200 mL) and ethyl acetate (200 mL) were added. The ethyl acetate layer was dried and evaporated. The reaction mixture was dried using 0-100% hexane / ethyl acetate on an 80 g silica gel column. Purification of the product afforded the title compound. Figures 1A to 1C The structure of compound 8 is given in 1 H NMR spectrum. MS (m / z) 701.3 [M+H] + .

[0445] Synthesis of compound 24

[0446] To 1 gram (compound 33), 95% ethanol (150 mL) degassed with argon was added. 120 mg of 10% Pd / C was added, and hydrogen was bubbled into the reaction mixture for 5 minutes. The mixture was then stirred in a hydrogen balloon for 3 hours. The reaction mixture was degassed with argon and evaporated. Purification was performed by preparative LC / MS using 0 to 100% water (containing 2 g per liter of ammonium acetate) on a 25×250 mm C18 chromatographic column. After free drying, compound 24 was obtained. Figure 2A and Figure 2B The structure of compound 9 is given in 1 H NMR spectrum (D2O).

[0447] Synthesis of compound 25

[0448]

[0449] A solution of compound 33 (5 mmol, 3.49 g, 1 eq) in anhydrous CHCl (100 ml) was cooled to 0°C under argon and trimethylsilyl bromide (50 mmol, 6.8 ml, 10 eq) was added via syringe. The reaction mixture was stirred at 0°C for 30 minutes and the conversion was monitored by HPLC. The mixture was then quenched with MeOH (50 mL) and stirred for 10 minutes. The solution was evaporated to dryness; this step was repeated four times.

[0450] The organic solvent was evaporated under vacuum, and the residue was suspended in a trace amount of MeOH, and EtOAc was added to cause precipitation of the phosphonic acid. The residue was filtered and washed with EtOAc (×2). The residue was then dried under vacuum to obtain the desired phosphoric acid.

[0451] The phosphonic acid was treated with NH4OAc (25 mmol, 1.93 g, 5 equivalents) and 150 ml of water at room temperature and stirred for another 15 minutes to give a clear red / orange solution. The reaction mixture was then lyophilized to give the final product. LC-MS: (ES, m / z) 518 [M+1] + . 1H-NMR: (400MHz, CD3OD) δ8.31–8.22(m,2H),8.08(dd,J=8.8,1.9Hz,1H),7.81(d,J=9.2Hz,1H),7.74(d,J=8.8Hz,1H),7.40(dd,J=9.2 ,2.5Hz,1H),7.18(d,J=2.5Hz,1H),4.08–3.98(m,2H),3.79–3.65(m,8H),3.58(t,J=5.5Hz,2H),3.45–3.39(m,4H),1.86–1.63(m,6H).

[0452] Example 4: In vivo assay

[0453] Experimental Design: In vivo fluorescence retinal imaging experiments were performed on ketamine-anesthetized mice, as shown in the following table:

[0454]

[0455] Because the balance of 3R and 4R tau isoforms is affected in a variety of tau diseases including AD, the 3RTau and 4RTau tg models will be used to explore the interaction of fluorescent compounds described herein with any variant of tau. Female tg mice can be used because they are reported to form amyloid plaques faster than males. The Phoenix Micron IV imaging system will be used to capture real-time in vivo fluorescence imaging of the retina. Increasing IV doses (selected from experimental pharmacokinetic studies using biocompatible formulations of compounds described herein) will be administered to mice, and retinal fluorescence will be measured at different times after administration. Systemic and retinal concentrations will be measured in satellite animals (WT control strains) to understand the relationship between dose, concentration, and response. After in vivo imaging is complete, mice will be sacrificed for in vitro brain and retinal analysis to confirm the presence of tau using antibodies that recognize total tau, hyperphosphorylated tau, and tau conformational epitopes (3RTau and 4RTau) by immunofluorescence (IF) microscopy.

[0456] ***

[0457] Unless defined otherwise, 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.

[0458] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like are to be read broadly and without limitation. Furthermore, the terms and expressions employed herein have been used as terms of description and not 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, but it is to be understood that various modifications are possible within the scope of the claimed disclosure.

[0459] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0460] It should be understood that, although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. For those skilled in the art to which the present disclosure pertains, other aspects, advantages and modifications within the scope of the present disclosure will be apparent.

Claims

1. Use of a compound of Formula Ic or a pharmaceutically acceptable salt thereof in the preparation of a composition for determining whether a patient suffers from a neurological disease or disorder by detecting an ex vivo positive signal generated by the presence of phosphorylated tau protein in the retina of the patient's eye, wherein the composition is used to contact the phosphorylated tau protein with the compound of Formula Ic or a pharmaceutically acceptable salt thereof: in EDG Ar is EWG is -CN; R 84 is hydrogen; X is C=O; Y is NH; and WSG is: i) or ii) Where n is an integer from 1 to 20 and R 81 is hydrogen, unsubstituted C1-C 10 Alkyl, unsubstituted C1-C 10 Alkenyl, or unsubstituted C1-C 10 Alkynyl.

2. The use according to claim 1, wherein the contacting is performed in vivo.

3. The use according to claim 1, wherein the contacting causes emission of a detectable signal when activated by light. The method according to claim 3 , wherein the signal is a fluorescent signal.

5. Use according to any preceding claim, wherein the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE).

6. The use according to claim 1, wherein the neurological disease or disorder is selected from age-related diseases or disorders, genetic diseases or disorders, injury-related diseases or disorders, and psychiatric diseases or disorders.

7. The use according to claim 6, wherein the age-related disease or condition is selected from Parkinson's dementia, vascular dementia and amyotrophic lateral sclerosis, wherein the genetic disease or condition is Down syndrome, wherein the injury-related disease or condition is selected from traumatic brain injury and chronic traumatic encephalopathy, and wherein the psychiatric disease or condition is selected from schizophrenia and depression.

8. The method of claim 1, wherein the phosphorylated tau protein comprises at least three moles of phosphate per mole of protein.

9. The method according to claim 1, wherein the phosphorylated tau protein is triple-repeat tau, quadruple-repeat tau or a combination thereof.

10. Use of a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for preparing a patient for diagnosis of a neurological disease or condition, wherein the composition is for administering the compound of Formula Ic, or a pharmaceutically acceptable salt thereof, to the patient and for detecting binding of the compound or a pharmaceutically acceptable salt thereof to phosphorylated tau protein, and wherein the compound of Formula Ic, or a pharmaceutically acceptable salt thereof, is administered for delivery to the retina of the patient's eye: in EDG Ar is EWG is -CN; R 84 is hydrogen; X is C=O; Y is NH; and WSG is: i) ii) Where n is an integer from 1 to 20 and R 81 is hydrogen, unsubstituted C1-C 10 Alkyl, unsubstituted C1-C 10 Alkenyl, or unsubstituted C1-C 10 Alkynyl.

11. The use according to claim 10, wherein the binding results in emission of a detectable signal when activated by light.

12. The use according to claim 11, wherein the signal is a fluorescent or infrared signal.

13. The use according to claim 10, wherein the administration is intravenous administration.

14. The use according to claim 10, wherein the administration is localized to the retina of the eye.

15. The use according to claim 10, wherein the administration is topical administration.

16. The use according to any one of claims 10 to 15, wherein the neurological disease or disorder is Alzheimer's disease or chronic traumatic encephalopathy (CTE).

17. The use according to claim 10, wherein the neurological disease or disorder is selected from age-related diseases or disorders, genetic diseases or disorders, injury-related diseases or disorders, and psychiatric diseases or disorders.

18. The use according to claim 17, wherein the age-related disease or condition is selected from Parkinson's dementia, vascular dementia and amyotrophic lateral sclerosis, wherein the genetic disease or condition is Down syndrome, wherein the injury-related disease or condition is selected from traumatic brain injury and chronic traumatic encephalopathy, and wherein the psychiatric disease or condition is selected from schizophrenia and depression.

19. The method of claim 10, wherein the phosphorylated tau protein comprises at least three moles of phosphate per mole of protein.

20. The use according to claim 10, wherein the phosphorylated tau protein is triple-repeat tau, quadruple-repeat tau, or a combination thereof.

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