Neurodegenerative modulators

Abstract

This disclosure provides, for example, benzo[c][1,2,5]thiadiazolyl compounds and methods using these compounds for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. This disclosure provides, 11 C, 18 F, or 123 / 125 The invention also provides methods using benzo[c][1,2,5]thiadiazolyl compounds radiolabeled with radioisotopes such as I, as well as radiolabeled compounds for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents for diagnosing and / or monitoring the treatment of neurodegenerative disorders.

Description

[Technical Field]

[0001] Claim of priority This application claims the benefits of U.S. Provisional Application No. 63 / 527,516, filed on 18 July 2023. The entire foregoing is incorporated herein by reference.

[0002] The present invention relates to chemical compounds, particularly benzo[c][1,2,5]thiadiazolyl compounds, which are binders having high affinity for α-synuclein fibrils in brain tissue (e.g., neurons, glial cells, and extracellular space), as well as for amyloid plaques and / or tau tangles. These compounds are useful for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. 11 C, 18 F, or 123 / 125 When labeled with radioactive isotopes such as I, the compound is also a useful positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agent, for example, as a diagnostic tool for the diagnosis and / or monitoring of neurodegenerative disorders. [Background technology]

[0003] There are numerous deadly diseases that affect the current human population. Neurodegenerative diseases, for example, affect significant segments of the population, particularly the elderly. As one example, Parkinson's disease ("PD"), a synucleinopathy affecting movement, affects more than 10 million people worldwide, with an estimated overall annual economic burden exceeding $52 billion. As another example, Alzheimer's disease ("AD"), a beta-amyloidopathy affecting approximately 44 million people worldwide, is the sixth leading cause of death, with an estimated socioeconomic burden exceeding $200 billion. In yet another example, Pick's disease, a rare tauopathy characterized by a range of progressive neurological symptoms, affects 1 in 250,000 individuals, with an estimated annual treatment cost per patient of approximately $100,000. In short, neurodegenerative diseases place a substantial burden on patients, their families, healthcare systems, and society as a whole. Due to the global aging population, neurodegenerative disorders pose an increasing threat to public health. [Overview of the Initiative]

[0004] This disclosure is based at least in part on the recognition that benzo[c][1,2,5]thiadiazolyl compounds bind to α-synuclein protein with high affinity. Furthermore, the compounds are relatively selective to α-synuclei fibrils rather than to amyloid plaques or tau tangles located in the brain tissue of individuals affected by neurodegeneration. In one example, benzo[c][1,2,5]thiadiazolyl compounds are approximately 30 × to approximately 50 × more selective to α-synuclei fibrils compared to β-amyloid plaques. Moreover, benzo[c][1,2,5]thiadiazolyl compounds can cross the blood-brain barrier, selectively and substantially accumulate in brain tissue (and not any other tissue in the subject) upon administration, exert their therapeutic effect, and can be rapidly eliminated from the subject's plasma. Advantageously, the specific affinity of the benzo[c][1,2,5]thiadiazolyl compounds in this claim to protein aggregates involved in the pathogenesis of neurodegenerative disorders allows these compounds to be used as brain imaging agents when the compounds are labeled with appropriate radioisotopes. 11 C or18 When labeled with F, the compound can be detected in the brain using PET, while 123 when labeled with I or 125 I, the compound can be detected in the brain using SPECT. The radiolabeled compound is a useful diagnostic tool that enables diagnosing neurodegenerative disorders, supporting the clinical development of potential therapies (e.g., screening drug candidate compounds for potential therapies), and monitoring the treatment of neurodegenerative disorders with existing drugs and treatments.

[0005] In one general aspect, the present disclosure provides a compound of formula (I):

[0006]

Chemical formula

[0007] In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In yet another general aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder as described herein, comprising administering a therapeutically effective amount of a compound of formula (I), or a therapeutically acceptable salt thereof, to a subject that needs it.

[0009] In yet another general aspect, the present disclosure provides a compound of formula (II):

[0010]

Chemical formula

[0011] In another general embodiment, the disclosure provides a pharmaceutical composition comprising a compound of formula (II), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In another general embodiment, the Disclosure provides a method for imaging the brain of a subject as described herein using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0013] In another general embodiment, the disclosure provides a method for diagnosing neurodegenerative diseases in subjects as described herein, using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0014] In another general embodiment, the disclosure provides a method for monitoring the treatment of neurodegenerative diseases in subjects as described herein, using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0015] Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs. Methods and materials are described herein for use in this application; other suitable methods and materials known in the art may also be used. Materials, methods and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references described herein are incorporated by reference in their entirety. In case of any inconsistency, this specification shall prevail, including definitions.

[0016] Other features and advantages of this application are evident from the following detailed description and figures, as well as from the claims. [Brief explanation of the drawing]

[0017] [Figure 1-1] Figure 1A shows the results of a radioligand binding assay for 3H-SIL26. [Figure 1-2] Figure 1B shows the results of a radioactive ligand binding assay to β-amyloid protein for compound SY-01. [Figure 1-3] Figure 1C shows the results of a radioligand binding assay to tau protein for compound SY-01. [Figure 1-4] Figure 1D shows the results of a radioligand binding assay to α-synuclein protein for compound SY-01. [Figure 2] This figure includes the results of cell binding studies for SY-01. [Figure 3] This figure includes images showing autoradiography studies of human postmortem tissue for 11C-SY-01. [Modes for carrying out the invention]

[0018] In neuropathology, neurodegeneration is often characterized by the accumulation of insoluble protein aggregates such as α-synuclein fibrils, amyloid-β plaques, and tau tangles in brain cells and intracellular spaces, as well as by marked neuroinflammation. Together, these conditions lead to a reduction in brain volume and brain cell number, neuronal degeneration, microglial dysfunction, and the development of a variety of neurodegenerative disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysplasia (PAF), Alzheimer's disease (AD), frontotemporal lobar degeneration (FTD), Huntington's disease (HD), Pick's disease, and dementia, which are specifically associated with any of the previously described disorders. Without being bound by any theory, in one general embodiment, this disclosure provides compounds that selectively bind to protein aggregates involved in neuropathology and neurodegeneration. Therefore, the compounds contribute to the improvement of neuronal loss and are thus advantageously useful in treating underlying neurological disorders (e.g., PD, MSA, PAF, AD, HD, or Pick's disease). Specific embodiments of therapeutic compounds (e.g., compounds of formula I) and illustrative embodiments of diseases treatable by these compounds (e.g., synucleinopathy) are described herein. Furthermore, the diagnosis of neurodegenerative states in clinics remains a persistent challenge due to the limitations of current neuropsychological testing and neuroimaging. Imaging pathological protein aggregates in the brain via PET or SPECT provides a useful way to both diagnose neurodegenerative processes and evaluate the pharmacological performance of drug treatments. In a general embodiment, without being constrained by any theory, PET or SPECT-imaging radioisotopes ( 11 C, 18 F, 123 I, or 125When a compound's chemical structure includes a compound such as formula I, the compound is useful as a radiotracer (imaging agent) for diagnosing or monitoring various neurodegenerative conditions. Specific embodiments of radiotracer compounds (e.g., compounds of formula II) and illustrative embodiments of imaging methods in which the radiotracer compounds of this disclosure are advantageously useful are described herein.

[0019] therapeutic compounds In one general embodiment, this disclosure relates to formula (I):

[0020] [ka] Compounds of or pharmaceutically acceptable salts thereof [wherein, X 1 It is selected from S and O; R 1 , R 2 and R 3 These are Halo, OH, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkalk, C(=O)OH, C(=O)O(C 1~3 Alkyl), C(=O)NH2, C(=O)NH(C 1~3 Alkyl), C(=O)N(C 1~3 Alkyl)2, amino, C 1~3 Alkylamino and di(C) 1~3 Each alkyl)amino is independently selected; R 4 H, C 1~3 Alkyl, and C 1~3 Selected from haloalkyl; L 1 It does not exist; or L 1 C 1~6 Alkylene and C 3~6 Selected from cycloalkylenes, the C 1~6 Alkylenes are selectively suspended by one or two groups independently selected from C(=O), S(=O)2, O, and NH; Ring A does not exist, or ring A is given by equation (i):

[0021] [ka] (In the formula, a is X 2 It shows the attachment point; b is L 1 It shows the attachment point; Ring C is C 3~6 Selected from cycloalkyl and 4- to 7-membered heterocycloalkyl groups, each of which is a halo, OH, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkalk, C(=O)OH, C(=O)O(C 1~3 Alkyl), C(=O)NH2, C(=O)NH(C 1~3 Alkyl), C(=O)N(C 1~3 Alkyl)2, amino, C 1~3 Alkylamino and di(C) 1~3 It is optionally substituted with one, two, or three substituents independently selected from alkyl)amino; R 5 and R 6 H, C 1~3 Alkyl, and C 1~3 (Each haloalkyl is independently selected.) This is part of it; X 2 It is selected from C(=O) and S(=O)²; Ring B is C 6~10 Selected from aryls and 5- to 14-membered heteroaryls, each of which is a halo, OH, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(C 1~3 Alkyl), C(=O)NH2, C(=O)NH(C1~3 (alkyl), C(=O)N(C 1~3 (alkyl)2, amino, C 1~3 alkylamino, and di(C 1~3 alkyl)amino, and is optionally substituted with one, two or three substituents independently selected from

[0022] In some embodiments, L 1 is absent. In some embodiments, ring A is absent.

[0023] In some embodiments, the compound of formula (I) has the formula

[0024] [Chemical formula] or is a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, L 1 is C 1~6 alkylene and C 3~6 cycloalkylene, and the C 1~6 alkylene is optionally interrupted by one or two groups independently selected from C(=O), S(=O)2, O, and NH. In some embodiments, ring A is a moiety of formula (i).

[0026] In some embodiments, ring C is substituted with halo, OH, CN, NO2, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, or C 1~3 haloalkoxy. In some embodiments, ring C is substituted with halo, OH, CN, NO2, C 1~3 alkyl, and C 1~3 haloalkyl.

[0027] In some embodiments, the moiety of formula (i) is the following formula:

[0028] [ka] It has one of the following:

[0029] In some embodiments, the compound of formula (I) is:

[0030] [ka] It contains or is a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of formula (I) is:

[0032] [ka] It contains or is a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound of formula (I) is:

[0034] [ka] It contains or is a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound of formula (I) is:

[0036] [ka] It contains or is a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, R 5 H is R 6 C 1~3 Alkyl and C 1~3 Selected from haloalkyls. In some embodiments, R 6 is C 1~3 It is alkyl.

[0038] In some embodiments, L 1 is C alkylene optionally interrupted by O or NH 1~6 In some embodiments, L 1 is C 1~6 alkylene (e.g., ethylene or propylene). In some embodiments, L 1 is C alkylene interrupted by O 1~6 In some embodiments, L 1- is C 1~3 alkylene - O - C 1~3 alkylene.

[0039] In some embodiments, L 1 is C 3~6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene).

[0040] In some embodiments, the compound of formula (I) has the formula:

[0041]

Chemical formula

[0042] In some embodiments, R 4 is H. In some embodiments, R 4 is C 1-3 alkyl.

[0043] In some embodiments, R 1 , R 2 and R 3 are each independently selected from halo, CN, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, C 1~3 haloalkoxy, and C(=O)NH2.

[0044] In some embodiments, X1 is O. In some embodiments, X 1 S is.

[0045] In some embodiments, X 2 is C (=O). In some embodiments, X 2 This is S(=O)2.

[0046] In some embodiments, ring B is halo, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(C 1~3 C(=O)NH2 is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0047] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0048] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with alkyl or C(=O)NH2. 6~10 It is Ariel.

[0049] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0050] In some embodiments, ring B is halo, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(C 1~3 It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2.

[0051] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2.

[0052] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl substituted with alkyl or C(=O)NH2 as an optional substitution.

[0053] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with two substituents independently selected from alkyl and C(=O)NH2.

[0054] In some embodiments, the compound is the following compound:

[0055] [ka]

[0056] [ka]

[0057] [ka] Selected from one of the following or a pharmaceutically acceptable salt thereof.

[0058] Radioactive tracer compounds In some embodiments, the compound of formula (I) as described above is 11 C, 18 F, 123 I, 125 I, and 131 It comprises at least one radioactive isotope selected from I. Thus, in one general embodiment, this disclosure relates to formula (II):

[0059] [ka] Compounds of or pharmaceutically acceptable salts thereof (wherein X 1 Group, R 1 Group, R 2 Group, R 3 Group, R 4 Base, L 1 group, ring A, X 2 The group and ring B are as described herein for formula (I), and X 1 , R 1, R 2 , R 3 , R 4 , L 1 , Ring A, X 2 and at least one of ring B is 11 C, 18 F, 123 I, 125 I, and 131 It provides a radioactive isotope selected from I.

[0060] In some embodiments, the compound of formula (II) is 11 Contains C. In some embodiments, the compound of formula (II) is 18 Contains F. In some embodiments, the compound of formula (II) is 123 It includes I. In some embodiments, the compound of formula (II) is 125 It includes I. In some embodiments, the compound of formula (II) is 131 It includes I. In some embodiments, the compound of formula (II) is 18 F, 123 I, 125 I, 131 I, 11 CN Sofa 11 C(=O)NH2, 11 CH3-, 11 CH3O-, 18 FCH2CH2-, 18 FCH2CH2O-, and 18 Contains a group selected from FCH2CH2CH2O-

[0061] In some embodiments, R 4 teeth, 11 CH3-, and 18 Selected from FCH2CH2-. In some embodiments, ring B is at least one 18 It is replaced with F.

[0062] In some embodiments, the compound of formula (II) is the following compound:

[0063] [ka] Selected from one of the following or a pharmaceutically acceptable salt thereof.

[0064] Pharmaceutically acceptable salts In some embodiments, a salt of any one of the compounds of the Disclosure (e.g., compounds of formula I or formula II) is formed between an amino functional group of the compound, or between a base and an acidic group, such as a carboxyl functional group, or between an acidic and a basic group of the compound. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0065] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of compounds include inorganic acids, such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids, such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. These pharmaceutically acceptable salts therefore include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexin-1,6-dioate. Examples of salts include ethates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and in particular, those formed with organic acids such as maleic acid.

[0066] In some embodiments, bases commonly used to form pharmaceutically acceptable salts of compounds include alkali metal hydroxides, including sodium, potassium, and lithium; alkaline earth metal hydroxides, such as calcium and magnesium; other metals, such as aluminum and zinc hydroxides; ammonia; organic amines, such as unsubstituted or hydroxyl-substituted mono, di, or trialkylamines, dicyclohexylamines; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono, bis, or tris(2-OH-(C1~C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids, such as arginine and lysine.

[0067] Compositions, formulations, and routes of administration This application also provides a pharmaceutical composition comprising an effective amount of a compound of the disclosure disclosed herein (e.g., formula (I) or formula (II)) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one of the additional therapeutic agents described herein. A carrier(s) is “acceptable” in the sense that it is compatible with the other components of the formulation and, in the case of a pharmaceutically acceptable carrier, is not harmful to the recipient in the amount used in the pharmaceutical.

[0068] Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, monopotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0069] The composition or dosage form may contain any one of the compounds and therapeutic agents described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of a suitable pharmaceutically acceptable excipient. The composition to be conceived may contain any one of the compounds and therapeutic agents provided herein in an amount ranging from 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, with the remainder consisting of any pharmaceutically acceptable excipient described herein or any combination thereof.

[0070] Route of administration and dosage form The pharmaceutical compositions of this application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, sinus, tracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, bronchial, sacral, intracerebral, cisterna magna, coronary, intradermal, intraductal, duodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, lymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, paranasal sinus, intramedullary, synovial, testicular, subarachnoid, intraductal, intratumoral, intrauterine, intravascular, intravenous, transnasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, transtracheal, ureter, urethra, and vaginal.

[0071] The compositions and formulations described herein may, conveniently, be present in unit dosage forms, e.g., tablets, sustained-release capsules, and liposomes, and may be prepared by any method well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparation methods involve the step of associating components, such as carriers constituting one or more minor components, with the molecules to be administered. Generally, compositions are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, liposomes, or a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0072] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is administered orally. Compositions of this application suitable for oral administration may be expressed as individual units such as capsules, sachets, granules or tablets, each containing a predetermined amount (e.g., an effective amount) of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; as oil-in-water liquid emulsions; as water-in-oil liquid emulsions; filled in liposomes; or as boluses, etc. Soft gelatin capsules may be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, as well as silicic acid and starch. Other acceptable excipients include: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption accelerators, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, lactose and dried corn starch are useful diluents. When an aqueous suspension is administered orally, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners and / or flavorings and / or colorings may be added if desired.Suitable compositions for oral administration include lozenges containing flavoring agents, usually sucrose and acacia or tragacanth; and aromatic tablets containing active ingredients in inert agents, such as gelatin and glycerin, or sucrose and acacia.

[0073] Suitable compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions or infusions that may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the intended recipient's blood; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, e.g., water for injection, physiological saline (e.g., 0.9% physiological saline solution), or 5% dextrose solution, immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injection solutions may be, for example, in the form of sterile, injectable aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may be, for example, a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils have traditionally been used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic mono or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable preparations, particularly natural pharmaceutically acceptable oils such as olive oil or castor oil in polyoxyethylated versions. Solutions or suspensions of these oils may also contain long-chain alcohol diluents or dispersants.

[0074] The pharmaceutical compositions of this application can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of this application with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the active components. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0075] The pharmaceutical compositions of this application can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, carbon fluoride, and / or other solubilizers or dispersants known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration can be found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0076] The topical compositions of this disclosure may be prepared and used in the form of aerosol sprays, creams, emulsions, solids, liquids, dispersions, foams, oils, gels, hydrogels, lotions, mousses, ointments, powders, patches, pomades, solutions, pump sprays, sticks, towels, soaps, or other forms commonly used in the art for topical administration, as well as / or cosmetic and topical formulations. The topical compositions may be in emulsion form. Topical administration of the pharmaceutical compositions of this application is particularly useful when the desired treatment involves a region or organ that is easily accessible by topical application. In some embodiments, the topical composition comprises one of the compounds and therapeutic agents disclosed herein, as well as one or more additional components, carriers, excipients, or diluents in combination, including but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (humidifiers), emulsifiers, film-forming / retaining agents, fragrances, leave-on exfoliants, formulating agents, preservatives, scrubs, silicones, skin-identifying / repairing agents, lubricants, sunscreens, surfactants / detergents, cleansing agents, penetration enhancers, and thickeners.

[0077] Dosage and regimen In the pharmaceutical compositions of this application, the compounds of the Disclosure (e.g., compounds of formula (I) or formula (II)) are present in an effective amount. For example, the compound of formula (I) may be present in a therapeutically effective amount. In another example, the compound of formula (II) may be present in an amount effective for imaging the organ and / or tissue of interest, for example, for brain imaging as described herein. The effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age and overall health status of the subject, the use of excipients, the possibility of co-use with other compounds, such as therapeutic treatments, other imaging agents, metabolic inhibitors, etc., and the judgment of the treating physician.

[0078] In some embodiments, the effective amount of the compound (e.g., formula (I) or formula (II)) is, for example, about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg) The range may be (kg; approximately 0.01 mg / kg to approximately 0.5 mg / kg; approximately 0.01 mg / kg to approximately 0.1 mg / kg; approximately 0.1 mg / kg to approximately 200 mg / kg; approximately 0.1 mg / kg to approximately 150 mg / kg; approximately 0.1 mg / kg to approximately 100 mg / kg; approximately 0.1 mg / kg to approximately 50 mg / kg; approximately 0.1 mg / kg to approximately 10 mg / kg; approximately 0.1 mg / kg to approximately 5 mg / kg; approximately 0.1 mg / kg to approximately 2 mg / kg; approximately 0.1 mg / kg to approximately 1 mg / kg; or approximately 0.1 mg / kg to approximately 0.5 mg / kg). In some embodiments, the effective amount of the compound of formula (I) or formula (II) is approximately 0.1 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, or approximately 5 mg / kg.

[0079] The aforementioned dosage may be administered daily (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, three times daily) or not daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month), as determined by the treating or diagnosing physician (e.g., the physician responsible for administering the imaging agent).

[0080] kit The present invention also includes a kit comprising one or more containers containing a pharmaceutical composition comprising, for example, a therapeutically effective amount of the compound of formula (I) of the present disclosure or an effective amount of the compound of formula (II) of the present disclosure for imaging a target brain, which is useful in the treatment of disorders, diseases and conditions referred to herein. Such kits may further, if desired, include one or more of various conventional pharmaceutical kit components, e.g., containers having one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions indicating the amount of component to be administered, guidelines for administration, and / or guidelines for mixing the components may be included in the kit, either as inserts or as labels. The kit may optionally include additional therapeutic agents as described herein.

[0081] Treatment method In some embodiments, the Disclosure provides a method for modulating α-synuclein, β-amyloid, and / or tau protein in cells, comprising contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. In some embodiments, modulation includes binding, inhibition, or activation, or any combination thereof. In some embodiments, contact occurs in vitro, in vivo, or ex vivo. In some embodiments, the cells are brain cells (e.g., neurons or glial cells). In some embodiments, the modulation is selective with respect to α-synuclein as opposed to β-amyloid and / or tau protein (e.g., the modulation is more selective with respect to 10×, 20×, 50×, 100×, or 1000× with respect to α-synuclein). In some embodiments, the Disclosure provides a method for modulating α-synuclein, β-amyloid, and / or tau protein in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject.

[0082] In some embodiments, compounds of formula (I) and related salts, as well as compositions of the present disclosure, are useful in treating neurodegenerative diseases or disorders affecting the motor system.

[0083] Numerous scientific publications provide reliable evidence of a link between multisystem neurodegeneration and the progressive aggregation of insoluble fibrillary synuclein (e.g., α-synuclein or αSyn) in neurons and glial cells. See, for example, Galvin et al., Arch Neurol., 2001, 58, 2, 186-190 and Sekiya et al., Mol Neurodegeneration 16, 83, 2021, Wong Y et al., Nat. Med., 2017, 23 (2), 1-13; Lashuel H et al., Nat. Rev. Neurosct., 2013, 14, 1, 38-48. Therefore, without being bound by any particular theory or speculation, as used herein, the term “synucleinopathy” refers to a group of neurodegenerative disorders in which the aggregation of insoluble synuclein (e.g., α-Syn) protein fibrils in various CNS and / or peripheral nervous system (PNS) cells is involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating synucleinopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with synucleinopathy), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to the subject. Appropriate examples of synucleinopathy include other neurodegenerative disorders in which synuclein is at least partially involved in the pathogenesis, such as Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysregulation (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), axonal dystrophy, Shy-Drager syndrome, Alzheimer's disease, Haller-Holden-Spats syndrome, and lysosomal storage disorders (e.g., Gaucher disease).

[0084] Numerous scientific publications describe neurodegeneration in the brain and amyloid peptides (e.g., Aβ) in amyloid peptide plaques. 40 Peptides and / or Aβ 42This provides reliable evidence of a relationship between β-amyloid misfolding of peptides and other substances, and the associated accumulation. See, for example, Spires-Jones et al., Acta Neuropathologica, 134, 187-205, 2017; Selkoe D et al, J EMBO Mol. Med., 2016, 8, 6, 595-608; and Selkoe D et al, Science, 2002, 19; 297, 5580, 353-6. In one example, β-amyloid is used as a diagnostic biomarker for Alzheimer's disease (see, e.g., Nakamura et al., Nature, 2018, 554, 7691, 249-254, and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804), as well as its primary target for therapeutic purposes (see, e.g., Swanson C et al., Alzheimer's Res. Ther., 2021, 13, 1, 80). Thus, without being bound by any particular theory or speculation, the terms “amyloidopathy” or “β-amyloidopathy” as used herein refer to a group of neurodegenerative disorders in which the aggregation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain is involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating amyloidopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with amyloidopathy), comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject. Suitable examples of amyloidopathy include progeria, cerebral amyloid angiopathy, Alzheimer's disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders in which the formation of amyloid plaques is at least partially involved in the pathogenesis of the disease.

[0085] Numerous scientific publications provide reliable evidence of a relationship between neurodegeneration in the brain (e.g., neurons, glial cells, and extracellular space) and tau protein misfolding and subsequent formation of neurofibrillary or glial fibrillary condensates. See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb Clin Neurol, 2017, 145, 355-368; Guo J et al., Cell, 2013, 154, 1, 103-17; Giasson et al., Science, 2003, 300, 5619, 636-40; and Bassil F et al., Neuron, 2020, 105, 2, 260-275. Accordingly, without being bound by any particular theory or speculation, as used herein, the term “tauopathy” refers to a group of neurodegenerative disorders in which tau-positive inclusions in the brain are involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating tauopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with tauopathy), comprising administering to the subject a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. Suitable examples of tauopathy include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic granule disease, primary age-related tauopathy, neurofibrillary sparse dementia, chronic traumatic brain injury (CTE), age-related tauastropathy, Richardson syndrome, cerebellar ataxia, globulogliary tauopathy, and argyrophilic granule disease, among other neurodegenerative disorders in which tau protein misfolding is at least partially involved in the pathogenesis.

[0086] In some embodiments, the disclosure provides methods for treating neurodegenerative disorders in which any combination of synuclein, amyloid, and / or tau peptides or proteins is involved in the disease pathogenesis. See, for example, Irwin D et al., Nat. Rev, Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol., Appl. Neurobiol., 2016, 42, 5, 436-50.

[0087] Without being bound by any particular theory or speculation, misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins appears to cause, induce, increase, and / or enhance neuroinflammation, and this process is thought to further contribute to the progression of neurodegeneration and associated total symptoms. See, for example, Gate D et al., Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al, Elife, 2020, 9, e54083. Accordingly, in some embodiments, the present disclosure provides a method for treating a neurodegenerative disorder (e.g., one in which inflammation is involved in the pathogenesis of the disease) in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with a neurodegenerative disorder), the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. In some embodiments, neurodegenerative disorders are selected from motor neuron disease (MND), prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Huntington's disease (HD), and dementia associated with HD, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger disease, dementia, multiple sclerosis ("MS"), hippocampal sclerosis, Gaucher disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinocerebellar ataxia, impaired consciousness, hearing and balance disorders, CNS hypoxia, cerebral aging, brain injury (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar degeneration (SCA), and spinal muscular atrophy (SMA). In some embodiments, disorders treatable by the compounds of this disclosure are selected from accessory neuropathy, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Vilaret syndrome, Charcot-Marie-Tooth disease, diabetic neuropathy, neuropathy, and Horner syndrome.

[0088] Combination treatment The compounds of this disclosure can be used in combination with at least one pharmacotherapy or treatment useful for treating or alleviating symptoms of neurodegenerative disorders, such as Parkinson's disease (PD). Suitable examples of such pharmacotherapy include levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, istradefylline, donepezil, rivastigmine, galantamine, memantine, midodrine, fludrocortisone, physostigmine, droxidopa, botulinum toxin, or pharmaceutically acceptable salts thereof. The compounds can also be used in combination with deep brain stimulation (DBS) neurosurgery. The compounds of this disclosure may be administered to a patient simultaneously with (in the same or different dosage forms) or consecutively with an additional therapeutic agent (the additional therapeutic agent may be administered before or after the administration of the compounds of this disclosure).

[0089] Image creation method In one general embodiment, this application relates to compounds of formula (II) useful in imaging techniques for various diseases and conditions described herein, for diagnosing them, and for monitoring their treatment. Such compounds are labeled in such a way that each compound contains at least one radioisotope (e.g., C, F, or I radioisotopes as described herein).

[0090] Imaging techniques such as PET and SPECT have become important clinical diagnostic and research modalities, as well as valuable scientific technologies in drug discovery and development. PET is a complete translation technique that provides picomolar sensitivity and requires specific probes radiolabeled with typically short-lived positron-emitting radionuclides. (e.g., carbon-11 (radioactive half-life (t)) 1 / 2 )=20.4 min) and fluorine 18(t 1 / 218 (109.7 min) is the most commonly used radionuclide in PET imaging. PET has provided the ability to measure biological processes at the molecular and metabolic levels in vivo by detecting photons formed as a result of the annihilation of emitted positrons. SPECT is a nuclear imaging scan that requires a radioactive tracer. The tracer allows doctors to see how blood flows through tissues and organs. Radioactive isotopes typically used in SPECT are iodine-123, technetium-99m, xenon-133, thallium-201, and fluorine-18. These radioactive forms of naturally occurring elements can pass through the body and be detected by a suitable scanner.

[0091] As a non-invasive medical and molecular imaging technique and a powerful tool in neurological research, PET offers the possibility of visualizing and analyzing target proteins and / or protein aggregates under physiological and pathophysiological conditions. PET has often been used to detect disease-related biochemical changes before disease-related anatomical changes can be found using standard medical imaging modalities.

[0092] In some embodiments, the Disclosure provides a method for identifying and / or quantifying α-synuclein fibrils, amyloid plaques and / or tau tangles in the brain of a subject. This can be achieved, for example, by imaging the brain (e.g., by the binding affinity of the compound of formula (II) to the proteins and protein aggregates described earlier). Imaging the brain may include imaging the midbrain, brainstem, thalamus, striatum, cerebellum and / or cortex. A method for imaging the brain may include (i) administering an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to a subject; (ii) waiting for a sufficient amount of time (e.g., 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, or 5 hours) to allow the compound to accumulate in the brain to be imaged; and (iii) imaging the brain using an imaging technique. In one example, within the compound of formula (II) 18F and / or 11 C is a positron-emitting radioactive isotope, and suitable imaging techniques include positron emission tomography (PET) and its modification. Therefore, imaging techniques can be selected from positron emission tomography (PET) imaging, positron emission tomography using computed tomography (PET / CT) imaging, and positron emission tomography using magnetic resonance imaging (PET / MRI). In another example, in the compound of formula (II) 123 / 125 / 131 I is a gamma-emitting tracer, and suitable imaging techniques include single-photon emission computed tomography (SPECT) and its various correction methods.

[0093] In some embodiments, the Disclosure provides a method for diagnosing (or early detection) a neurodegenerative disorder in a subject (e.g., a neurodegenerative disorder involving α-synuclein fibrils, amyloid plaques and / or tau tangles, e.g., any of the neurodegenerative disorders described herein), comprising imaging the brain of the subject according to any of the imaging methods described herein. In some embodiments, the method for diagnosing a subject comprises (i) administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject; (ii) waiting for a sufficient amount of time to allow the compound to accumulate in the brain to be imaged (e.g., 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); and (iii) imaging the brain using an imaging technique. In some embodiments, the method comprises observing a signal in step iii) that may be attributable to a radioisotope in the compound of formula (II) indicating a neurodegenerative disorder in the subject (e.g., observing a signal in the image obtained in step iii). The method may also include comparing images obtained from a subject exhibiting symptoms of a disease or condition with images obtained from a healthy subject. In one example, an excess of alpha-synuclein fibrils, amyloid plaques, and / or tau tangles in the subject's brain may indicate a neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, Pick's disease, dementia, or a related condition.

[0094] In some embodiments, the radioactive tracer of formula (II) in this claim is useful for studying molecular mechanisms involved in neurodegenerative diseases. For example, the compound can be used to study molecular mechanisms leading to α-synuclei fibril formation, amyloid plaque formation, and / or tautangle formation. For example, the compound of formula (II) can be administered co-administered with modulators of molecular mechanisms suspected to be involved in α-synuclei fibril formation, amyloid plaque formation, and / or tautangle formation, and the absence or presence of these protein aggregates can be detected using imaging techniques as discussed herein. In some embodiments, this disclosure provides a method to support the clinical development of potential therapeutic agents that either prevent or inhibit the formation of α-synuclei fibril, amyloid plaque formation, and / or tautangle formation, or lead to the dissolution / degradation of these protein aggregates. In vivo imaging of pathological protein aggregates can help answer many critical questions in the drug discovery and development process, such as whether a potential drug reaches its molecular target, the relationship between therapeutic dose and desired outcome, the correlation between therapeutic effect and plasma drug levels, and the duration of time a drug remains at its target, as well as similar information. In some embodiments, the disclosure provides a method for screening for potential therapeutics by detecting, for example, the competitive binding of a drug candidate and a compound of formula (II) to α-synuclein fibrils, amyloid plaques and / or tau tangles in the brain. In one example, a compound of formula (II) can be administered first, and a first brain image can be obtained with a signal that may be attributable to the radioisotope in the compound of formula (II), followed by administration of a test compound and a second brain image can be obtained. The absence of a signal that may be attributable to the radioisotope of the compound of formula (II) in the second brain image may indicate a greater affinity of the test compound for α-synuclein fibrils, amyloid plaques, and / or tau tangles in the brain, as well as its potential therapeutic efficacy in treating associated neurodegenerative disorders.

[0095] In some embodiments, the Disclosure provides a method for monitoring the treatment of a neurodegenerative disease in a subject (e.g., a neurodegenerative disease in a condition involving α-synuclein fibrils, amyloid plaques and / or tau tangles, e.g., any of the diseases described herein), comprising: (i) administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject; (ii) waiting for a sufficient amount of time (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours) to allow the compound of formula (II) to accumulate in the brain of the subject; (iii) imaging the brain of the subject using an imaging technique; and (iv) administering the therapeutic agent to the subject in an effective amount for treating the neurodegenerative disorder. In one example, aducanumab, lecanemab, donepezil, rivastigmine, galantamine, memantine, suvorexant, or experimental drug substances for treating AD or DLB, respectively, may be administered to subjects receiving treatment for AD or DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, alpha-synuclein, or LRRK2 (dardaline) antisense oligonucleotides (e.g., ION 859 and ION 464 by Biogen or ASO), or experimental drug substances for treating PD or DLB, respectively, may be administered to subjects receiving treatment for PD or DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, fludrocortisone, midodrine, physostigmine, droxidopa, or experimental drug substances for treating MSA may be administered to subjects receiving treatment for MSA.In some embodiments, the method further includes, after (iv), step (v) administering an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject; (vi) waiting for a sufficient amount of time (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours) to allow the compound of formula (II) to accumulate in the subject's brain; (vii) imaging the subject's brain using an imaging technique; and (viii) comparing the image from step (iii) with the image from step (vii). In one example, observing a reduction in the signal that may be attributable to the radioisotope of the compound of formula (II) in step viiii) indicates the progress of treatment for a neurodegenerative disease. Suitable examples of diseases for which treatment can be monitored according to the method of the present disclosure include any of the diseases described herein. Some specific examples include Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic dysplasia (PAF). Other appropriate examples include Alzheimer's disease (AD), familial AD (FAD), frontotemporal dementia (FTD), Huntington's disease (HD), dementia associated with PD, AD, FAD, or HD, Pick's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic granule disease, dementia, chronic traumatic brain injury (CTE), age-related tauastropathies, Richardson syndrome, cerebellar ataxia, spheroclamic glial tauopathy, argyrophilic granule disease, motor neuron diseases (MND), and prion diseases.

[0096] definition As used herein, the term “about” means “approximately” (for example, approximately plus or minus 10% of the indicated value).

[0097] In various places in this specification, substituents of the compounds of the present invention are disclosed in groups or as a range. The present invention is specifically intended to include each of the members of such groups and ranges and any individual subcombinations. For example, "C 1~6The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0098] Various aryl rings, heteroaryl rings, cycloalkyl rings, and heterocycloalkyl rings are described in various places in this specification. Unless otherwise specified, these rings may be attached to the rest of the molecule with any ring member, where permitted by valence. For example, the terms “pyridine ring” or “pyridinyl” may refer to a pyridine-2-yl ring, a pyridine-3-yl ring, or a pyridine-4-yl ring.

[0099] Furthermore, for clarity, it is understood that certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity may also be provided separately or in any suitable sub-combination.

[0100] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that are aromatic (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

[0101] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a given part, where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0102] As used herein, the phrase "substituted by choice" means either unsubstituted or substituted. Substituents are selected independently, and substitutions may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. Substitutions at a given atom should be understood to be limited by their valence.

[0103] Furthermore, for clarity, it is understood that certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity may also be provided separately or in any suitable sub-combination.

[0104] Throughout the definition, "C n~m The term "C" indicates a range that includes the endpoints, where n and m are integers and represent the number of carbon atoms. For example, C 1~4 , C 1~6 These are some examples.

[0105] As used herein, "C" when used alone or in combination with other terms n~m The term "alkyl" refers to a saturated hydrocarbon group that may be linear or branched, having n to m carbon atoms. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl; and higher-order homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, alkyl groups contain one to six carbon atoms, one to four carbon atoms, one to three carbon atoms, or one to two carbon atoms.

[0106] As used herein, "C" when used alone or in combination with other termsn~m The term "alkylene" refers to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methylpropane-1,3-diyl. In some embodiments, the alkylene portion contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0107] As used herein, "C" when used alone or in combination with other terms n~m The term "haloalkyl" refers to an alkyl group having 2s+1 halogen atoms, which may be the same or different from one halogen atom, where "s" is the number of carbon atoms in the alkyl group, and where the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is simply fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0108] As used herein, the term “aryl,” used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (for example, having two, three, or four fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, and indenyl. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0109] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon including a cyclized alkyl group and / or alkenyl group. Cycloalkyl groups may include monocyclic or polycyclic groups (e.g., having two, three, or four fused rings) and spiro rings. The ring-forming carbon atoms of a cycloalkyl group may be optionally substituted with one or two independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Further included in the definition of cycloalkyl is a moiety having one or more aromatic rings condensed (i.e., generally bonded) to a cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing condensed aromatic rings may be attached via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. Cycloalkyl groups may have three, four, five, six, seven, eight, nine, or ten ring-forming carbon atoms (C 3~10 ) can have. In some embodiments, the cycloalkyl is C 3~10 It is a monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3~7 It is a monocyclic cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0110] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl portion may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl having one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl ring having five ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Illustrative five-membered heteroaryl rings include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl ring having six ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Illustrative six-membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0111] As used herein, “heterocycloalkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyls include monocyclic 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Examples of heterocycloalkyl groups include pyrrolidine-2-one, 1,3-isoxazolidine-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, and benzazepine. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally substituted with one or two independently selected oxo or sulfide groups (e.g., C(O), S(O), C(S), or S(O)2). Heterocycloalkyl groups can be attached via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain zero to three double bonds. In some embodiments, heterocycloalkyl groups contain zero to two double bonds. Further included in the definition of a heterocycloalkyl group is a moiety having one or more aromatic rings condensed (i.e., generally having bonds) to a cycloalkyl ring, such as benzo or thienyl derivatives like piperidine, morpholine, and azepine. Heterocycloalkyl groups containing condensed aromatic rings can be attached via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and one or more oxidation ring members.In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4- to 10-membered heterocycloalkyl having one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, or sulfur, and having one or more oxidation ring members.

[0112] In certain contexts, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valence does not exceed that of the atom. For example, an azetidine ring may be attached at any position on the ring, while a pyridine-3-yl ring is attached at position 3.

[0113] As used herein, "C" when used alone or in combination with other terms n~m The term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy and tert-butoxy). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0114] When used herein, "C n~m A "haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is simply fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0115] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0116] As used herein, the term "amino" refers to the group of formula -NH2.

[0117] When used herein, "C n~m The term "alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), and N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino).

[0118] When used herein, "Ji (C) n~m The term "-alkyl)amino" refers to a group of the formula -N(alkyl)2, where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0119] The term “compound,” as used herein, means all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structure. Compounds identified herein by name or structure as a particular tautomer form are intended to include other tautomer forms unless otherwise specified. Any atom not identified in a compound herein that is not specifically designated as a radioactive isotope exists in its natural isotopic abundance.

[0120] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inert starting materials are known in the art, such as by the division of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins, C=N double bonds, and N=N double bonds, may also be present in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers. In some embodiments, the compounds have a (R)-configuration. In some embodiments, the compounds have a (S)-configuration.

[0121] The compounds provided herein also include tautomer forms. Tautomer forms result from the exchange of adjacent double and single bonds along with the simultaneous transfer of protons. Tautomer forms include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomer forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0122] As used herein, the terms “individual,” “patient,” or “subject” are interchangeable and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0123] As used herein, the terms “effective dose” or “therapeutic dose” refer to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human being being explored by a researcher, veterinarian, physician, or other clinician.

[0124] As used herein, the terms “to treat” or “treatment” mean 1) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual experiencing or presenting the pathology or overall symptoms of a disease, condition or disorder (i.e., preventing further development of the pathology and / or overall symptoms), or 2) relieving a disease; for example, relieving a disease, condition or disorder in an individual experiencing or presenting the pathology or overall symptoms of a disease, condition or disorder (i.e., reversing the pathology and / or overall symptoms).

[0125] As used herein, the terms “preventing” or “preventing” a disease, condition, or disorder mean reducing the risk of the disease, condition, or disorder occurring in a subject or group of subjects (e.g., a subject or group of subjects who are susceptible to or prone to the disease, condition, or disorder). In some embodiments, preventing a disease, condition, or disorder means reducing the likelihood of acquiring the disease, condition, or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition, or disorder means completely or almost completely stopping the occurrence of the disease, condition, or disorder.

[0126] As used herein, the term “radioisotope” refers to an atom having an atomic mass or mass number different from that which is typically found in nature (i.e., spontaneously occurring).

[0127] As used herein, the term "isotopic enrichment coefficient" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0128] " 18 "F" refers to the radioactive isotope of fluorine that has 9 protons and 9 neutrons. "F" refers to the stable isotope of fluorine that has 9 protons and 10 neutrons (i.e., " 19 This refers to the F isotope. The compounds disclosed herein contain at least 3500 (each designated 18 52.5% of F atoms 18 (F built-in), at least 4000 (60%) 18 (F built-in), at least 4500 (67.5% 18 (F built-in), at least 5000 (75%) 18 F) at least 5500 (82.5% 18 (F built-in), at least 6000 (90%) 18 (F built-in), at least 6333.3 (95%) 18 (F built-in), at least 6466.7 (97%) 18 (F built-in), at least 6600 (99%) 18 F (integrated), or at least 6633.3 (99.5% 18 Each specification (built into F) 18 It has an isotope enrichment coefficient for the fluorine atom.

[0129] " 11 "C" refers to the radioactive isotope of carbon that has 6 protons and 5 neutrons. "C" refers to the stable isotope of carbon that has 6 protons and 6 neutrons (i.e., " 12 This refers to a 1C isotope. The compounds disclosed herein contain at least 3500 (each designated 11 52.5% of C atoms 11 (C built-in), at least 4000 (60%) 11(C built-in), at least 4500 (67.5% 11 (C built-in), at least 5000 (75%) 11 C) at least 5500 (82.5% 11 (C built-in), at least 6000 (90%) 11 (C built-in), at least 6333.3 (95%) 11 (C built-in), at least 6466.7 (97%) 11 (C built-in), at least 6600 (99% 11 C built-in), or at least 6633.3 (99.5% 11 Each specification (built into C) 11 It has an isotope enrichment coefficient for the C atom.

[0130] " 123 "I" refers to the radioactive isotope of iodine that has 53 protons and 70 neutrons. 125 "I" refers to the radioactive isotope of iodine that has 53 protons and 72 neutrons. 131 "I" refers to the radioactive isotope of iodine that has 53 protons and 78 neutrons. "I" can refer to any abundant stable isotope of iodine or a combination of stable non-radioactive isotopes (e.g., 127 The compound disclosed herein is at least 3500 (each designated 123 / 125 / 131 Each designation includes: 1 atom (52.5% inclusion), at least 4000 (60% inclusion), at least 4500 (67.5% inclusion), at least 5000 (75% inclusion), at least 5500 (82.5% inclusion), at least 6000 (90% inclusion), at least 6333.3 (95% inclusion), at least 6466.7 (97% inclusion), at least 6600 (99% inclusion), or at least 6633.3 (99.5% inclusion). 123 / 125 / 131 It has an isotope enrichment coefficient for the I atom. [Examples]

[0131] material and method All commercially available reagents were used without further purification unless otherwise specified. Analytical thin-layer chromatography (TLC) was performed using SilicaGelGF254 plates (Merck Millipore co., ltd, 0.2 mm thick). Compounds were analyzed using CombiFlash R f Purification was performed using 150 (Teledyne ISCO Co., Ltd). 1 H and 13 The C spectrum was recorded on a Bruker 500MHz antenna. 1 Chemical shifts in 1H NMR spectra were reported in parts per million (ppm) on the delta scale from the internal standard of CDCl3 (7.26 ppm). The data were reported as follows: chemical shift (δ ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad), coupling constant in Hertz (Hz), and integral value. 13 The chemical shifts of the 13C NMR spectra are reported in ppm on a delta scale, starting from the central peak of CDCl3 (77.0 ppm). MS data were recorded using an Agilent Technologies 6310 quadrupole mass spectrometer.

[0132] PET / CT / MR imaging was performed on animals anesthetized (isoflurane) to minimize discomfort. Highly trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for routine care. All mice were housed in groups in cages appropriate to the physical and behavioral health of each individual animal, given unlimited access to food and water, and provided with additional nutritional supplements as prescribed by the veterinary staff in charge.

[0133] [Example 1] Compound N-(benzo[c][1,2,5]thiadiazole-5-ylmethyl)-N-(methyl-11C)-3-(methylsulfonyl)benzenesulfonamide([ 11 Synthesis of C]SY-01)

[0134] [ka] Using an 11 MeV proton (Siemens Eclipse cyclotron), a nitrogen atmosphere with 2.5% oxygen was used. 14 N(p, α) 11 [via the C reaction] 11 [C]CO2 was obtained and captured on a molecular sieve in a TRACERlab FX-MeI synthesizer (General Electric). [ ]CO2 was obtained at 350°C in the presence of Ni / hydrogen. 11 By the reduction of C]CO2, [ 11 [C]CH4 is obtained and then recirculated by passing it through an oven containing I2, which causes a radical reaction [ 11 C]CH3I was generated.

[0135] In anhydrous DMF (300 μL) containing SY-01 precursor (1.0 mg) and K2CO3 (1.0 mg), the prepared [ 11 [C]CH3I was captured. The reaction vessel was heated to 80°C and held there for 3 minutes. 11 A radioactive mixture containing [C]SY-01 was quenched by adding HPLC mobile phase (0.7 mL), and then subjected to reversed-phase half-step HPLC (Phenomenex Gemini-NX 5u C18 110A, 250 × 10 mm, 5.0 mL / min, gradient of 10-90% CH3CN in H2O with 0.1% ammonium formate). The radioactive fraction with a retention time of 8 minutes was collected in a flask and diluted in water (30 mL). The final product was reformulated by placing it on a solid-phase exchange (SPE) C-18 cartridge (Waters WAT020515 Sep-Pak Plus Short C18), rinsing with water (4 × 5 mL), eluting with EtOH (0.3 mL), and diluting with physiological saline (2.7 mL). The chemical and radiochemical purity of the final product was tested by analytical HPLC (VARIAN Puruit XRs 5 C18, 150 × 4.6 mm) using a gradient of 10–90% CH3CN in 0.1% TFA H2O at a flow rate of 2 mL / min.

[0136] The following compounds [ 11 It can be prepared using the same methods and procedures as those used to prepare C]SY-01:

[0137] [ka]

[0138] Regarding compound SY-01 (binding affinity tested by radioligand-free binding test using biolayer interferometry (BLI)): Alpha-synuclein aggregates: K d :50nM. A Beta-amyloid aggregates: K d :29.41μM. Tau aggregates: K d :213nM.

[0139] SY-01 was evaluated in an α-synuclein binding assay and compared with the α-synuclein fibril-binding radioligand SIL23:

[0140] [ka]

[0141] Further experimental details are provided in Figures 1A-3.

[0142] Other Embodiments Although this application has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, not to limit, the scope of this application as defined by the scope of the attached claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Equation (I): 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts thereof [wherein, X １ It is selected from S and O; R １ 、 R ２ and R ３ are each independently selected from halo, OH, CN, NO ２ , C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, C(=O)OH, C(=O)O(C １～３ alkyl), C(=O)NH ２ , C(=O)NH(C １～３ alkyl), C(=O)N(C[[ID=​​​​​​​ R ４ H, C １～３ Alkyl and C １～３ Selected from haloalkyls; L １ It does not exist; or L １ C １～６ Alkylene and C ３～６ Selected from cycloalkylenes, the C １～６ Alkylenes are C(=O), S(=O) ２ It is optionally suspended by one or two bases independently selected from , O, and NH; Ring A does not exist, or ring A is given by equation (i): 【Chemistry 2】 (In the formula, a is X ２ It shows the attachment point; b is L １ It shows the attachment point; Ring C is C ３～６ Selected from cycloalkyl and 4- to 7-membered heterocycloalkyl groups, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , C(=O)NH(C １～３ Alkyl), C(=O)N(C １～３ Alkyl) ２ , amino, C １～３ Alkylamino and di(C) １～３ It is optionally substituted with one, two, or three substituents independently selected from alkyl)amino; R ５ and R ６ H, C １～３ Alkyl and C １～３ (Each haloalkyl group is independently selected.) This is the part; X ２ C (=O) and S (=O) ２ Selected from; Ring B is C ６～１０ Selected from aryls and 5- to 14-membered heteroaryls, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, S (=O) ２ (C １～３ Alkyl), S (=O) ２ OH, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , C(=O)NH(C １～３ Alkyl), C(=O)N(C １～３ Alkyl) ２ , amino, C １～３ Alkylamino and di(C) １～３ [Optionally substituted with one, two, or three substituents independently selected from alkyl)amino.

2. The compound of formula (I) is: 【Transformation 3】 The compound according to claim 1, having or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is: 【Chemistry 4】 (In the formula: L １ C １～６ Alkylene and C ３～６ Selected from cycloalkylenes, the C １～６ Alkylenes are C(=O), S(=O) ２ (Optionally interrupted by one or two bases independently selected from O and NH) The compound according to claim 1, having or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) is: 【Transformation 5】 The compound according to claim 3, having or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) is: 【Transformation 6】 The compound according to claim 3, having or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) is: 【Transformation 7】 The compound according to claim 3, having or a pharmaceutically acceptable salt thereof.

7. L １ However, C is interrupted by choice in O or NH. １～６ The compound according to any one of claims 3 to 6, which is an alkylene.

8. L １ C １～６ The compound according to any one of claims 3 to 6, which is an alkylene.

9. L １ However, C is interrupted at O. １～６ The compound according to any one of claims 3 to 6, which is an alkylene.

10. L １ However, C １～３ Alkylene-OC １～３ The compound according to any one of claims 3 to 6, which is an alkylene.

11. L １ C ３～６ A compound according to any one of claims 3 to 6, which is a cycloalkylene.

12. R ４ However, H or C １～３ The compound according to any one of claims 1 to 11, wherein it is alkyl.

13. R １ , R ２ and R ３ However, Haro, CN, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy and C(=O)NH ２ A compound according to any one of claims 1 to 12, each independently selected from the above.

14. The compounds are the following: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 The compound according to claim 1, selected from any one of the or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound described in claim 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method for treating a neurodegenerative disease or disorder selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysplasia (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington's disease (HD), dementia associated with PD, AD, FAD or HD, Pick's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic granule disease, dementia, chronic traumatic brain injury (CTE), age-related tauastropathy, Richardson syndrome, cerebellar ataxia, spheroclamic glial tauopathy, argyrophilic granule disease, motor neuron disease (MND), and prion diseases, comprising administering a therapeutically effective amount of the compound described in claim 1, or a therapeutically acceptable salt thereof, to a subject in need.

17. Formula (II): 【Chemistry 9】 Compounds of or pharmaceutically acceptable salts thereof [wherein, The compound １１ C １８ F １２３ I １２５ I, and １３１ contains at least one radioisotope selected from I; X １ It is selected from S and O; R １ 、 R ２ and R ３ are each independently selected from halo, OH, CN, NO ２ , C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, C(=O)OH, C(=O)O(C １～３ alkyl), C(=O)NH ２ , C(=O)NH(C １～３ alkyl), C(=O)N(C １～３ alkyl) ２ , amino, C １～３ alkylamino, and di(C １～３ alkyl)amino; R ４ H, C １～３ Alkyl and C １～３ Selected from haloalkyls; L １ It does not exist; or L １ C １～６ Alkylene and C ３～６ Selected from cycloalkylenes, the C １～６ Alkylenes are C(=O), S(=O) ２ It is optionally suspended by one or two bases independently selected from , O, and NH; Ring A does not exist, or ring A is given by equation (i): 【Chemistry 10】 (In the formula, a is X ２ It shows the attachment point; b is L １ It shows the attachment point; Ring C is C ３～６ Selected from cycloalkyl and 4- to 7-membered heterocycloalkyl groups, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , C(=O)NH(C １～３ Alkyl), C(=O)N(C １～３ Alkyl) ２ , amino, C １～３ Alkylamino and di(C) １～３ It is optionally substituted with one, two, or three substituents independently selected from alkyl)amino; R ５ and R ６ H, C １～３ Alkyl and C １～３ (Each of the following can be independently selected from haloalkyl groups.) This is the part; X ２ C (=O) and S (=O) ２ Selected from; Ring B is C ６～１０ Selected from aryls and 5- to 14-membered heteroaryls, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, S (=O) ２ (C １～３ Alkyl), S (=O) ２ OH, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , C(=O)NH(C １～３ Alkyl), C(=O)N(C １～３ Alkyl) ２ , amino, C １～３ Alkylamino and di(C) １～３ [Optionally substituted with one, two, or three substituents independently selected from alkyl)amino.

18. The compound of formula (II) １１ C, １８ F, １２３ I, １２５ I, and １３１ The compound according to claim 17, comprising at least one radioactive isotope selected from I.

19. The compound of formula (II) １８ F, １２３ I, １２５ I, １３１ I, １１ CN, １１ C(=O)NH ２ , １１ CH ３ - １１ CH ３ O-, １８ FCH ２ CH ２ - １８ FCH ２ CH ２ O-, and １８ FCH ２ CH ２ CH ２ A compound according to claim 17, selected from O-.

20. The compound of formula (II) is: 【Chemistry 11】 The compound according to any one of claims 17 to 19, having or a pharmaceutically acceptable salt thereof.

21. The compound of formula (II) is: 【Chemistry 12】 (In the formula, L １ C １～６ Alkylene and C ３～６ Selected from cycloalkylenes, the C １～６ Alkylenes are C(=O), S(=O) ２ (Optionally interrupted by one or two bases independently selected from O and NH) The compound according to any one of claims 17 to 19, having or a pharmaceutically acceptable salt thereof.

22. The compound of formula (II) is: 【Chemistry 13】 The compound according to claim 21, having or a pharmaceutically acceptable salt thereof.

23. The compound of formula (II) is: 【Chemistry 14】 The compound according to claim 21, having or a pharmaceutically acceptable salt thereof.

24. The compound of formula (II) is: 【Chemistry 15】 The compound according to claim 21, having or a pharmaceutically acceptable salt thereof.

25. L １ However, C is interrupted by choice in O or NH. １～６ The compound according to any one of claims 21 to 24, wherein it is an alkylene.

26. L １ C １～６ The compound according to any one of claims 21 to 24, wherein it is an alkylene.

27. L １ However, C is interrupted at O. １～６ The compound according to any one of claims 21 to 24, wherein it is an alkylene.

28. L １ However, C １～３ Alkylene-OC １～３ The compound according to any one of claims 21 to 24, wherein it is an alkylene.

29. L １ C ３～６ The compound according to any one of claims 21 to 24, wherein it is a cycloalkylene.

30. R ４ However, H or C １～３ The compound according to any one of claims 17 to 29, wherein it is alkyl.

31. R ４ but, １１ CH ３ -or １８ FCH ２ CH ２ The compound according to claim 30, comprising -.

32. R １ , R ２ and R ３ However, Haro, CN, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy and C(=O)NH ２ A compound according to any one of claims 17 to 29, each independently selected from the above.

33. The compound of formula (II) is the following compound: 【Chemistry 16】 The compound according to claim 17, selected from any one of the or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising the compound according to claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A method for imaging the brain of a subject, i) administering to the subject an effective amount of the compound according to claim 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 34; ii) waiting a sufficient amount of time to allow the compound to accumulate in the brain to be imaged; and iii) To image the brain using imaging techniques. Methods that include...

36. The method according to claim 35, wherein the compound binds to α-synuclein fibrils, amyloid plaques, or tau tangles in the brain.

37. A method for diagnosing a neurodegenerative disease in a subject, wherein the method comprises imaging the brain of the subject according to the method of claim 35, and observing a signal in step iii) which may be due to a radioactive isotope in the compound described in claim 17, thereby indicating a neurodegenerative disease in the subject.

38. A method for monitoring the treatment of neurodegenerative diseases in a subject, i) administering to the subject an effective amount of the compound according to claim 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 34; ii) Waiting for a sufficient amount of time to allow the compound to accumulate in the brain of the subject; iii) To image the brain of the subject using imaging techniques; iv) Administering a therapeutic agent to the subject in an effective dose for treating neurodegenerative diseases; Following (v) and (iv), administer to the subject an effective amount of the compound according to claim 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 34; vi) Waiting for a sufficient amount of time to allow the compound to accumulate in the brain of the subject; vii) To image the brain of the subject using imaging techniques; iii) Compare the image from step iii) with the image from step vi) A method comprising, in step viiii), observing a reduction in the signal that may be due to a radioisotope in the compound according to claim 17, which indicates the progress of treatment for a neurodegenerative disease.

39. The method according to any one of claims 35 to 38, wherein the imaging technique is selected from positron emission tomography (PET) imaging, positron emission tomography (PET / CT) imaging using computed tomography, positron emission tomography (PET / MRI) imaging using magnetic resonance imaging, and single-photon emission computed tomography (SPECT) imaging.

40. The method according to claim 37 or 38, wherein the neurodegenerative disease is selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysplasia (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington's disease (HD), dementia associated with PD, AD, FAD or HD, Pick's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic granule disease, dementia, chronic traumatic brain injury (CTE), age-related tauastropathy, Richardson syndrome, cerebellar ataxia, spheroclamic glial tauopathy, argyrophilic granule disease, motor neuron disease (MND), and prion disease, and comprises administering a therapeutically effective amount of the compound according to claim 1, or a therapeutically acceptable salt thereof, to a subject in need.

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