Modulators of neurodegeneration

Abstract

This disclosure provides, for example, piperidine-1-carboxylic acid ester compounds and methods of using these compounds, for example, to treat neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. This disclosure also provides the use of radioactive isotopes, for example... 11 C 18 F or 123 / 125 I. Methods for using a radiolabeled piperidine-1-carboxylic acid ester compound and the use of said radiolabeled compound as a positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agent for the diagnosis of neurodegenerative diseases and / or for monitoring the treatment of neurodegenerative diseases.

Description

[0001] Claiming priority

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 527,506, filed July 18, 2023. The entire contents of the aforementioned application are incorporated herein by reference. Technical Field

[0003] This invention relates to chemical compounds, and particularly to piperidine-1-carboxylic acid ester compounds, which are binding agents with high affinity for α-synuclein fibrils, amyloid plaques, and / or tau protein tangles in brain tissue (e.g., neurons, glial cells, and extracellular space). These compounds can be used, for example, to treat neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. When used with radioactive isotopes, for example... 11 C 18 F or 123 / 125 When labeled with I, the compound is also a positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agent, which can be used as a diagnostic tool, for example, for diagnosing neurodegenerative diseases and / or monitoring the treatment of neurodegenerative diseases. Background Technology

[0004] Many deadly diseases affect current human populations. For example, neurodegenerative diseases impact a large segment of the population, particularly the elderly. As one example, Parkinson's disease (“PD”), a synucleinic disorder affecting movement, affects more than 10 million people globally, with an estimated total economic burden exceeding $52 billion annually. Another example is Alzheimer's disease (“AD”), a beta-amyloid disorder affecting approximately 44 million people worldwide, the sixth leading cause of death, with an estimated socioeconomic burden exceeding $200 billion. Yet another example is Pick's disease, a rare tau protein disorder characterized by a series of progressive neurological symptoms, affecting approximately 1 in 250,000 people, with an estimated annual treatment cost of approximately $100,000 per patient. In summary, neurodegenerative diseases impose a significant burden on patients, their families, healthcare systems, and society as a whole. Due to the aging global population, neurodegenerative diseases pose an increasing threat to public health. Summary of the Invention

[0005] This disclosure is based, at least in part, on the understanding that piperidine-1-carboxylic acid ester compounds bind to α-synuclein with high affinity. Furthermore, the compounds exhibit relative selectivity for α-synuclein fibrils compared to amyloid plaques or tau protein tangles located in the brain tissue of individuals affected by neurodegeneration. In one instance, the selectivity of the piperidine-1-carboxylic acid ester compound for α-synuclein fibrils is about 30 to about 50 times higher than that for β-amyloid plaques. Moreover, the piperidine-1-carboxylic acid ester compounds are capable of crossing the blood-brain barrier, thereby selectively and extensively accumulating in brain tissue (compared to any other tissue in the subject) after administration and rapidly being cleared from the subject's plasma after exerting therapeutic effects. Advantageously, the specific affinity of the piperidine-1-carboxylic acid ester compounds within the scope of these claims for protein aggregates involved in the pathology of neurodegenerative diseases allows for their use as brain imaging agents after labeling with appropriate radioisotopes. 11 C or 18 When labeled with F, the compound can be detected in the brain using PET, while when labeled with... 123 I or 125 When labeled with I, the compound can be detected in the brain using SPECT. Radiolabeled compounds are useful diagnostic tools, allowing for the diagnosis of neurodegenerative diseases, supporting the clinical development of potential therapeutics (e.g., screening drug candidate compounds for potential therapeutics), and monitoring the treatment of neurodegenerative diseases with existing drugs and therapies.

[0006] In one general aspect, this disclosure provides compounds of formula (I):

[0007] (I),

[0008] Or a pharmaceutically acceptable salt thereof, wherein R 1 L 1 X 1 X 2 and R 3 As described in this article.

[0009] In another general aspect, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0010] In another general aspect, this disclosure provides a method for treating neurodegenerative diseases or conditions as described herein, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof.

[0011] In yet another general aspect, this disclosure provides compounds of formula (II):

[0012] (II),

[0013] Or a pharmaceutically acceptable salt thereof, wherein R 1 L 1 X 1 X 2 and R 3 As described herein with respect to formula (I), and the compound comprises at least one selected from 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes in I.

[0014] In another general aspect, this disclosure provides pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0015] In another general aspect, this disclosure provides a method for imaging the brain of a subject using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof, as described herein.

[0016] In yet another general aspect, this disclosure provides a method for diagnosing neurodegenerative diseases in subjects using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof, as described herein.

[0017] In another general aspect, this disclosure provides a method for treating a neurodegenerative disease in a subject by using a radiolabeled compound of formula (II) or a pharmaceutically acceptable salt thereof, as described herein.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Methods and materials used in this application are described herein; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification, including the definitions, shall prevail.

[0019] Other features and advantages of this application will be apparent from the following detailed description, drawings, and claims. Attached Figure Description

[0020] Figure 1A Includes the binding affinity (K) of SY08 to biotinylated alpha-synuclein preformed fibril.D (a bar chart of )

[0021] Figure 1B Includes the binding affinity (K) of SY08 to biotinylated α-synuclein preformed fibrils. a (a bar chart of )

[0022] Figure 1C Includes R estimated from the sensor map eq A line graph of values ​​relative to analyte concentrations was used to estimate the equilibrium dissociation constant (K0) of the test compound. D ).

[0023] Figure 2 A table showing the off-target binding profiling of SY08 is included. SY08 did not bind significantly to the test targets at 10 µM. MAO-A and MAO-B human enzyme assays were performed at Cerep / Eurofins. Binding assays for the remaining targets were performed via the NIMH Psychoactive Drug Screening Program (PDSP).

[0024] Figure 3 Includes radioactive ligands 3 Linear diagram showing the binding of H-SIL26 to tau, β-amyloid, and α-synuclein.

[0025] Figure 4 Includes a line graph showing the binding of radioligands to tau, β-amyloid and α-synuclein in the presence of SY-08.

[0026] Figure 5 An iPSC model used for radioactive cell binding assays is schematically illustrated. In short, an iPSC model (see PCT / US2022 / 050468) was constructed with piggyBac cells exhibiting either induced rapid neuronal transdifferentiation with α-synuclein overexpression (top panel) or α-synuclein expression at only endogenous levels (bottom panel). These cells were seeded with synthetic brain-derived α-synuclein pre-fabricated fibrils (schematically shown at the top).

[0027] Figure 6 The graph contains a line graph showing the increased binding of compound SY08 in the piggyBac inclusion model (the line above, solid line) of overexpressing α-synuclein, relative to the control (dashed line).

[0028] Figure 7AIHC (left) targeting phosphorylated α-synuclein and C on human postmortem tissue are shown. 11 -SY08 ARG image (right) (LBD, anterior cingulate band). Note that the black circle represents a technical artifact.

[0029] Figure 7B This shows human postmortem tissue washed with non-radioactively labeled SY08. 3 H-SY08 ARG image (LBD, gray matter in the frontal cortex).

[0030] Figure 7C Includes a line graph showing the selective binding affinity of SY08 in PD tissues compared to compounds C05-05, ACI-12589, and BF-227 (F18-C05-05, F18-ACI-12589, and F18-BF-227 have been used in PET imaging in MSA patients).

[0031] Figure 8 Includes showing the compound 11 Images of the results of a radiographic study of human postmortem tissues, C SY08.

[0032] Figure 9 Showing the use of C 11 - PET imaging results of SY08 in α-synuclein A53T transgenic mice (9 months old, n = 3). The results showed higher brain uptake than WT control mice.

[0033] Figure 10 This study illustrates the use of the AAV1 / 2 expression system to drive overexpression of mutant A53T human α-synuclein (aSyn) in rat SNpcs, resulting in approximately 60% loss of ipsilateral dopaminergic neurons after 21 days. Injection of empty AAV1 / 2 into contralateral SNpcs provides a vector-matched in vivo control. The model is characterized by ipsilateral dopaminergic cell loss identified by tyrosine hydroxylase staining (top panel), strong ipsilateral phosphorylation of aSyn at serine 129 (a pathological feature of PD-associated aSyn A53T toxicity) (middle panel), and the formation of proteinase K-resistant aSyn aggregates (bottom panel).

[0034] Figure 11A The results show that C was used in AAV-αSynA53T rats (n = 3). 11 -Altropane PET imaging showed dopamine loss in the right striatum, consistent with the loss of TH+ cells in the right substantia nigra and the loss of dopamine concentration in the right striatum as measured by HPLC.

[0035] Figure 11B The results show that C was used in AAV-A53T-αSyn rats (n = 3). 11 - SY08 PET imaging showed specific binding in the right substantia nigra deposited with aSyn.

[0036] Figure 12A This demonstrates the use of the HDAC11 inhibitor PB94 in the treatment of AAV-A53T-αSyn rats (daily intraperitoneal treatment for 3 weeks, n = 2). Treatment resulted in increased C... 11 -SY08 PET imaging showed a reduction in aSyn aggregates.

[0037] Figure 12B The results before and after PB94 treatment were shown via C 11 -Altropane PET imaging measured dopamine transporter concentrations. The right striatum showed more severe dopamine loss at baseline. PB94 increased DAT concentrations in both the right SN and the right striatum (n = 2).

[0038] Figure 13A This image shows PET-MRI images of the brain in a non-human primate (rhesus monkey), and was included in the baseline study via injection. 11 Total PET SUVR images (0–90 min, normalized by whole-brain uptake) superimposed with MEMPRAGE-MRI of rhesus monkey brain after C]SY08.

[0039] Figure 13B This image shows PET-MRI images of the brain of a non-human primate (rhesus monkey). Local brain analysis indicates that SUV values ​​for various brain regions were between 1 and 2 at early time points.

[0040] Figure 13C PET-MRI images of the brain in a non-human primate (rhesus monkey) are shown. Plasma radioactivity analysis indicates that the radiation was rapidly cleared from the blood (<30 minutes). 11 The main radioactive metabolites of C]SY08 are highly polar, indicating limited uptake of radioactive metabolites in the brain. Detailed Implementation

[0041] In neuropathology, neurodegeneration is typically characterized by the accumulation of insoluble protein aggregates such as α-synuclein fibrils, amyloid-β plaques, and tau protein tangles in brain cells and intracellular spaces, as well as significant neuroinflammation. These pathologies collectively lead to a reduction in brain volume and number of brain cells, neuronal degeneration, microglial dysfunction, and the development of various neurodegenerative conditions such as Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer's disease (AD), frontotemporal degeneration (FTD), Huntington's disease (HD), Pick's disease, and dementia (including dementia specifically associated with any of the aforementioned conditions). Without being bound by any theory, in one general aspect, this disclosure provides compounds that selectively bind to protein aggregates involved in neuropathology and neurodegeneration. Therefore, said compounds contribute to improving neuronal loss and are thus advantageously used to treat underlying neurological conditions (e.g., PD, MSA, PAF, AD, HD, or Pick's disease). This article describes certain embodiments of therapeutic compounds (e.g., compounds of Formula I) and exemplary embodiments of diseases (e.g., synucleinopathy) that can be treated by these compounds. Furthermore, the clinical diagnosis of neurodegenerative conditions remains a persistent challenge due to the limitations of existing neuropsychological tests and neuroimaging. Imaging pathological protein aggregates in the brain via PET or SPECT provides a useful method for both diagnosing neurodegenerative processes and evaluating the pharmacological performance of drug treatments. Without being bound by any theory, in a general sense, when the chemical structure of a compound includes a PET- or SPECT-imageable radioisotope (e.g., 11 C 18 F, 123 I or 125 When I), the compound can be used as a radiotracer (imaging agent) for diagnosing or monitoring the treatment of various neurodegenerative conditions. Certain embodiments of radiotracer compounds (e.g., compounds of formula II) and exemplary embodiments of imaging methods in which the radiotracer compounds of this disclosure are advantageously useful are described herein.

[0042] Therapeutic compounds

[0043] In some embodiments, this application provides compounds of formula (I):

[0044] (I),

[0045] Or a pharmaceutically acceptable salt thereof, wherein R 1 L 1 X 1 X 2 and R3 As described in this article.

[0046] In some implementation schemes:

[0047] X 1 Selected from O, NH and S;

[0048] L 1 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0049] R 1 Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1A Substituents of the substituents;

[0050] Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino;

[0051] Each Cy 1 Selected independently from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14-membered heteroaryl, and 4-10-membered heterocycloalkyl, each optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 1-3Alkylamino and di(C) 1-3 alkyl)amino;

[0052] X 2 Selected from CR 2 and N;

[0053] R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: OH, CN, NO2, C. 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0054] L 2 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0055] Each R 3 Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1B Substituents of the substituents;

[0056] Each R 1B Independently selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino;

[0057] Each R 1a Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0058] Each R 4 Independently selected from H and C1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino;

[0059] Each Cy 2 Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by 1, 2 or 3 independent substituents selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; and

[0060] Each R Cy Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino.

[0061] In some implementation schemes, X 1 For O. In some implementations, X 1 For S. In some implementations, X 1 For O or S. In some implementations, X 1 It is NH.

[0062] In some implementations, L 1 As a key. In some implementations, L 1 C 1-3 Alkylene, optionally substituted by one or two independent substituents selected from: halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene, optionally coated with halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene, optionally coated with halogen, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene (e.g., unsubstituted alkylene). In some embodiments, L 1 Selected from methylene, ethylene, and propylene.

[0063] In some implementation schemes, R 1 Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally selected independently from R 1A Substituents are substituted.

[0064] In some implementation schemes, R 1 For optional use by R 1A Replacement C 6-10 Aryl. In some implementations, R 1 For optional use by R 1A Substituted 5-14 heteroaryl groups. In some embodiments, R 1 For R 1A Replacement C 6-10 Aryl (e.g., phenyl or naphthyl). In some embodiments, R 1 For R 1ASubstituted 5-14 membered heteroaryl groups (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine). In some embodiments, R 1 For example, in adjacent, intermediate, or opposite positions, R is used. 1A Substituted phenyl groups. In some embodiments, R 1 For example, in 1, 2, 3, 5, 6, 7, or 8 bits, R is used. 1A Substituted naphthyl group.

[0065] In some embodiments, the compound of formula (I) has the following formula:

[0066] ,

[0067] Or its pharmaceutically acceptable salt.

[0068] In some embodiments, the compound of formula (I) has the following formula:

[0069] ,

[0070] Or its pharmaceutically acceptable salt.

[0071] In some embodiments, the compound of formula (I) has the following formula:

[0072] ,

[0073] Or its pharmaceutically acceptable salt.

[0074] In some implementation schemes, R 1A Selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino. In some embodiments, R 1A Selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C1-3 Alkyl group). In some embodiments, R 1A Selected from halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C 1-3 Alkyl group). In some embodiments, R 1A Selected from halogens, CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2. In some embodiments, R 1A Selected from halogens, CN, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1A It is a halogen. In some implementations, R 1A For CN. In some implementations, R 1A C 1-3 Alkyl group. In some embodiments, R 1A C 1-3 Halogenated alkoxy groups.

[0075] In some implementation schemes, R 1A For Cy 1 In some implementations, Cy 1 Selected from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 6-10 Aryl. In some implementations, Cy 1 C 3-10 Cycloalkyl. In some embodiments, Cy 1 C 6-10 The aryl group, optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 3-10 Cycloalkyl groups, optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 6-10 Aryl groups, optionally bonded by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C(=O)NH2 substitution. In some embodiments, Cy 1 For (or R) 1A (for) halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C(=O)NH2-substituted C 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) halogens, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy-substituted C 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) C replaced by halogen 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) C replaced by halogens or CN 6-10 Aryl.

[0076] In some implementation schemes:

[0077] X 1 It is O;

[0078] L 1 Selected from key and C 1-3 Alkylene;

[0079] Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Haloalkoxy groups, C(=O)OH and C(=O)NH2; and

[0080] Each Cy 1 Selected independently from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH and C(=O)NH2.

[0081] In some implementation schemes, X 2 For CR 2 In some implementations, X 2 Let N be the number of elements in the array.

[0082] In some embodiments, the compound of formula (I) has the following formula:

[0083] ,

[0084] Or its pharmaceutically acceptable salt.

[0085] In some embodiments, the compound of formula (I) has the following formula:

[0086] ,

[0087] Or its pharmaceutically acceptable salt.

[0088] In some implementation schemes, R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 Alkyl groups are optionally surrounded by OH, CN, NO2, or C. 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups are substituted. In some embodiments, R... 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ).

[0089] In some implementation schemes, R 2 For H. In some implementations, R2 C 1-3 Alkyl group. In some embodiments, R 2 C 1-3 Halogenated alkyl groups. In some embodiments, R 2 For L 2 -C(=O)N(R 1a (R) 4 In some implementations, R 2 Selected from H and L 2 -C(=O)N(R 1a (R) 4 In some implementations, R 1a Selected from H and C 1-3 Alkyl group. In some embodiments, R 1a For H. In some implementations, R 1a C 1-3 alkyl.

[0090] In some embodiments, the compound of formula (I) has the following formula:

[0091] ,

[0092] Or its pharmaceutically acceptable salt.

[0093] In some embodiments, the compound of formula (I) has the following formula:

[0094] ,

[0095] Or its pharmaceutically acceptable salt.

[0096] In some implementations, L 2 As a key. In some implementations, L 2 C 1-3 Alkylene, optionally substituted by one or two independent substituents selected from: halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, L... 2 C 1-3 Alkylene, optionally coated with halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 2 C 1-3 Alkylene (e.g., methylene, ethylene, or propylene).

[0097] In some implementation schemes, R4 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino.

[0098] In some implementation schemes, R 4 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 4 For H. In some implementations, R 4 C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R 4 C 1-3 Halogenated alkyl groups. In some embodiments, R 4 C is optionally substituted with one or two independent substituents selected from the following 1-3 Alkyl: Cy 2 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino. In some embodiments, R 4 For Cy 2 Replaces and optionally is selected from CN, NO2, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)NH(C 1-3 Alkyl) and C(=O)N(C1-3 C substituents of alkyl)2 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 C that is substituted and optionally replaced by halogen or CN 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 and C(=O)NH(C 1-3 C(alkyl) substituted and optionally substituted with halogen or CN 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 Replacement C 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 and C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl.

[0099] In some implementations, Cy 2 Selected from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted with a substituent selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl) and C(=O)N(C 1-3 Alkyl)2.

[0100] In some implementations, Cy 2 C 6-10 aryl group, optionally substituted with a substituent selected from the following: R Cy Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, Cy 2 For R Cy Replaced and optionally replaced by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy-substituted C 6-10 Aryl. In some implementations, Cy 2For R Cy Replacement C 6-10 Aryl. In some implementations, Cy 2 It is a 5-14 membered heteroaryl group, which is optionally substituted by substituents selected from the following: R Cy Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, Cy 2 For R Cy Replaced and optionally replaced by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 5-14 membered heteroaryl groups substituted with haloalkoxy groups. In some embodiments, Cy 2 For R Cy Substituted 5-14 heteroaryl groups.

[0101] In some implementation schemes, R Cy Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally bonded by a halogen, OH, CN, NO2, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 or di(C) 1-3 Alkyl)amino substitution.

[0102] In some implementation schemes, R Cy C 6-10 Aryl groups, optionally bonded by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C(=O)OH, or C(=O)NH2 substitution. In some embodiments, R Cy For optional halogen, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy-substituted C 6-10 Aryl. In some implementations, R Cy C can be optionally replaced by halogen or CN. 6-10Aryl. In some implementations, R 4 For being C 6-10 Aryl-C 6-10 aryl-substituted C 1-3 Alkyl, wherein the C 6-10 The aryl groups are each optionally coated with halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0103] In some implementation schemes:

[0104] L 2 C 1-3 Alkylene;

[0105] R 4 For Cy 2 and C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl;

[0106] Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and

[0107] Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl compounds.

[0108] In some implementation schemes:

[0109] L 2 For key;

[0110] R 4 For Cy 2 Replacement C 1-3 alkyl;

[0111] Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and

[0112] Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl compounds.

[0113] In some implementations, Cy 2 and R Cy The C mentioned 6-10The aryl and 5-14 membered heteroaryl groups are each optionally substituted by one, two, or three substituents (e.g., one or two substituents), said substituents being independently selected from halogens, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

[0114] In some implementation schemes, R 3 For R 1B Replacement C 6-10 Aryl (phenyl or naphthyl). In some embodiments, R 3 For example, in adjacent, intermediate, or opposite positions, R is used. 1B Substituted phenyl groups. In some embodiments, R 3 For R 1B Substituted naphthyl group. In some embodiments, R 3 For R 1B Substituted 5-14 heteroaryl groups (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine).

[0115] In some embodiments, the compound of formula (I) has the following formula:

[0116] ,

[0117] Or its pharmaceutically acceptable salt.

[0118] In some implementation schemes, X 3 Selected from N and CH. In some implementations, X 3 For N. In some implementations, X 3 For CH.

[0119] In some embodiments, the compound of formula (I) has the following formula:

[0120] ,

[0121] Or its pharmaceutically acceptable salt.

[0122] In some embodiments, the compound of formula (I) has the following formula:

[0123] ,

[0124] Or its pharmaceutically acceptable salt.

[0125] In some embodiments, the compound of formula (I) has the following formula:

[0126] ,

[0127] Or its pharmaceutically acceptable salt.

[0128] In some embodiments, the compound of formula (I) has the following formula:

[0129] ,

[0130] Or its pharmaceutically acceptable salt.

[0131] In some embodiments, the compound of formula (I) has the following formula:

[0132] ,

[0133] Or its pharmaceutically acceptable salt.

[0134] In some implementation schemes, R 1B Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)NH2, C(=O)OH, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C 1-3 Alkyl group). In some embodiments, R 1B Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups or C(=O)NH2. In some embodiments, R 1B Halogen, CN, C(=O)NH2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B It is halogen or CN. In some implementations, R 1B It is a halogen. In some implementations, R 1B For CN. In some implementations, R 1B For C(=O)NH2. In some implementations, R 1B C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B C 1-3Alkyl group.

[0135] In some embodiments, the compound of formula (I) has the following formula:

[0136] ,

[0137] Or its pharmaceutically acceptable salt.

[0138] In some embodiments, the compound of formula (I) has the following formula:

[0139] ,

[0140] Or its pharmaceutically acceptable salt.

[0141] In some embodiments, the compound of formula (I) has the following formula:

[0142] ,

[0143] Or its pharmaceutically acceptable salt.

[0144] In some embodiments, the compound of formula (I) is selected from any of the following formulas:

[0145]

[0146] Or its pharmaceutically acceptable salt.

[0147] In some implementation schemes, X 2 Selected from N, CH and CL 2 -C(=O)N(R 1a (R) 4 ).

[0148] In some embodiments, the compound of formula (I) is selected from any of the following formulas:

[0149]

[0150] Or its pharmaceutically acceptable salt.

[0151] In some embodiments, the compound of formula (I) has the following formula:

[0152]

[0153] Or its pharmaceutically acceptable salt.

[0154] In some embodiments, the compound of formula (I) has the following formula:

[0155]

[0156] Or its pharmaceutically acceptable salt.

[0157] In some embodiments, the compound of formula (I) is selected from any of the following compounds:

[0158]

[0159]

[0160] Or its pharmaceutically acceptable salt.

[0161] Radioactive tracer compounds

[0162] In some embodiments, the compound of formula (I) as described above contains at least one selected from... 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes in I. Therefore, in a general aspect, this disclosure provides compounds of formula (II):

[0163] (II),

[0164] Or a pharmaceutically acceptable salt thereof, wherein the group R 1 L 1 X 1 X 2 and R 3 As described in this paper with respect to equation (I), and R 1 L 1 X 1 X 2 and R 3 At least one of them contains selected from 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes of I.

[0165] In some embodiments, the compound of formula (II) contains 11 C. In some embodiments, the compound of formula (II) contains 18 F. In some embodiments, the compound of formula (II) contains 123 I. In some embodiments, the compound of formula (II) contains 125 I. In some embodiments, the compound of formula (II) contains 131 I. In some embodiments, the compound of formula (II) comprises a group selected from: 18 F, 123 I, 125 I, 131 I,11 CN 11 C(=O)NH2、 11 CH3-、 11 CH3O-、 18 FCH2CH2-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

[0166] In some implementation schemes, R 1B Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2. In some embodiments, R 1B Contains at least one selected from 11 C 18 F, 123 I, 125 I and 131 The radioactive isotope in I. In some implementations, R 1B Selected from 18 F, 123 I, 125 I, 131 I, 11 CN 11 C(=O)NH2、 11 CH3-、 11 CH3O-、 18 FCH2CH2-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

[0167] In some embodiments, the compound of formula (II) has the following formula:

[0168] ,

[0169] Or its pharmaceutically acceptable salt, wherein:

[0170] X 3 Selected from N and CH; and

[0171] R 1B Selected from 18 F, 123 I and 125 I.

[0172] In some implementation schemes, R 1B Selected from 11 CN and 11 C(=O)NH2. In some implementations, R1B Selected from 18 F, 11 CN and 11 C(=O)NH2. In some implementations, R 1B Selected from 123 I and 125 I. In some implementations, R 1B Selected from 11 CH3- and 18 FCH2CH2-. In some implementations, R 1B Selected from 11 CH3O-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

[0173] In some implementation schemes, X 2 For N. In some implementations, X 2 For CR 2 In some implementations, X 2 For CH.

[0174] In some implementation schemes:

[0175] R 2 For L 2 -C(=O)NHR 4 ;

[0176] L 2 Selected from key and C 1-3 Alkylene;

[0177] R 4 For Cy 2 Replaced and optionally by C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl;

[0178] Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and

[0179] Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups,

[0180] Wherein C 6-10 The aryl and 5-14 heteroaryl groups are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

[0181] In some implementation schemes:

[0182] X 1 It is O; and

[0183] L 1 Selected from key and C 1-3 Alkylene;

[0184] Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, C(=O)OH and C(=O)NH2; and

[0185] Each Cy 1 Selected independently from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH and C(=O)NH2.

[0186] In some embodiments, the compound of formula (II) has the following formula:

[0187] ,

[0188] Or its pharmaceutically acceptable salt.

[0189] In some embodiments, the compound of formula (II) has the following formula:

[0190] ,

[0191] Or its pharmaceutically acceptable salt.

[0192] In some embodiments, the compound of formula (II) has the following formula:

[0193] ,

[0194] Or its pharmaceutically acceptable salt.

[0195] In some implementation schemes, R 1A Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2. In some embodiments, R 1A Contains at least one selected from 11 C 18 F, 123 I, 125 I and 131 The radioactive isotope in I. In some implementations, R 1A Selected from 18 F, 123 I, 125 I, 131 I, 11 CN 11 C(=O)NH2、 11 CH3-、 11 CH3O-、 18 FCH2CH2-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-. In some implementations, R 1A Selected from 11 CN and 11 C(=O)NH2. In some implementations, R 1A Selected from 18 F, 11 CN and 11 C(=O)NH2. In some implementations, R 1A Selected from 123 I and 125 I. In some implementations, R 1A Selected from 11 CH3- and 18 FCH2CH2-. In some implementations, R 1A Selected from 11 CH3O-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

[0196] In some embodiments, the compound of formula (II) is selected from any of the following compounds:

[0197]

[0198]

[0199] Or its pharmaceutically acceptable salt.

[0200] Pharmaceutically acceptable salts

[0201] In some embodiments, the salt of any of the compounds disclosed herein (e.g., compounds of Formula I or II) is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0202] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of said 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-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprates, acrylates, formates, isobutyrates, caprates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebates, fumarates, and malonic acid salts. Salts, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, 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, especially those formed with organic acids such as maleic acid.

[0203] In some embodiments, the bases typically used to form pharmaceutically acceptable salts of said compounds include hydroxides of alkali metals (including sodium, potassium, and lithium); hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia; organic amines such as unsubstituted or hydroxylated monoalkylamines, dialkylamines, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucosamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine and lysine.

[0204] Compositions, formulations and routes of administration

[0205] This application also provides pharmaceutical compositions comprising an effective amount of a compound 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 additional therapeutic agent described herein. In some embodiments, this application also provides pharmaceutical compositions and dosage forms comprising any additional therapeutic agent described herein. The carrier is "acceptable" in the sense of compatibility with the other components of the formulation, and in the case of a pharmaceutically acceptable carrier, is harmless to the recipient at the amount used in the pharmaceutical process.

[0206] Pharmaceutically acceptable carriers, adjuvants, and solvents that can be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers (e.g., phosphates, glycine, sorbic acid, potassium sorbate, a mixture of glycerides of saturated vegetable fatty acids), water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0207] The composition or dosage form may contain 0.005% to 100% of any of the compounds and therapeutic agents described herein, with the balance consisting of suitable pharmaceutically acceptable excipients. The intended composition may contain 0.001% to 100% of any of the compounds and therapeutic agents provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, wherein the balance may consist of any pharmaceutically acceptable excipients described herein or any combination of such excipients.

[0208] route of administration and dosage form

[0209] 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, cervix, sinus, trachea, intestine, epidural, interstitial, intraperitoneal, intraarterial, bronchial, intrabursal, brain, cisterns, coronary artery, skin, catheter, duodenum, epidural, epidermal, esophagus, stomach, gingiva, ileum, lymphatic, intramedullary, intrameningeal, intramuscular, intranasal, ovarian, peritoneum, prostate, lung, sinus, intraspinal, synovium, testis, intrasheath, tube, tumor, uterus, blood vessel, vein, nose, nasogastric, oral, parenteral, percutaneous, epidural, rectum, respiratory tract (inhalation), subcutaneous, sublingual, submucosal, local, percutaneous, transmucosal, trachea, ureter, urethra, and vagina.

[0210] The compositions and formulations described herein can be conveniently present in unit dosage forms (e.g., tablets, sustained-release capsules) and in liposomes, and can be prepared by any method known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th edition, 2000). Such preparation methods involve the step of associating the molecule to be administered with a component constituting one or more auxiliary ingredients, such as a carrier. Typically, compositions are prepared by homogeneously and tightly associating the active ingredient with a liquid carrier, liposomes, or finely fragmented solid carrier, or both, and then shaping the product if desired.

[0211] In some embodiments, any of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of this application suitable for oral administration may be present as discrete units, each comprising a predetermined amount (e.g., an effective amount) of the active ingredient, such as capsules, sachets, granules, or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water liquid emulsions; water-in-oil liquid emulsions; packaged in liposomes; or as bolus formulations, etc. Soft gelatin capsules may be used to contain such suspensions, which can advantageously increase the rate of compound absorption. In the case of oral tablets, commonly used carriers include lactose, sucrose, glucose, mannitol, as well as silicic acid and starch. Other acceptable excipients may include: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners and / or flavorings and / or colorings may be added. Suitable compositions for oral administration include tablets containing ingredients in a flavoring matrix (typically sucrose and gum arabic or tragacanth gum); and soft tablets (pastilles) containing the active ingredient in an inert matrix (e.g., gelatin and glycerin, or sucrose and gum arabic).

[0212] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable or infusion solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. The formulations may be present in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions, requiring only the immediate addition of a sterile liquid carrier, such as water for injection, saline (e.g., 0.9% saline solution), or 5% glucose solution, prior to use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injectable solutions may be in the form of, for example, sterile injectable aqueous or oily suspensions. The suspension may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable solvents and media that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or diglycerides of glycerol. Fatty acids such as oleic acid and its glycerol derivatives can be used in the preparation of injections, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil (especially their polyoxyethylated forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0213] The pharmaceutical compositions of this application can be administered in the form of suppositories for rectal use. These compositions can be prepared by mixing the compounds of this application with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and thus melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0214] The pharmaceutical compositions of this application can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art. See, for example, U.S. Patent No. 6,803,031. Other formulations and methods for intranasal administration are described in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0215] The topical compositions disclosed herein can be prepared and used in the following forms: aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly used in the fields of topical application and / or cosmetic and skin care preparations. The topical compositions may be in emulsion form. Topical application of the pharmaceutical compositions of this application is particularly useful when the desired treatment involves areas or organs easily accessible through topical application. In some embodiments, the topical composition comprises any of the compounds and therapeutic agents disclosed herein combined with one or more additional ingredients, carriers, excipients, or diluents (including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients, emulsifiers, film-forming / holding agents, fragrances, no-rinse exfoliants, prescription drugs, preservatives, scrubs, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / cleaners, penetration enhancers, and thickeners).

[0216] Dosage and regimen

[0217] In the pharmaceutical compositions of this application, the compounds disclosed herein (e.g., compounds of formula (I) or (II)) are present in an effective amount. For example, a compound of formula (I) may be present in a therapeutically effective amount. In another example, a compound of formula (II) may be present in an amount effective for imaging organs and / or tissues of a subject, such as 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 subject's sex, age and general health condition, the use of excipients, the possibility of co-use with other compounds (e.g., therapeutic treatments, other imaging agents, metabolic inhibitors, etc.), and the judgment of the attending physician.

[0218] In some embodiments, the effective amount of the compound (e.g., formula (I) or formula (II)) can be from, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg). g; about 0.01 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 2 mg / kg; about 0.1 mg / kg to about 1 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the effective amount of the compound of formula (I) or formula (II) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0219] The aforementioned dosage may be administered daily (e.g., as a single dose or as two or more fractionated doses, such as once daily, twice daily, or three times daily) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month) as determined by the attending physician or diagnostic physician (e.g., the practitioner responsible for administering the imaging agent).

[0220] Reagent test kit

[0221] The present invention also includes kits for the treatment of conditions, diseases, and illnesses, such as those mentioned herein, comprising one or more containers containing a pharmaceutical composition having a therapeutically effective amount of a compound of formula (I) of the present disclosure or an amount of a compound of formula (II) of the present disclosure effective for brain imaging of a subject. If desired, such kits may further include one or more of various conventional pharmaceutical kit components, such as, for example, containers having one or more pharmaceutically acceptable carriers, other containers, etc. The kit may also include, as inserts or labels, instructions indicating the amount of components to be administered, administration guidelines, and / or instructions for mixing components. The kit may optionally include additional therapeutic agents as described herein.

[0222] Treatment

[0223] In some embodiments, this disclosure provides a method for regulating α-synuclein, β-amyloid, and / or tau protein in cells, the method comprising contacting the cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. In some embodiments, the regulation comprises binding, inhibition, or activation, or any combination thereof. In some embodiments, the 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 regulation is selective for α-synuclein compared to β-amyloid and / or tau protein (e.g., the regulation is 10-fold, 20-fold, 50-fold, 100-fold, or 1000-fold more selective for α-synuclein). In some embodiments, this disclosure provides a method for regulating α-synuclein, β-amyloid, and / or tau protein in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0224] In some embodiments, the compounds of formula (I) of this disclosure, as well as related salts and compositions, can be used to treat neurodegenerative diseases or conditions affecting the motor system.

[0225] Numerous scientific publications provide robust evidence of a link between multisystem neurodegeneration and the progressive accumulation of insoluble fibrillary synuclein proteins (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. Neurosci., 2013, 14, 1, 38–48, etc. Therefore, without being bound by any particular theory or speculation, as used herein, the term "synucleinopathy" refers to a group of neurodegenerative conditions in which the accumulation of insoluble synuclein (e.g., αSyn) protein fibrils is involved in various CNS and / or peripheral nervous system (PNS) cells. In some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a diagnosis of synucleinopathy) with synucleinopathy, said method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof. Suitable examples of synucleinic diseases include Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Alzheimer's disease, Hallervorden-Spatz syndrome, and lysosomal storage diseases (e.g., Gaucher's disease), as well as neurodegenerative diseases in which synuclein is involved at least partially in the disease pathology.

[0226] Numerous scientific publications provide information on neurodegeneration and amyloid peptides (e.g., β-amyloid protein such as Aβ). 40 Peptides and / or Aβ 42Reliable evidence linking misfolding of peptides and the resulting accumulation of amyloid plaques in the brain. 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, etc. In one instance, β-amyloid is used as a diagnostic biomarker for Alzheimer's disease (see, for example, Nakamura et al., Nature, 2018, 554, 7691, 249-254 and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804) and a primary target for its therapeutics (see, for example, Swanson C et al., Alzheimer's Res. Ther., 2021, 13, 1, 80). Therefore, without being bound by any particular theory or speculation, as used herein, the terms "amyloidosis" or "β-amyloidosis" refer to a group of neurodegenerative conditions in which the accumulation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain is involved in pathology. In some embodiments, this disclosure provides a method of treating amyloidosis in a subject (e.g., a subject requiring treatment, such as a subject identified as having a diagnosis of amyloidosis), said method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. Suitable examples of amyloidosis include premature aging, cerebral amyloid angiopathy, Alzheimer's disease (AD), familial AD (FAD), and dementia associated with AD or FAD, as well as neurodegenerative conditions in which the pathology of the disease is at least partially involved in the formation of amyloid plaques.

[0227] Numerous scientific publications provide robust evidence of a link between neurodegeneration and the misfolding of tau protein, and the subsequent formation of neurofibrils or glial fibrillary tangles in the brain (e.g., neurons, glial cells, and the extracellular space). See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb ClinNeurol, 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, etc. Therefore, without being bound by any particular theory or speculation, as used herein, the term "tau proteinopathy" refers to a group of neurodegenerative conditions with pathological involvement of tau-positive inclusions in the brain. In some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a diagnosis of tau proteinopathy) with tau proteinopathy, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof. Suitable examples of tau protein diseases include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glialtauopathy, and argyrophilic grain disease, as well as neurodegenerative diseases in which the pathology of the disease involves at least part of the misfolding of tau protein.

[0228] In some embodiments, this disclosure provides methods for treating neurodegenerative diseases in which any combination of synuclein, amyloid, and / or tau peptides or proteins is involved in the disease pathology. See, for example, Irwin D et al., Nat. Rev. Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodegener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol. Appl. Neurobiol., 2016, 42, 5, 436-50, etc.

[0229] Without being bound by any particular theory or speculation, it is believed that the misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins causes, induces, increases, and / or enhances neuroinflammation, a process that further contributes to the advancement of neurodegeneration and related symptomatology. See, for example, Gate D et al., Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al., Elife, 2020, 9, e54083, etc. Therefore, in some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a neurodegenerative disease) with a neurodegenerative condition (e.g., one involving inflammation in the disease pathology), said method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereto. In some implementations, neurodegenerative disorders are selected from motor neuron disease (MND), prion disease, frontotemporal degeneration (FTD), FTD-related dementia, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Huntington's disease (HD), HD-related dementia, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger's disease, dementia, multiple sclerosis (“MS”), hippocampal sclerosis, Gaucher's disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinocerebellar ataxia, and disorders of consciousness. Disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injury (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA).In some embodiments, the conditions that can be treated by the compounds of this disclosure are selected from accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, Charcot–Marie–Tooth disease, diabetic neuropathy, nerve paralysis, and Horner's syndrome.

[0230] Combination therapy

[0231] The compounds disclosed herein can be used in combination with at least one drug or therapy that can be used, for example, to treat or alleviate symptoms of neurodegenerative diseases such as PD. Suitable examples of such drugs include levodopa, 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 can be administered to patients simultaneously (in the same dosage form or in different dosage forms) or sequentially (the additional therapeutic agent can be administered before or after the administration of the compounds of this disclosure).

[0232] Imaging methods

[0233] In one general aspect, this application relates to compounds of formula (II) that can be used in imaging techniques, for diagnosing the various diseases and conditions described herein, and for monitoring treatments for the various diseases and conditions described herein. Such compounds are labeled as long as each compound contains at least one radioactive isotope (e.g., C, F, or I radioactive isotopes as described herein).

[0234] Imaging techniques such as PET and SPECT have become important forms of clinical diagnosis and research, and are also valuable technologies in drug discovery and development. PET offers picomolar sensitivity and is a fully convertible technology that requires specific probes radiolabeled with positron-emitting radionuclides, which typically have short lifetimes. Carbon-11 (radioactive half-life (t...) 1 / 2 )=20.4min) and Fluorine-18(t) 1 / 2 = 109.7 min) is the most commonly used radionuclide in PET imaging. PET provides the ability to measure biological processes in the body at the molecular and metabolic levels by detecting photons formed due to the annihilation of emitted positrons. SPECT is a nuclear imaging scan that requires a radioactive tracer. The tracer allows doctors to observe how blood flows to tissues and organs. Commonly used radioactive isotopes in SPECT are iodine-123, technetium-99m, xenon-133, thallium-201, and fluorine-18. The radioactive forms of these naturally occurring elements pass through the body and can be detected by a suitable scanner.

[0235] As a powerful tool in non-invasive medical and molecular imaging techniques and neurological research, PET offers the possibility of visualizing and analyzing target proteins and / or protein aggregates under physiological and pathophysiological conditions. PET has been frequently used to detect disease-related biochemical changes before standard medical imaging methods can detect disease-related anatomical changes.

[0236] In some embodiments, this disclosure provides methods for identifying and / or quantifying α-synuclein fibrils, amyloid plaques, and / or tau protein tangles in the brain of a subject. This can be achieved, for example, by imaging the brain (e.g., due to the binding affinity of the compound of formula (II) for the aforementioned proteins and protein aggregates). Imaging the brain may include imaging the midbrain, brainstem, thalamus, striatum, cerebellum, and / or cortex. Methods for imaging the brain include (i) administering to the subject an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing thereof; (ii) waiting for a time sufficient for the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 1 hour, 2 hours, 3 hours, or 5 hours); and (iii) imaging the brain using imaging techniques. In one example, the compound of formula (II) contains 18 F and / or 11 C is a radioactive isotope that emits positrons, and suitable imaging techniques include positron emission tomography (PET) and its variations. Therefore, imaging techniques can be selected from positron emission tomography (PET) imaging, positron emission tomography and computed tomography (PET / CT) imaging, and positron emission tomography and magnetic resonance (PET / MRI) imaging. In another example, the compound of formula (II) contains... 123 / 125 / 131 I is a radioactive tracer that emits gamma rays, and suitable imaging techniques include single-photon emission computed tomography (SPECT) and its various variants.

[0237] In some embodiments, this disclosure provides a method for diagnosing (or early detection) a subject's neurodegenerative condition (e.g., a neurodegenerative condition involving α-synuclein fibrils, amyloid plaques, and / or tau tangles, such as any of the neurodegenerative conditions described herein), the method comprising imaging the subject's brain according to any of the imaging methods described herein. In some embodiments, the method for diagnosing a subject comprises (i) administering to the subject an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing thereof; (ii) waiting a sufficient time for the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 45 min, 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) (e.g., observing a signal attributable to a radioisotope in a compound of formula (II) in the image obtained in step (iii)) as an indication of the subject's neurodegenerative disease. The method may also include comparing images obtained from subjects exhibiting symptoms of a disease or condition with images obtained from healthy subjects. In one instance, an excess of α-synuclein fibrils, amyloid plaques, and / or tau tangles in a subject's brain can be an indicator of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Pick's disease, dementia, or related conditions.

[0238] In some embodiments, the radiotracer of formula (II) within the scope of this claim can be used to study molecular mechanisms involved in neurodegenerative diseases. For example, the compound can be used to study the molecular mechanisms leading to the formation of α-synuclein fibrils, amyloid plaques, and / or tau tangles. For example, the compound of formula (II) can be co-administered with a modulator of the molecular mechanisms suspected of being involved in the formation of α-synuclein fibrils, amyloid plaques, and / or tau tangles, and the presence or absence of these protein aggregates can be detected using imaging techniques as discussed herein. In some embodiments, this disclosure provides methods for supporting the clinical development of potential therapeutics that prevent or inhibit the formation of α-synuclein fibrils, amyloid plaques, and / or tau tangles or cause the dissolution / degradation of these protein aggregates. In vivo imaging of pathological protein aggregates can help answer many key 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, the duration of drug residence at its target, and similar information. In some embodiments, this disclosure provides methods for screening potential therapeutic agents, for example, by detecting competitive binding of a drug candidate and a compound of formula (II) to α-synuclein fibrils, amyloid plaques, and / or tau protein tangles in the brain. In one example, a compound of formula (II) may be administered first, and a first brain image may be obtained having a signal attributable to a radioisotope in the compound of formula (II), followed by administration of a test compound and obtaining a second brain image. The absence of a signal attributable to a radioisotope in the second brain image may be an indication of the greater affinity of the test compound for α-synuclein fibrils, amyloid plaques, and / or tau protein tangles in the brain and its potential therapeutic efficacy for related neurodegenerative conditions.

[0239] In some embodiments, this disclosure provides a method for monitoring the treatment of neurodegenerative diseases in a subject (e.g., neurodegenerative diseases pathologically involving α-synuclein fibrils, amyloid plaques, and / or tau tangles, such as any of the diseases described herein), the method comprising (i) administering to the subject an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereto, (ii) waiting for a time sufficient for the compound of formula (II) to accumulate in the subject's brain (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (iii) imaging the subject's brain using imaging techniques; and (iv) administering to the subject an effective amount of a therapeutic agent to treat the neurodegenerative condition. In one instance, aducanumab, lecanemab, donepezil, rivastigmine, galantamine, memantine, suvorexant, or an investigational drug substance for the treatment of AD or DLB may be administered to a subject undergoing treatment for AD or DLB, respectively. In another instance, levodopa, carbidopa, safenamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, benztropine, benzalkonium chloride, selegiline, rasagiline, tocapone, entacapone, α-synuclein or LRRK2 (dardarin) antisense oligonucleotides (e.g., Biogen's ASO or Ionis's ION859 and ION464), or an investigational drug substance for the treatment of PD or DLB, may be administered to a subject undergoing treatment for PD or DLB, respectively. In another instance, levodopa (L-dopa), carbidopa, safenamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, benztropine, selegiline, rasagiline, tocapone, entacapone, fludrocortisone, midodrine, physostigmine, droxidopa, or an investigational pharmaceutical substance used to treat MSA may be administered to a subject undergoing treatment for MSA. In some embodiments, the method further includes, following step (v) after (iv), administering to the subject an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing thereof; (vi) waiting for a sufficient time for the compound of formula (II) to accumulate in the subject's brain (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (vii) imaging the subject's brain using imaging techniques; and (viii) comparing the images from step (iii) with the images from step (vii).In one instance, the signal of a decrease in the radioactive isotope attributable to the compound of formula (II) observed in step viii) is an indication of the progression of treatment for a neurodegenerative disease. Suitable examples of diseases for which the methods of this disclosure can be used to monitor treatment 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 failure (PAF). Other suitable examples include Alzheimer's disease (AD), familial AD (FAD), frontotemporal 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, aerobatic granuloma, dementia, chronic traumatic encephalopathy (CTE), age-related tau astropathy, Richardson's syndrome, cerebellar ataxia, glioblastoma tau disease, aerobatic granuloma, motor neuron disease (MND), and prions.

[0240] definition

[0241] As used herein, the term "about" means "approximately" (e.g., specifying a value ± about 10%).

[0242] Throughout this specification, substituents of the compounds of the present invention are disclosed by group or by scope. The invention is particularly intended to include each individual sub-combination of members of such groups and scopes. For example, the term "C" 1-6 The term "alkyl" is specifically intended to separately disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0243] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described throughout this specification. Unless otherwise stated, these rings may be attached to the remainder of the molecule at any ring member, provided that the valence allows. For example, the terms "pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0244] It is further recognized that certain features of the invention described in the context of separate embodiments for clarity 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 brevity may also be provided separately or in any suitable sub-combination.

[0245] The term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings with aromatic characteristics (i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer).

[0246] The term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion having n cyclic atoms. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cyclic alkyl group.

[0247] As used herein, the phrase “optionally substituted” means either unsubstituted or substituted. Substituents are chosen independently, and substitution can occur 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, such as an oxo group, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence.

[0248] It is further recognized that certain features of the invention described in the context of separate embodiments for clarity 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 brevity may also be provided separately or in any suitable sub-combination.

[0249] Throughout the definition, the term "C" n-m "" indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C. 1-4 and C 1-6 wait.

[0250] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkyl" refers to a saturated hydrocarbon group that can be n to m carbon atoms, and can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group comprises 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0251] As used herein, the term "C" is used alone or in combination with other terms. n-m"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-1,1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methyl-propane-1,3-diyl. In some embodiments, the alkylene moiety comprises 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0252] As used herein, the term "C" is used alone or in combination with other terms. n-m "Halogenated alkyl" refers to an alkyl group having 1 to 2s+1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the halogenated alkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0253] As used herein, the term "aryl" alone or in combination with other terms refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m "Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthraceneyl, phenanthryl, indenyl, and indenyl. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0254] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon, including cyclic alkyl and / or alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. The cyclic carbon atom of the cycloalkyl group may optionally be substituted with one or two independently selected oxo or sulfide groups (e.g., C(O) or C(S)). The definition of cycloalkyl also includes a portion having one or more aromatic rings (e.g., benzo or thiophene derivatives of cyclopentane and cyclohexane, etc.) fused with the cycloalkyl ring (i.e., sharing a common bond with the cycloalkyl ring). Cycloalkyl groups containing fused aromatic rings can be linked by any cyclic atom (including the cyclic atom of the fused aromatic ring). Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbons (C 3-10 In some embodiments, the cycloalkyl group is C10. 3-10 Monocyclic or bicyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 3-7Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0255] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from nitrogen, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any cyclic N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five- or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl having a ring containing 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl groups are thienyl, furanyl, 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. Six-membered heteroaryl rings are heteroaryl groups having a ring containing six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0256] As used herein, “heterocyclic alkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more cyclic heteroatoms selected from O, N, or S. Heterocyclic alkyl groups include monocyclic 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may also include spirocyclic groups. Examples of heterocyclic alkyl groups include pyrrolidine-2-one, 1,3-isooxazolidinyl-2-one, pyranyl, tetrahydropyran, oxoheterocyclic butyl, azaheterocyclic butyl, morpholino, thiomorpholino, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolidine, isoxazolidinyl, isothiazolidinyl, pyrazolidine, oxazolidinyl, thiazolyl, imidazolyl, azaheptanyl, and benzo[a]azolidinyl, etc. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with one or two independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocyclic alkyl group may be linked by a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings (e.g., benzo or thiophene derivatives of piperidine, morpholine, aziridine, etc.) fused with a cyclic aromatic ring (i.e., sharing a common bond with the cyclic alkyl ring). The heterocyclic alkyl group containing the fused aromatic ring may be linked by any cyclic atom (including the cyclic atom of the fused aromatic ring). In some embodiments, the heterocyclic alkyl is a monocyclic 4-6 membered heterocyclic alkyl having one or two independently selected heteroatoms selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocyclic alkyl group is a monocyclic or bicyclic 4-10 membered heterocyclic alkyl group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or sulfur and having one or more oxidized ring members.

[0257] In some places, the definition or embodiment refers to a specific ring (e.g., azahexacyclic butane ring, pyridine ring, etc.). Unless otherwise stated, these rings can be attached to any ring member, provided it does not exceed the valence of the atom. For example, azahexacyclic butane ring can be attached at any position on the ring, while a pyridine-3-yl ring is attached at the 3-position.

[0258] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkoxy" refers to a group of the formula -O-alkyl, wherein 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.

[0259] As used in this article, "C" n-m"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 only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0260] As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, the halogen is F, Cl, or Br.

[0261] As used herein, the term "amino" refers to a group of the formula -NH2.

[0262] As used in this article, the term "C" n-m "Alkylamino" refers to a group of the formula -NH(alkyl), wherein 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).

[0263] As used in this article, the term "two (C)" n-m "-alkyl)amino" refers to a group of the formula -N(alkyl)2, wherein 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.

[0264] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein by name or structure as a particular tautomer are intended to include other tautomers. Any atom in compounds identified herein that is not specifically designated as a radioactive isotope is present at its natural isotopic abundance.

[0265] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended to be covered. 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 inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, and N=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this invention. Cis and trans geometric isomers of the compounds of the present invention are described, and they can be isolated as mixtures of isomers or as separate isomeric forms. In some embodiments, the compounds have an (R)-configuration. In some embodiments, the compounds have an (S)-configuration.

[0266] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds, accompanied by the migration of protons. Tautomeric forms include proton-transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-transfer tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or stereolocked into one form by appropriate substitution.

[0267] As used herein, the interchangeable terms “individual,” “patient,” or “subject” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0268] As used herein, the phrase “effective amount” or “therapeutic effective amount” refers to the amount of an active compound or agent that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician in an tissue, system, animal, individual or human.

[0269] As used herein, the terms “treating” or “treatment” mean 1) suppressing a disease; for example, suppressing a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., preventing further development of the pathology and / or symptoms), or 2) improving a disease; for example, improving a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., reversing the pathology and / or symptoms).

[0270] As used herein, the term "preventing" or "prevention" of a disease, condition, or symptom refers to reducing the risk of a disease, condition, or symptom occurring in a subject or subject group (e.g., a subject or subject group susceptible to or affected by a disease, condition, or symptom). In some embodiments, preventing a disease, condition, or symptom means reducing the likelihood of acquiring a disease, condition, or symptom and / or its associated symptoms. In some embodiments, preventing a disease, condition, or symptom means completely or almost completely preventing the occurrence of a disease, condition, or symptom.

[0271] As used herein, the term “radioactive isotope” refers to an atom having a different atomic mass or mass number than that of atoms commonly found in nature (i.e., naturally occurring).

[0272] As used in this article, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance.

[0273] “ 18 "F" refers to a radioactive isotope of fluorine with 9 protons and 9 neutrons. "F" refers to a stable isotope of fluorine with 9 protons and 10 neutrons (i.e., "F"). 19 F isotopes”). The compounds disclosed herein are for each specified 18 The isotopic enrichment factor of F atoms is at least 3500 (in each specified...) 18 52.5% at the F atom 18 F incorporated), at least 4000 (60%) 18 F incorporated), at least 4500 (67.5%) 18 F incorporated), at least 5000 (75%) 18 F), at least 5500 (82.5%) 18 F incorporated), at least 6000 (90%) 18 F incorporated), at least 6333.3 (95%) 18 F incorporated), at least 6466.7 (97%) 18 F incorporated), at least 6600 (99%)18 F incorporated) or at least 6633.3 (99.5%) 18 F doping).

[0274] “ 11 "C" refers to the radioactive isotope of carbon with 6 protons and 5 neutrons. "C" refers to the stable isotope of carbon with 6 protons and 6 neutrons (i.e., "C"). 12 C isotopes”). The compounds disclosed herein are for each specified 11 The isotopic enrichment factor of C atoms is at least 3500 (in each specified...) 11 52.5% at the C atom 11 C incorporated), at least 4000 (60%) 11 C incorporated), at least 4500 (67.5%) 11 C incorporated), at least 5000 (75%) 11 C) At least 5500 (82.5%) 11 C incorporated), at least 6000 (90%) 11 C doping), at least 6333.3 (95%) 11 C doping), at least 6466.7 (97%) 11 C incorporated), at least 6600 (99%) 11 C incorporated) or at least 6633.3 (99.5%) 11 C doping).

[0275] “ 123 "I" refers to the radioactive isotope of iodine, which has 53 protons and 70 neutrons. 125 "I" refers to the radioactive isotope of iodine, which has 53 protons and 72 neutrons. 131 "I" refers to a radioactive isotope of iodine having 53 protons and 78 neutrons. "I" also refers to any abundant stable isotope of iodine or a combination of stable non-radioactive isotopes (e.g., "I-1"). 127 I isotopes”). The compounds disclosed herein are for each specified 123 / 125 / 131 The isotopic enrichment factor of I atoms is at least 3500 (in each specified...) 123 / 125 / 131 52.5% doping at I atom), at least 4000 (60% doping), at least 4500 (67.5% doping), at least 5000 (75% doping), at least 5500 (82.5% doping), at least 6000 (90% doping), at least 6333.3 (95% doping), at least 6466.7 (97% doping), at least 6600 (99% doping), or at least 6633.3 (99.5% doping).

[0276] Example

[0277] Materials and methods

[0278] Unless otherwise stated, all commercially available reagents were used without further purification. Analytical thin-layer chromatography (TLC) was performed using silica gel GF254 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). Recording was performed on a Bruker 500 MHz recorder. 1 H and 13 C spectrum. 1 Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the delta scale, with CDCl3 (7.26 ppm) as an internal standard. Data are reported as follows: chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak), coupling constant in Hertz (Hz), and integral. 13 Chemical shifts in the C10 NMR spectra are reported on the δ scale in ppm from the central peak of CDCl3 (77.0 ppm). MS data were recorded on an Agilent Technologies 6310 quadrupole mass spectrometer.

[0279] PET / CT / MR imaging was performed on anesthetized (isoflurane) animals to minimize discomfort. Trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for daily care. All mice were housed in groups in cages appropriate for their individual physical and behavioral health, with unlimited access to food and water, and were provided with additional nutritional supplements prescribed by the attending veterinarian.

[0280] Example 1—Compound 7-(methoxy- 11 C) Naphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester ([ 11 Synthesis of C]SY-08

[0281] Step 1—Preparation of 7-methoxynaphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester

[0282]

[0283] CDI (4.07 g, 25.1 mmol) was added to a solution of compound 4-(4-fluorophenyl)piperidine (4.5 g, 25.1 mmol) and compound 7-methoxynaphthyl-2-ol (4.37 g, 25.1 mmol) in dioxane (45 mL). The mixture was stirred at 100°C for 12 hours. TLC (petroleum ether / EtOAc = 10 / 1, R f = 0.2) indicates the reaction is complete. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to produce a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give the compound 7-methoxynaphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester as a white solid (5.50 g, 3.32 mmol, purity 22.9%, yield 13.2%).

[0284] Step 1—Preparation of 7-hydroxynaphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester

[0285]

[0286] TMSI (20.6 g, 103 mmol, 14.0 mL) was added to a solution of 7-methoxynaphthyl-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (4.90 g, 12.9 mmol) in CH2Cl2 (150 mL). The mixture was stirred at 50 °C for 24 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to produce a residue, which was purified by preparative HPLC (column: Phenomenex luna C18250 × 50 mm × 10 µM; mobile phase: [water (TFA)-ACN]; gradient: 35%–75% B) to give the title compound as a white solid (200 mg, 547 μmol, yield 4.24%, purity 100%). LCMS: m / z = 366.0(M+H) + R t = 1.879 min. 1H NMR: (400 MHz, CD3OD) δ 7.76(dd, J = 8.8, 4.4 Hz, 2H), 7.44(d, J= 2.4 Hz, 1H), 7.31-7.38(m, 2H), 7.05-7.19(m, 5H), 4.32(d, J = 11.2 Hz, 1H),4.17(d, J = 12.4 Hz, 1H), 3.14(t, J = 12.4 Hz, 1H), 2.92-3.03(m, 1H), 2.81-2.87(m, 1H), 1.80-1.83(m, 2H), 1.59-1.74(m, 2H). LCMS: m / z = 366.1(M+H) + R t =2.813 min.

[0287] Step 3—Reaction with radiolabeled reagent

[0288]

[0289] Using 11 MeV protons (Siemens Eclipse cyclotron), nitrogen gas containing 2.5% oxygen was subjected to... 14 N(p, α) 11 C reaction to obtain [ 11 C]CO2, and it was captured on a molecular sieve in a TRACERlab FX-MeI synthesizer (General Electric). This was achieved by reduction at 350°C in the presence of Ni / hydrogen. 11 C]CO2 to obtain [ 11 C]CH4 is recycled through an oven containing I2, thereby producing […] via a free radical reaction. 11 C]CH3I.

[0290] Prepared [ 11 [C]CH3I was captured in 300 μL of anhydrous DMF containing 1.0 mg of 7-hydroxynaphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester and 1.0 mg of K2CO3. The reaction vessel was heated at 80°C and held for 3 min. [C]CH3I was captured in 300 μL of anhydrous DMF containing 1.0 mg of 7-hydroxynaphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester and 1.0 mg of K2CO3. 11The radioactive mixture of C]SY-08 was quenched by adding HPLC mobile phase (0.7 mL) and then applied to a reversed-phase semi-preparative HPLC system (Agilent Eclipse XDB 5µ C18, 250 × 9.4 mm, 5.0 mL / min, with a 10-90% CH3CN gradient in 0.1% TFA in H2O). The radioactive fraction with a retention time of 12 min was collected in a flask and diluted in water (30 mL). The final product was reconstituted by loading onto a solid-phase exchange (SPE) C-18 column (Waters WAT020515 Sep-Pak Plus Short C18), washing with water (4 × 5 mL), eluting with EtOH (0.3 mL), and diluting with brine (2.7 mL). The chemical and radiochemical purity of the final product was determined by analytical HPLC (VARIAN Puruit XRs 5 C18, 150 × 4.6 mm) with gradient elution of 10-90% CH3CN in 0.1% TFA H2O at a flow rate of 2 mL / min.

[0291] Example 2—Compound 7-methoxynaphthalene-2-yl 4-(4- 18 F-phenyl)piperidine-1-carboxylic acid ester ([ 18 Synthesis of F]SY-08)

[0292]

[0293] [ 18 F]SY08 at the Athenola A. Martinos Biomedical Imaging Center, MGH, Radioligand Laboratory, from CNY07 precursor, copper tetra(pyridine)trifluoromethanesulfonate, pyridine, and radioactive... 18 F - Synthesis. The SY08 precursor, copper tetra(pyridine)trifluoromethanesulfonate, and pyridine were dissolved in DMF. This solution was added to [amount missing] in the presence of K₂CO₃ and KOTf. 18 F - After stirring at 110°C for 20 minutes, the synthesized [[ ] was purified by high performance liquid chromatography. 18 F]SY08. The drug product was then reconstituted into vials containing 90% sterile isotonic saline and 10% ethanol. 18 The final product of F]SY08 is sterile filtered before application.

[0294] Example 3—Preparation of piperidine-1-carboxylic acid ester compounds

[0295] Preparation of naphth-2-yl 4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (SY08-A)

[0296] .

[0297] Preparation of naphth-2-yl 4-(6-fluoropyridin-3-yl)piperidine-1-carboxylic acid ester (SY08-B)

[0298] .

[0299] Preparation of 4-(4-fluorophenyl)piperidine-1-carboxylic acid phenyl ester

[0300] .

[0301] Preparation of 4-(6-fluoropyridin-3-yl)piperidine-1-carboxylic acid phenyl ester

[0302] .

[0303] Preparation of 7-methoxynaphth-2-yl 4-(6-fluoropyridin-3-yl)piperidine-1-carboxylic acid ester (SY08-C)

[0304]

[0305] Preparation of 2-bromobenzo[d]thiazolyl-5-yl-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (SY08-D)

[0306]

[0307] Preparation of (2-methoxypyrimidin-4-yl)methyl4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (SY08-E)

[0308] Route 1

[0309]

[0310] Route 2

[0311]

[0312] The mixture of compound (2-methoxypyrimidin-4-yl)methanol (250 mg, 1.78 mmol), compound 4-(4-fluorophenyl)piperidine (319 mg, 1.78 mmol), and CDI (289 mg, 1.78 mmol) in dioxane (2.50 mL) was degassed and purged three times with N2. The mixture was then stirred at 100°C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 µM; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%–65% B, for 15 min). The title compound (30.0 mg, 86.8 μmol, purity 99.5%, yield 4.87%) was obtained as a yellow oil. 1 H NMR: 400 MHz, MeOD) δ 8.54(d,J = 5.2 Hz, 1H), 7.31 - 7.22(m, 2H), 7.09(d, J = 5.2 Hz, 1H), 7.05 - 6.98(m,2H), 5.17(s, 2H), 4.46 - 4.22(m, 2H), 4.01(s, 3H), 3.16 - 2.87(m, 2H), 2.79(tt, J = 3.6, 12.2 Hz, 1H), 1.86(br d, J = 13.0 Hz, 2H), 1.77 - 1.54(m, 2H).

[0313] Preparation of 4'-cyano-[1,1'-biphenyl]-4-yl 4-(6-fluoropyridin-3-yl)piperidine-1-carboxylic acid ester (SY08-F)

[0314] Route 1

[0315]

[0316] Route 2

[0317]

[0318] The mixture of compound 4'-hydroxy-[1,1'-biphenyl]-4-carboxynitrile (200 mg, 1.02 mmol), compound 4-(4-fluorophenyl)piperidine (183 mg, 1.02 mmol), and CDI (166 mg, 1.02 mmol) in dioxane (2.00 mL) was degassed and purged three times with N2. The mixture was then stirred at 100°C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 µM; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52%–82% B, for 15 min). The title compound was given as a white solid (30.0 mg, 74.9 μmol, purity 98.1%, yield 7.31%). 1 H NMR: (400 MHz, CDCl3) δ 7.76 -7.65(m, 4H), 7.60(d, J = 8.8 Hz, 2H), 7.25(br s, 2H), 7.21(dd, J = 5.4, 8.6Hz, 2H), 7.03(t, J = 8.8 Hz, 2H), 4.54 - 4.35(m, 2H), 3.20 - 2.90(m, 2H), 2.81 - 2.70(m, 1H), 1.94(br d, J = 13.4 Hz, 2H), 1.74(dq, J = 4.6, 12.8 Hz, 2H.

[0319] The following compounds were prepared using the same methods and procedures as those used to prepare SY08-A to F:

[0320] 7-Hydroxynaphth-2-yl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (SY101)

[0321]

[0322] Step 1 — Preparation of tert-butyl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid

[0323]

[0324] To a solution of compound 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-carboxylic acid (0.90 g, 2.78 mmol) in DCM (7.00 mL), HATU (1.06 g, 2.78 mmol), DIEA (359 mg, 2.78 mmol, 484 μL), and compound [1,1'-biphenyl]-4-ylmethylamine (510 mg, 2.78 mmol) were added. The mixture was stirred at 20°C for 1.5 hours. TLC (ethyl acetate, starting material: R) was performed. f = 0.00, Product: R f = 0.49) indicates the reaction is complete. The reaction mixture was extracted with H2O (10.0 mL). The combined organic layers were washed with DCM (35.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 25 / 1 to 2 / 1). The title compound was given as a white solid (1.30 g, 2.66 mmol, yield 95.6%). 1 H NMR: (400 MHz, CDCl3) δ 7.55(d, J = 7.4 Hz, 2H), 7.50(d, J = 8.0 Hz, 2H), 7.44(t, J = 7.6 Hz, 2H), 7.35(dd, J = 5.4, 8.4Hz, 3H), 7.15 - 7.03(m, 4H), 4.41(d, J = 5.6 Hz, 2H), 3.74 - 3.59(m, 2H), 3.51 - 3.37(m, 2H), 2.45 - 2.31(m, 2H), 2.08 - 1.93(m, 2H), 1.46(s, 9H).

[0325] Step 2—Preparation of N-([1,1'-biphenyl]-4-ylmethyl)-4-(4-fluorophenyl)piperidine-4-carboxamide

[0326]

[0327] To a solution of compound 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidin-1-carboxylic acid tert-butyl ester (1.20 g, 2.46 mmol) in EtOAc (3.00 mL), HCl / EtOAc (4.00 M, 30.0 mL) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The title compound was given as a white solid (0.80 g, 2.06 mmol, yield 83.8%). 1H NMR: (400 MHz, DMSO) δ 8.15(t, J= 6.0 Hz, 1H), 7.65 - 7.60(m, 2H), 7.52(d, J = 8.4 Hz, 2H), 7.48 - 7.32(m,5H), 7.23 - 7.09(m, 4H), 4.27(d, J = 5.8 Hz, 2H), 2.84 - 2.74(m, 2H), 2.71 -2.64(m, 2H), 2.47 - 2.40(m, 2H), 1.80 - 1.64(m, 2H).

[0328] Step 3—Preparation of 7-methoxynaphth-2-yl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester

[0329]

[0330] CDI (250 mg, 1.54 mmol) and 7-methoxynaphthalene-2-ol (269 mg, 1.54 mmol) were added to a solution of N-([1,1'-biphenyl]-4-ylmethyl)-4-(4-fluorophenyl)piperidin-4-carboxamide (0.60 g, 1.54 mmol) in dioxane (5.00 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The title compound (0.40 g, 679 μmol, yield 44.0%) was given as a colorless oil. 1 H NMR: (400MHz, CDCl3) δ 7.73(dd, J = 9.0, 11.8 Hz, 2H), 7.58 - 7.48(m, 4H), 7.47 - 7.32(m, 6H), 7.17 - 7.05(m, 7H), 5.57 - 5.49(m, 1H), 4.44(d, J = 5.8 Hz, 2H), 3.90(s, 3H), 3.81 - 3.45(m, 3H), 2.59 - 2.42(m, 2H), 2.23 - 2.06(m, 2H), 1.47(s, 2H).

[0331] Step 4 — Preparation of SY101

[0332]

[0333] BBr3 (520 mg, 2.08 mmol, 0.20 mL) was added to a solution of 7-methoxynaphthyl-2-yl-4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidin-1-carboxylic acid ester (400 mg, 679 μmol) in DCM (3.00 mL). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding an aqueous solution of Na2CO3 at 0°C to a pH of about 7, then diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with 20.0 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge 150 × 25 mm × 5 µM; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52.0%-82.0% B, for 9 min). The title compound was obtained as a grayish-white solid (30.0 mg, 52.2 μmol, purity 98.9%, yield 7.68%). 1 H NMR: (400 MHz, DMSO) δ 9.78(br s, 1H), 8.34(br t, J = 5.8Hz, 1H), 7.75(d, J = 8.8 Hz, 2H), 7.63(d, J = 7.4 Hz, 2H), 7.55(d, J = 8.2Hz, 2H), 7.50 - 7.39(m, 5H), 7.38 - 7.32(m, 1H), 7.27 - 7.13(m, 4H), 7.11 -6.99(m, 3H), 4.32(br d, J = 5.8 Hz, 2H), 4.11 - 3.82(m, 2H), 3.28 - 3.09(m,2H), 2.60(br d, J = 11.0 Hz, 2H), 2.03 - 1.85(m, 2H).

[0334] 7-Methoxynaphth-2-yl 4-(([1,1'-biphenyl]-4-ylmethyl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (SY102)

[0335]

[0336] 4'-Cyano-[1,1'-Biphenyl]-4-yl4-(2-((1-([1,1'-Biphenyl]-4-yl)-3-(methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (Compound 415)

[0337]

[0338] (2-Methoxypyrimidin-4-yl)methyl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (compound 419)

[0339]

[0340] 7-Methoxynaphth-2-yl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (Compound 423)

[0341]

[0342] 2-Bromobenzo[d]thiazolyl-6-yl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (compound 427)

[0343]

[0344] 4-Cyclopropylphenyl 4-(2-((1-([1,1'-biphenyl]-4-yl)-3-(methylamino)-3-oxopropyl)amino)-2-oxoethyl)-4-(4-fluorophenyl)piperidine-1-carboxylic acid ester (Compound 431)

[0345]

[0346] Example 4 – Radiolabeled piperidine-1-carboxylic acid ester compounds

[0347] The following radiolabeled compounds were prepared using the same methods and procedures as those provided in Examples 1 and 2.

[0348]

[0349] Example 5 - Radioligand binding assay for SY-08

[0350] Store brain tissue at -80°C until sectioning. Trim frozen tissue with a razor blade and fix it onto the cryostat chuck in a cryostat (Bright OTF 5000). Section the tissue to a thickness of 20µm. Then thaw and fix the sections onto Superfrost® slides (4 sections per slide). Store the slides with silica gel desiccant at 4°C until needed. After removing from the 4°C freezer, allow the slide box to warm to room temperature before opening. Pre-wash the slides with ice-cold buffer for 15 to 110 minutes, then place them horizontally in a humidified box. Add 1 mL of […] 3 Spread SY-08 (10 nM) (total) or incubation buffer in the presence of a competing drug onto the slides. The slides are then incubated at room temperature for 60 minutes. Nonspecific binding is defined using unlabeled SY-08 (10 µM). At the end of the incubation period, the radioligand solution is rapidly aspirated and the slides are washed in ice-cold buffer (2 × 5 or 2 × 10 min, GBL_0715; 2 × 10 min, GBL_0731). The slides are then allowed to dry under an airflow. After drying, the slides are placed on a tritium-sensitive phosphor screen (Cytiva) and exposed for 7 days. The screen is then scanned on a PerkinElmer Cyclone® phosphorescence imager. After phosphorescence imaging, selected slides are scraped from the slides using a razor blade, digested in 0.1 M NaOH for 1 hour, neutralized, mixed with a scintillation mixture, and then counted in a liquid scintillation counter to measure the CPM of each slide.

[0351] ImageJ (NIH) was used to analyze image files from a phosphorescence imager (16-bit TIFF files). Regions of interest (ROIs) were plotted on each slice. Radiotracer bindings in the ROIs were quantized to digital light units (DLUs) and averaged across the slices. Phosphorescence imager background, identified in areas without slices on the screen, was subtracted. Specific bindings were then determined by subtracting nonspecific bindings identified in the presence of SY-08 10µM from the total bindings. Nonlinear curve fitting was used in Prism® (Graphpad Software Inc.) to fit the data. Phosphorescence images are shown in both grayscale and colorscale. The grayscale or colorscale range used for converting from 16-bit phosphorescence imager files to 8-bit TIFF files is shown next to each image.

[0352] Using reference compound SIL26 and radioactive ligands 3 H-SIL26 was measured. Results were obtained in... Figure 3 and Figure 4The results show that there are different binding sites on the synuclein protofibrils.

[0353] Example 6 - Radioactive ligand binding assay of SY-08 using biofilm layer interferometry (BLI)

[0354] The binding interactions between SY-08 and SIL-23 and α-synuclein prefibrils were investigated via BLI using an Octet Red384 instrument (Sartorius) and 1X PBS with 0.01% Brij-35 as the assay buffer. Recombinant α-synuclein prefibrils (rPeptide, catalog number ASF-1001-1) were biotinylated using the EZ-Link NHS-PEG4 biotinylation kit, and excess label was removed using a Zeba centrifugation desalting column according to the manufacturer's instructions (Thermo Fisher Scientific, Waltham, MA). Biotinylated protein samples to be used as the 'load' in the BLI experiments were purified in 1X PBS. For BLI, a super streptavidin (SSA) sensor was used to detect the biophysical interactions between small molecule ligands and biotinylated proteins. Prior to the BLI assay, the superstreptavidin sensor was immersed in 200 mL of assay buffer in a 96-well Greiner Bio-One black flat-bottom plate (#655209). The assay was performed in an 80 mL reaction volume in a Greiner Bio-One 384-well black flat-bottom PP plate (#781209, Greiner, Monroe, North Carolina), with an initial baseline step followed by loading of 4 mM (4000 nM) biotinylated protein. Biotinylated loaded protein and small molecule samples were arranged in the 384-well plate according to a plate plot compatible with 8-channel mode kinetic analysis, where the sensor moved from low to high concentrations of the small molecule ligand. For subsequent cycles, other steps included a second baseline (120 s), binding (240 s), and dissociation (240 s). All sensors were loaded with biotinylated protein, and three sensors with appropriate concentrations of DMSO (equivalent to the small molecule samples) in the assay buffer were used as references. After subtracting the reference (the average of three sensors containing DMSO in the assay buffer), the data were analyzed using DataAcquisition HT 12.0 software, and a 1:1 binding model was used to globally fit the replicate samples (n=5). The global fit assumed complete dissociation of the binding chaperone (the signal would return to zero at an infinitely long time point).

[0355] Steady-state analysis was also used, employing equilibrium data from the concentrations of various available small molecule ligands to estimate the equilibrium dissociation constant (KD). The instrument manufacturer (Fortebio, article #137) recommends the steady-state option for analyzing interactions with low affinity or very fast binding and dissociation rates (on and off rates). For steady-state analysis, the equation Response = (R...) is used according to the 1:1 binding model. max ×Conc.) / (K D + Conc.) Regarding R equilibrium (R equilibrium, R...) eq Fit the data.

[0356] When the “R-equilibrium” option is selected, Fortebio’s software calculates the affinity constant based on the Req value determined from the resulting curve fitting. In steady-state analysis, Req is plotted against the small molecule sample concentration to infer Rmax. KD is estimated as the small molecule concentration at which 50% of Rmax is achieved. According to the instrument manufacturer, if all curves have reached equilibrium, these two sets of values ​​should correspond to the “Response” and the Req values ​​should match. Further descriptions of BLI determination are available on the manufacturer’s (ForteBio) website.

[0357] SY-08 was evaluated in an α-synuclein binding assay and compared with the α-synuclein fibril-binding radioligand SIL23:

[0358] .

[0359] The result is Figures 1A-1C As shown in the figure. BLI data indicate that SY08 binds strongly, based on estimates of the equilibrium dissociation constant, compared to SIL-23. Furthermore, the estimated binding rate constant for SY-08 is at least 7 times higher than that for SIL-23. Binding rate constant (K... a The value indicates the number of complexes formed per second between small molecules and biotinylated proteins in a 1M solution. These data strongly support the use of SY08 for α-synuclein imaging, suggesting it is a more effective tracer than SIL-23.

[0360] Example 7 – Radioactive cell binding assays using SY-08 showed increased binding in the integrated model.

[0361] Figure 5 and Figure 6Details of assays in a human iPSC model and results for compound SY08 are provided. Ultimately, the goal is to utilize SY-08 in a human neuronal setting. The human iPSC model enables testing of SY-08 not only in human neurons but also in a neuronal model system engineered with piggyBac, which can be scaled up at large scale in a patient-specific manner and incorporates α-syn overexpression to improve the signal-to-noise ratio. The failure of α-syn binders in clinical use to date can be attributed to insufficient testing in appropriate human CNS settings prior to clinical use. This model system attempts to bridge this gap.

[0362] Example 8 - Autoradiography of SY08 in postmortem human tissue

[0363] Comprehensive characterization of PET tracers is a lengthy and expensive procedure, requiring multiple assays to establish confidence that the tracer will provide useful data in the target species (typically humans). These assays should also serve as background to select or discard tracers at early time points, saving valuable resources and time. In this regard, autoradiography, as an ex vivo binding technique or as an ex vivo record of tracer distribution in vivo, is a crucial tool. Autoradiographic binding methods allow for the sectioning of a series of frozen tissues and incubation with PET tracers, and, with appropriate caution and controls for selectively blocking binding, quantitative values ​​regarding tracer binding and its regional distribution can be obtained. Ex vivo autoradiography of selected organs or whole animals provides qualitative images of tracer distribution with high resolution. This method is attractive as a complement to small animal imaging due to its high resolution and anatomical correlation. In short, brain sections are prepared from frozen brains at a thickness of 20 µm and stored at -20°C until they are used in experiments. Tissue sections were pre-incubated for 20 min at ambient temperature with Tris·HCl buffer (pH 7.4, 50 mM), and then incubated with a radioactive tracer (5 mC) at ambient temperature. i Incubate with Tris-HCl buffer for 30 min. After incubation, wash the tissue sections twice with Tris-HCl buffer for 5 min each time, and immerse them in cold distilled water for 10 seconds. Dry the tissue sections with cold air and then place them on an imaging plate for 120 min. Obtain autoradiography and carefully draw the Region of Interest (ROI) based on visual observation. Radioactivity is expressed in digital light units per square millimeter (DLU / mm²). 2 In this experiment, significantly higher binding was observed in regions rich in α-synuclein aggregates compared to healthy control tissues, demonstrating the specific binding of our tracer in vitro.

[0364] Figures 7A-8 The results were provided. Compared to AD tissue, SY08 showed over 70-fold selectivity in binding to PD tissue. Reference Figure 7C See also amyloid-β radioactive tracer [ 18 F]BF-227 does not bind to glial contents in postmortem multisystem atrophic brain tissue (Amyloid-Beta Radiotracer [ 18 F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy BrainTissue), Contrast Media Mol Imaging. 2018; 2018: 9165458; A Novel and Promising α-Synuclein PET Tracer [ 18 The discovery of ACI-12589 (F) (Discovery of [ 18 [F]ACI-12589, a Novel and Promising PET-Tracer for Alpha-Synuclein. ALZHEIMER'S & DEMENTIA, V. 18, S6, Supplement: Biomarkers – Part 2, December 2022, E064680; High-Contrast Imaging of α-Synuclein Pathologies in Living Patients with Multiple System Atrophy. Movement Disorders, V. 37, 10, October 2022, 2159-2161.

[0365] (BF-227).

[0366] Example 9 – For PET imaging [ 11 C]SY08

[0367] [ 11 C]SY08 shows a radiochemical yield (RCY) of 12%–16% (relative to the captured [ 11[C]CH3I (uncorrected for decay), high molar activity of 1.82 ± 0.2 Ci / μmol (end of bombardment, EOB), chemical and radiochemical purity exceeding 99%, affinity for α-syn of 0.3–6 nM, binding affinity selectivity for α-syn exceeding 70 times higher than Aβ / tau (human tissue), and binding potential exceeding 10 (B max / K d The results showed that the ratio of [specific parameters], off-target binding exceeding 10 µM, early peak uptake exceeding 0.5% ID / cc in rat brain, BB osmotic SUV of 1-2 in early peak uptake (0-10 min) in non-human primates (NHP), rapid plasma clearance in less than 30 min, and limited radiometabolites in the brain. Figure 9 - As shown in Figure 13. Referring to Figure 12, the HDAC11 inhibitor PB94 has the following chemical structure:

[0368] .

[0369] Other implementation plans

[0370] It should be understood that although this application has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of this application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A compound of formula (I): (I)， Or its pharmaceutically acceptable salt, wherein: X 1 Selected from O, NH and S; L 1 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; R 1 Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1A Substituents of the substituents; Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each Cy 1 Selected independently from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14-membered heteroaryl, and 4-10-membered heterocycloalkyl, each optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; X 2 Selected from CR 2 and N; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: OH, CN, NO2, C. 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; L 2 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; Each R 3 Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1B Substituents of the substituents; Each R 1B Independently selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each R 1a Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R 4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each Cy 2 Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by 1, 2 or 3 independent substituents selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; and Each R Cy Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino.

2. The compound according to claim 1, wherein: X 1 It is O; L 1 Selected from key and C 1-3 Alkylene; Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, C(=O)OH and C(=O)NH2; and Each Cy 1 Selected independently from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH and C(=O)NH2.

3. The compound according to claim 1, wherein R 3 For R 1B Replacement C 6-10 Aryl.

4. The compound according to claim 1, wherein R 3 For R 1B Substituted 5-14 heteroaryl groups.

5. The compound according to any one of claims 1-4, wherein R 1B Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2.

6. The compound according to claim 1, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

7. The compound according to claim 1, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

8. The compound according to claim 1, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

9. The compound according to any one of claims 1-5, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

10. The compound according to claim 9, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

11. The compound according to claim 9, wherein the compound of formula (I) has the following formula: ， Or its pharmaceutically acceptable salt.

12. The compound according to any one of claims 1-10, wherein: L 2 C 1-3 Alkylene; R 4 For Cy 2 and C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl; Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, Wherein C 6-10 The aryl and 5-14 heteroaryl groups are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

13. The compound according to any one of claims 1-10, wherein: L 2 For key; R 4 For Cy 2 Replacement C 1-3 alkyl; Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, Wherein C 6-10 The aryl and 5-14 heteroaryl groups are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

14. The compound according to claim 1, wherein the compound is selected from any of the following compounds: Or its pharmaceutically acceptable salt.

15. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. A method for treating a neurodegenerative disease or condition selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal 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, aerobatic granuloma, dementia, chronic traumatic encephalopathy (CTE), age-related tau astropathy, Richardson's syndrome, cerebellar ataxia, glioblastoma tau disease, aerobatic granuloma, motor neuron disease (MND), and prions, the method comprising administering to a subject in need a therapeutically effective amount of the compound of claim 1 or a therapeutically acceptable salt thereof.

17. A compound of formula (II): (II), Or its pharmaceutically acceptable salt, wherein: The compound contains at least one selected from... 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes in I; X 1 Selected from O, NH and S; L 1 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; R 1 Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1A Substituents of the substituents; Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each Cy 1 Selected independently from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14-membered heteroaryl, and 4-10-membered heterocycloalkyl, each optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; X 2 Selected from CR 2 and N; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: OH, CN, NO2, C. 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; L 2 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; Each R 3 Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1B Substituents of the substituents; Each R 1B Independently selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each R 1a Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R 4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; Each Cy 2 Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by 1, 2 or 3 independent substituents selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 alkyl)amino; and Each R Cy Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, 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 Alkyl)amino.

18. The compound according to claim 17, wherein R 3 For R 1B Replacement C 6-10 Aryl.

19. The compound according to claim 17, wherein R 3 For R 1B Substituted 5-14 heteroaryl groups.

20. The compound according to any one of claims 17-19, wherein R 1B Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2.

21. The compound according to claim 20, wherein R 1B Contains at least one selected from 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes in I.

22. The compound according to claim 21, wherein R 1B Selected from 18 F, 123 I, 125 I, 131 I, 11 CN 11 C(=O)NH2、 11 CH3-、 11 CH3O-、 18 FCH2CH2-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

23. The compound according to claim 22, wherein the compound of formula (II) has the following formula: ， Or its pharmaceutically acceptable salt, wherein: X 3 Selected from N and CH; and R 1B Selected from 18 F, 123 I and 125 I.

24. The compound according to any one of claims 17-23, wherein X 2 Let N be the number of elements in the array.

25. The compound according to any one of claims 17-23, wherein X 2 For CR 2 .

26. The compound according to claim 25, wherein X 2 For CH.

27. The compound according to claim 25, wherein: R 2 For L 2 -C(=O)NHR 4 ; L 2 Selected from key and C 1-3 Alkylene; R 4 For Cy 2 Replaced and optionally by C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl; Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl groups, Wherein C 6-10 The aryl and 5-14 heteroaryl groups are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

28. The compound according to any one of claims 17-27, wherein: X 1 It is O; and L 1 Selected from key and C 1-3 Alkylene; Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, C(=O)OH and C(=O)NH2; and Each Cy 1 Selected independently from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH and C(=O)NH2.

29. The compound according to claim 28, wherein R 1A Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2.

30. The compound according to claim 29, wherein R 1A Contains at least one selected from 11 C 18 F, 123 I, 125 I and 131 Radioactive isotopes in I.

31. The compound according to claim 30, wherein R 1A Selected from 18 F, 123 I, 125 I, 131 I, 11 CN 11 C(=O)NH2、 11 CH3-、 11 CH3O-、 18 FCH2CH2-、 18 FCH2CH2O- and 18 FCH2CH2CH2O-.

32. The compound according to claim 30 or 31, wherein the compound of formula (II) is selected from any of the following compounds: Or its pharmaceutically acceptable salt.

33. The compound of claim 17, wherein the compound is selected from any of the following compounds: Or its pharmaceutically acceptable salt.

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

35. A method for imaging the brain of a subject, the method comprising: 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) Wait for sufficient time for the compound to accumulate in the brain to be imaged; and iii) Image the brain using imaging techniques.

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

37. A method for diagnosing neurodegenerative disease in a subject, the method comprising imaging the subject's brain using the method of claim 35, wherein a signal attributable to a radioactive isotope in the compound of claim 17 observed in step iii) is an indication that the subject has a neurodegenerative disease.

38. A method for monitoring the treatment of neurodegenerative diseases in a subject, the method comprising: 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) Wait for sufficient time for the compound to accumulate in the subject's brain; iii) Image the subject's brain using imaging techniques; iv) Administer an effective amount of the therapeutic agent to the subject to treat the neurodegenerative disease; v) Following iv), administer to the subject an effective amount of the compound of claim 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34; vi) Wait for sufficient time for the compound to accumulate in the subject's brain; vii) Image the subject's brain using imaging techniques; and viii) Compare the image from step iii) with the image from step vii). The signal observed in step viii) that can be attributed to the reduction of the radioisotope in the compound according to claim 17 is an indication of the therapeutic progress of the neurodegenerative disease.

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

40. The method of claim 37 or 38, wherein the neurodegenerative disease is selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal 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, aerobatic granuloma, dementia, chronic traumatic encephalopathy (CTE), age-related tau astropathy, Richardson's syndrome, cerebellar ataxia, glioblastoma tau disease, aerobatic granuloma, motor neuron disease (MND), and prions, the method comprising administering to a subject in need a therapeutically effective amount of the compound of claim 1 or a therapeutically acceptable salt thereof.

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