Novel compounds for the diagnosis of TDP-43 proteinopathy

Abstract

The present invention relates to compounds suitable for imaging TDP-43 (transactive response (TAR) DNA-binding protein 43 kDa) aggregates. The compounds can be used, for example, to diagnose diseases, disorders, or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant late-stage TDP-43 encephalopathy (LATE).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds suitable for imaging TDP-43 (transactive response (TAR) DNA-binding protein 43 kDa) aggregates. The compounds can be used, for example, to diagnose diseases, disorders, or abnormalities associated with TDP-43 aggregates, or TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant late-stage TDP-43 encephalopathy (LATE). The present invention also relates to methods for preparing the compounds, diagnostic compositions comprising the compounds, methods of using the compounds, kits comprising the compounds, and uses thereof. [Background technology]

[0002] Background of the Invention Late-life brain disorders, characterized by the pathological aggregation of proteins (proteinopathies in the CNS) in the central nervous system (CNS) and peripheral organs, are one of the leading causes of disability and death worldwide. The best-characterized protein that forms extracellular aggregates is amyloid beta (Aβ) in Alzheimer's disease (AD) and Aβ-related disorders. Other aggregation-prone disease-associated proteins that cause neurodegeneration include, but are not limited to, tau, α-synuclein (a-syn), huntingtin, fused in sarcoma (FUS), dipeptide repeat proteins (DPRs) produced by atypical translation of the C9orf72 repeat expansion, superoxide dismutase 1 (SOD1), and TDP-43. Diseases involving TDP-43 aggregates are collectively known as TDP-43 proteinopathies, and include, but are not limited to, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), including frontotemporal lobar dementia with TDP-43 pathology (FTLD-TDP, frontotemporal lobar degeneration with TDP-43 inclusions), and limbic-predominant late-life TDP-43 encephalopathy (LATE).

[0003] Introduction to TDP-43The transactivation response (TAR) DNA-binding protein 43 kDa (TDP-43) is a 414-amino acid protein encoded by the TARDBP gene (ALS10) on chromosome 1p36.2. TARDBP consists of six exons (exon 1 is noncoding; exons 2–6 encode proteins). TDP-43 belongs to the heterogeneous ribonucleoprotein (hnRNP) RNA-binding protein family (Wang et al., Trends in Molecular Medicine, Vol. 14, No. 11, 2008, pp. 479–485; Lagier-Tourenne et al., Human Molecular Genetics, Vol. 19, Review Issue 1, 2010, R46–R64). TDP-43 contains five functional domains (Figure 1 in Warraich et al., The International Journal of Biochemistry & Cell Biology, 42 (2010) 1606-1609): two RNA recognition motifs (RRM1 and RRM2) with two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions; a nuclear export signal (NES); a nuclear localization signal (NLS) that enables the NES to shuttle between the nucleus and cytoplasm, thereby transporting bound mRNA; and a C-terminal glycine-rich domain that mediates protein-protein interactions. TDP-43 is involved in multiple aspects of RNA processing, including transcription, splicing, transport, and stabilization (Buratti and Baralle, FEBS Journal, 277 (2010) 2268-2281). It is a highly conserved, ubiquitously expressed protein with tightly autoregulated expression levels, which continuously shuttles between the nucleus and cytoplasm, but is usually primarily localized in the nucleus.In 2006, TDP-43 was identified as a protein that accumulates in most cases of frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions (then called FTLD-TDP) and in most cases of amyotrophic lateral sclerosis (ALS) (Arai et al., Biochemical and Biophysical Research Communications, 351 (2006) 602-611; Neumann et al., Science, 314, (2006), 130-133).

[0004] Thirty-eight dominant-negative mutations in TDP-43, primarily located in the glycine-rich domain, have been identified in patients with sporadic and familial ALS and in patients with hereditary FTD (K263E, N267S) (Figure 1; Lagier-Tourenne and Cleveland, Cell, 136, 2009, 1001-1004). TDP-43 is intrinsically prone to aggregation, as shown by sedimentation assays, and this tendency is increased by several ALS-associated TARDBP mutations (Ticozzi et al., CNS Neurol Disord Drug Targets, 2010, 9(3), 285-296).

[0005] TDP-43 in neurodegeneration TDP-43 aggregates are associated with various diseases, including frontotemporal dementia (sporadic or familial with or without motor neuron disease (MND), those with progranulin (GRN) mutations, those with TARDBP mutations, those with valosin-containing protein (VCP) mutations, chromosome 9p-linked dementia, corticobasal degeneration, frontotemporal lobar degeneration with ubiquitin-positive inclusions, argyrophilic grain disease, and Pick's disease), amyotrophic lateral sclerosis (sporadic ALS, those with TARDBP mutations, and ANGI). It has been identified in an increasing number of pathological conditions, including but not limited to: HIV-1 mutations), Alzheimer's disease (sporadic and familial), Down's syndrome, familial British dementia, polyglutamine diseases (Huntington's disease and SCA3), hippocampal sclerosis dementia, and myopathies (sporadic inclusion body myositis, inclusion body myopathy with VCP mutations, oculopharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathy with MYOT or DES mutations) (Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64).

[0006] Aggregated TDP-43 derived from patient brains exhibits several abnormal modifications, including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragmentation through proteolytic cleavage (Arai et al., Biochemical and Biophysical Research Communications, 351 (2006) 602-611; Neumann et al., Science, 314, (2006), 130-133; Neumann et al., Acta Neuropathol, (2009) 117:137-149; Hasegawa et al., Annals of Neurology, 2008, 64(1), 60-70; Cohen et al., Nat Commun.; 2015, 6:5845). Another hallmark of TDP-43 pathology is the redistribution and accumulation of TDP-43 from the nucleus to the cytoplasm. The hallmark lesions of FTLD-TDP are neuronal and glial cytoplasmic inclusions (neuronal cytoplasmic inclusions (NCIs) and glial cytoplasmic inclusions (GCIs) respectively) and degenerating neurites (DNs), which are immunoreactive for TDP-43, ubiquitin, and p62, but negative for other neurodegenerative disease-associated proteins. Differences in inclusion morphology and their tissue distribution are associated with specific mutations and / or clinical features. Four histologically characterized TDP-43 pathologies have been described (Mackenzie and Neumann, J. Neurochem., (2016), 138 (Suppl. 1), 54-70). FTLD-TDP type A cases are characterized by abundant short DNs and small, oval, or semilunar NCIs, primarily in layer II of the neocortex (Mackenzie et al., J. Neurochem., 2016, 138 (Suppl. 1), 54-70, Fig. 2f). This condition usually presents clinically as behavioral vulnerabilities in frontotemporal dementia (bvFTD) or non-fluent / agrammatic primary progressive aphasia (nfvPPA) and is associated with progranulin (GRN) mutations.Type B cases show a moderate number of small or granular NCIs in both superficial and deep cortical layers, with relatively few DNs and NIIs (Mackenzie et al., J. Neurochem., 2016, 138 (Suppl. 1), 54-70, Fig. 2g). Most cases with concurrent FTD and ALS symptoms have been found to have FTLD-TDP type B pathology. Type C cases have abundant, long, and tortuous neurites, primarily in superficial cortical layers, with few or no NCIs (Mackenzie et al., J. Neurochem., 2016, 138 (Suppl. 1), 54-70, Fig. 2j). This pathology is particularly seen in cases with semantic primary progressive aphasia (svPPA). FTLD-TDP type D exhibits abundant lentinuclear neuronal intranuclear inclusions (NIIs) in the neocortex and short DNs, with only rare NCIs (Fig. 2k in Mackenzie et al., J. Neurochem., 2016, 138 (Suppl. 1), 54-70). This pattern of pathology is seen only in cases with VCP mutations associated with inclusion body myositis.

[0007] TDP-43 in FTD Frontotemporal dementia (FTD) is a clinical term encompassing a wide range of disorders based on degeneration of the frontal and temporal lobes, a pathological feature known as frontotemporal lobar degeneration (FTLD). FTD is the second most common cause of early degenerative dementia in people under 65 years of age (Le Ber, Revue Neurologique, 169 (2013), 811-819). FTD is manifested by several syndromes, including bvFTD, characterized by changes in personality and behavior; semantic dementia (SD) and progressive non-fluent aphasia (PNFA), characterized by changes in language function; and corticobasal syndrome (CBS), progressive supranuclear palsy syndrome, and motor neuron disease (FTD-MND), characterized by motor dysfunction. Diagnosis of these syndromes is complex, and a definitive conclusion can only be reached through postmortem tissue analysis based on immunohistochemistry to detect aggregated proteins and description of the affected brain regions. With regard to pathological protein inclusions, approximately 45% of cases show pathological accumulation of misfolded tau, 45% have pathological TDP-43, and a smaller subgroup has aggregates of FUS and other proteins. FTLD-TDP is a pathological term describing FTD cases with TDP-43 pathology found primarily as cytoplasmic or neurite protein aggregates in neurons and glial cells containing misfolded, insoluble, phosphorylated, and truncated TDP-43.

[0008] TDP-43 in ALS Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the early loss of upper and lower motor neurons. ALS progression is characterized by fatal paralysis and respiratory failure, with a disease course of 1–5 years from illness to death. In most cases of sporadic ALS, neuropathology is characterized by abnormal cytoplasmic accumulation of TDP-43 in neurons and glial cells in the primary motor cortex, brainstem motor nuclei, spinal cord, and associated white matter tracts. ALS dementia is associated with accumulation of TDP-43 in the supplementary motor area, neocortex, and hippocampus. The role of TDP-43 phosphorylation in ALS patients has been investigated using a phospho-specific antibody that strongly binds to nuclear and cytoplasmic TDP-43 inclusions. Amino acids S379, S403, S404, S409, and S410 have been identified as the major phosphorylation sites of TDP-43 (Hasegawa et al., Ann Neurol., 2008;64:60-70; Neumann et al., Acta Neuropathol., 2009, 117:137-149).

[0009] TDP-43 in LATE Neuropathological changes in limbic-predominant late-life TDP-43 encephalopathy (LATE) (LATE-NC) are defined by a stereotypical TDP-43 proteinopathy in older adults, with or without comorbid hippocampal sclerosis. LATE-NC is a common TDP-43 proteinopathy associated with an amnestic dementia syndrome mimicking Alzheimer's disease in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiological characteristics (LATE generally affects older subjects) and the relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. No molecular-specific biomarkers for LATE exist. The discovery of the TDP-43 PET tracer may enable accurate and potentially earlier diagnosis and monitoring of disease progression to facilitate long-term drug efficacy measurements in patients during clinical trials (including as a potential exclusion criterion for Alzheimer's disease clinical trials) and longitudinal studies of LATE clinical and pathological progression (Nelson et al., Brain, 2019, Vol. 142; Issue 6, 1503-1527).

[0010] TDP-43 in AD and other diseases TDP-43 pathology occurs in up to 57% of brains of Alzheimer's disease patients (Josephs KA et al., Acta Neuropathol., 2014;127(6):811-824; Josephs KA et al., Acta Neuropathol., 2014;127(3):441-450; McAleese et al., Brain Pathol., 2017 Jul;27(4):472-479). TDP-43 aggregation is associated with cognitive decline, memory loss, and medial temporal lobe atrophy in AD. TDP-43-positive patients are 10 times more likely to have cognitive impairment at death than TDP-43-negative subjects. TDP-43 appears to target the medial temporal lobe, resulting in a secondary or independent pathology that shares overlapping features with AD. Pathological TDP-43 follows the stereotypical deposition pattern captured by TDP-43 in the AD (TAD) staging scheme: TDP-43 is deposited first in the amygdala (stage I), then in the hippocampus, limbic system, temporal lobe, and finally in the frontostriatum (stage V) (Josephs KA et al., Acta Neuropathol., 2014;127(6):811-824; Josephs KA et al., Acta Neuropathol., 2014;127(3):441-450).

[0011] Diagnostic methods in FTD and ALS Diagnosing FTD based on clinical features is insufficient because the clinical features can overlap with other diseases, especially in the early stages. Therefore, the development of sensitive and specific biomarkers that allow differentiation between pathologies within the FTD spectrum is urgently needed. Such tools would enable better detection and understanding of the specific pathologies that cause neurodegeneration. Ultimately, this would lead to the development of diagnostic biomarkers that allow more efficient and accurate patient selection for long-term monitoring in clinical trials and to support the development of novel therapeutics for ALS and FTD.

[0012] Several approaches have aimed to develop biochemical biomarkers to distinguish different types of FTD pathology. Several studies have shown that TDP-43 concentrations are increased in the cerebrospinal fluid (CSF) of clinically defined FTD or FTD-MND populations, but there is significant overlap with control or AD subjects, and it remains unclear whether this approach is clinically useful (Foulds et al., Acta Neuropathol., 2008, 116:141-146; Steinacker et al., Arch. Neurol., 2008;65(11):1481-1487). Levels of total tau or Thr181-phosphorylated tau do not distinguish FTLD-tau from controls. A potential diagnostic tool for distinguishing FTLD-tau from FTLD-TDP is a low CSF p-tau181 to tau ratio of less than 0.37 (Hu et al., Neurology., 2013;81(22):1945-1952). Another study showed that CSF phosphorylated tau levels were positively associated with brain tau burden in FTD and may be useful for distinguishing TDP-43 proteinopathies from tauopathies (Irwin et al., Ann. Neurol., 2017 Aug;82(2):247-258).

[0013] Along with biochemical biomarkers, the development of imaging biomarkers will enable early and specific detection of pathology in FTD, ALS, and other neurodegenerative disorders. The ability to image TDP-43 deposition in the brain would be a significant achievement in diagnostics and drug development for FTD, ALS, and other neurodegenerative disorders. Progressive TDP-43 accumulation in the CNS is associated with disease progression, making it an obvious target for the development of novel therapeutics and diagnostic tools to study pharmacodynamics and disease progression. Given the relative novelty of TDP-43 as a target, the development of PET tracers targeting this protein has only just begun. However, the majority of compounds reported to date are not specific for TDP-43, and none of these compounds have demonstrated direct binding to this target.

[0014] The development of a TDP-43-specific PET tracer faces several challenges, including the low abundance and heterogeneous distribution of the target in patient brains and the lack of a reference compound. To reduce background signal interference caused by nonspecific off-target binding and to reduce dosage requirements, TDP-43 imaging compounds should bind to the target with high affinity and selectivity. To image TDP-43 aggregates associated with neurological disorders such as FTD and ALS, imaging compounds must penetrate and cross the blood-brain barrier to enter relevant brain regions. To target intracellular amyloid-like inclusions such as TDP-43 aggregates, cell permeability is an additional requirement for imaging compounds. Rapid washout of the compound from the brain (or other target organs) is an additional requirement to avoid compound accumulation in tissues, which may increase the risk of undesirable side effects. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] US 8,932,557 [Non-patent literature]

[0016] [Non-Patent Document 1] Wang et al., Trends in Molecular Medicine, Vol. 14, No. 11, 2008, 479-485 [Non-patent document 2] Lagier-Tourenne et al., Human Molecular Genetics, 2010, Volume 19, Review Issue 1 R46-R64 [Non-patent document 3] Warraich et al., The International Journal of Biochemistry & Cell Biology, 42 (2010) 1606-1609 [Non-patent document 4] Buratti and Baralle, FEBS Journal, 277 (2010) 2268-2281 [Non-patent document 5] Arai et al., Biochemical and Biophysical Research Communications, 351 (2006) 602-611 [Non-patent document 6] Neumann et al., Science, 314, (2006), 130-133 [Non-Patent Document 7] Lagier-Tourenne and Cleveland, Cell, 136, 2009, 1001-1004 [Non-patent document 8] Ticozzi et al., CNS Neurol Disord Drug Targets, 2010, 9(3), 285-296. [Non-Patent Document 9] Neumann et al., Acta Neuropathol, (2009) 117:137-149 [Non-Patent Document 10] Hasegawa et al., Annals of Neurology, 2008, Vol. 64, No. 1, 60-70 [Non-Patent Document 11] Cohen et al., Nat Commun.;2015, 6:5845 [Non-Patent Document 12] Mackenzie and Neumann, J. Neurochem., (2016), 138 (Suppl. 1), 54-70 [Non-Patent Document 13] Le Ber, Revue Neurologique, 169 (2013), 811-819 [Non-Patent Document 14] Nelson et al., Brain, 2019, Volume 142; Issue 6, 1503-1527 [Non-Patent Document 15] Josephs KAら, Acta Neuropathol., 2014;127(6):811-824

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[0017] The object of the present invention was to provide compounds capable of binding to TDP-43 aggregates. In particular, the compounds of the present invention should be useful for identifying and differentiating patients and patient groups with TDP-43 proteinopathies (e.g., FTD, FTLD-TDP, LATE, and ALS) and for distinguishing TDP-43 proteinopathies from other proteinopathies. [Means for solving the problem]

[0018] Surprisingly, the present inventors have discovered that compounds having formula (I) are capable of recognizing and binding to TDP-43 aggregates.

[0019] Summary of the Invention The present invention is summarized in the appended claims. In particular, the present invention relates to a compound of formula (I):

[0020] [ka]

[0021] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R A is H or F; R 2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof; and the derived formula (Ia):

[0022] [ka]

[0023] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R 2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof; Or the derived formula (Ib):

[0024] [ka]

[0025] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R 2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof.

[0026] In another aspect, the present invention provides a diagnostic composition comprising a compound of formula (I) or a derivative thereof as defined herein and, optionally, at least one physiologically acceptable carrier, diluent, adjuvant, and / or excipient, which can be used for imaging TDP-43 aggregates, in particular by positron emission tomography, or for diagnosing a disease, disorder, or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy, in particular by positron emission tomography.

[0027] In another aspect, the present invention provides a method comprising: A method for diagnosing a disease, disorder, or condition associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, in a subject; · A method for positron emission tomography (PET) imaging of TDP-43 aggregates in tissue of a subject; A method for the detection and optional quantification of TDP-43 aggregates in tissue of a subject; Methods of collecting data for the diagnosis of a disease, disorder, or abnormality associated with TDP-43 aggregates or for the diagnosis of a TDP-43 proteinopathy: · A method for collecting data to determine a disease, disorder, or abnormality associated with TDP-43 aggregates or a predisposition to a TDP-43 proteinopathy; A method of collecting data to monitor the progression of a disease, disorder, or abnormality associated with TDP-43 aggregates or to monitor the progression of a TDP-43 proteinopathy in a patient; and A method for collecting data to predict the responsiveness of a patient suffering from a disease, disorder, or abnormality associated with TDP-43 aggregates or suffering from a TDP-43 proteinopathy to pharmaceutical treatment. The present invention provides compounds of formula (I) or derivatives thereof that can be used in the following:

[0028] In another aspect, the present invention provides compounds of formula (I) or derivatives thereof that can be used as biomarkers for TDP-43 aggregates or biomarkers for TDP-43 proteinopathies, as diagnostic agents or tools for TDP-43 proteinopathies, or as standards for in vitro analysis or as in vitro screening tools.

[0029] Precursors of compounds of formula (I) or derivatives thereof, having formula (II), (III), and (IV), or derivatives thereof, are also an aspect of the present invention.

[0030] In yet another aspect, the present invention relates to a kit for preparing a radiopharmaceutical preparation, the kit comprising a precursor of a compound of formula (I) or a derivative thereof. [Brief explanation of the drawings]

[0031] [Figure 1] Saturation binding curve of [3H]Compound 1 for human FTD sarkosyl-insoluble brain extract. Each point represents the mean ± standard error of the mean (SEM) of two independent experiments. [Figure 2] Saturation binding curve of [3H]Compound 11 for human FTD sarkosyl-insoluble brain extract. [Figure 3] Saturation binding curve of [3H]Compound 12 for human FTD sarkosyl-insoluble brain extract. [Figure 4] Saturation binding curve of [3H]Compound 4 for human FTD sarkosyl-insoluble brain extract. [Figure 5] Saturation binding curve of [3H]Compound 8 for human FTD sarkosyl-insoluble brain extract. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition Unless otherwise defined, the following definitions apply within the meaning of this application and, where appropriate, terms used in the singular also include the plural and vice versa.

[0033] The compounds of the present invention may have one or more optically active carbons, which may exist as racemates and racemic mixtures, stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, conformer mixtures and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described herein that contain olefinic double bonds include E and Z geometric isomers. All pharmaceutically acceptable salt forms, such as salts, polymorphs, hydrates, solvates, and mixtures thereof are also included in the present invention. Unless otherwise specified, the term "compound of Formula (X)" or "compound of the present invention" means "a compound of Formula (X), or a detectably labeled compound thereof, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof." Unless otherwise specified, the term "compounds of formula (X)" or "compounds of the invention" refers to compounds of formula (X) and derivative formulae thereof, as well as isotopically labeled compounds ( 18 F and 3 The term "compound of formula (X)" or "compound of the invention" means a compound as defined in any one of the embodiments mentioned below.

[0034] Unless otherwise specified, "----X" indicates that "X" is an optional substituent, i.e., "X" may or may not be present.

[0035] The term "polymorph" refers to various crystalline structures of the compounds of the present invention. This may include, but is not limited to, crystalline forms (and amorphous materials) and all crystalline lattice forms. Salts may be crystalline and may exist as two or more polymorphs.

[0036] Solvates, hydrates, and anhydrous forms of the salts are also encompassed by the present invention. The solvent contained in the solvate is not particularly limited and may be any pharmaceutically acceptable solvent. Examples include C 1~4 Alcohols such as methanol or ethanol are included.

[0037] "Pharmaceutically acceptable salts" are defined as derivatives of the compounds of the present invention where the parent compound has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. Pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate acid or base in water or an organic solvent, or in a mixture of both. Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, the disclosure of which is incorporated herein by reference. th ed., Mack Publishing Company, Easton, PA, 1990, page 1445. Typically, the pharmaceutically acceptable salts are salts of amine residues in the compounds of the invention.

[0038] A "patient" or "subject" in the present invention is usually an animal, particularly a mammal, more particularly a human and a mouse, and even more particularly a human.

[0039] For purposes of the present invention, a "diagnostic composition" is defined as a composition comprising a compound of the present invention in a form suitable for administration to a patient, eg, a mammal, such as a human.

[0040] "TDP-43 aggregates" refer to TDP-43-positive, multimer-rich aggregates of TDP-43. They are found as intracellular deposits in a series of diseases called TDP-43 proteinopathies, particularly amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant late-stage TDP-43 encephalopathy (LATE). TDP-43 aggregates can be found in the following morphologies: small, oval, or crescentic neuronal cytoplasmic inclusions (NCIs), lentiform neuronal intranuclear inclusions (NIIs), glial cytoplasmic inclusions (GCIs), degenerating neurites (DNs), and long, serpentine neurites. In pathological aggregates, TDP-43 often exhibits significantly increased post-translational modifications, such as phosphorylation, ubiquitination, acetylation, sumoylation, and proteolytic cleavage to generate C-terminal fragments.

[0041] The "preclinical state" of a disease is defined as a stage of the disease in which disease-related changes at the molecular level have not yet resulted in an overt clinical picture in the patient.

[0042] The "clinical state" of a disease is defined as the stage of the disease at which disease-related changes at the molecular level give rise to a clear clinical picture in the patient.

[0043] The term "diagnosing" or "diagnosis" generally refers to the process or act of recognizing, determining, or concluding a disease or condition in a patient based on symptoms and signs and / or from the results of a diagnostic procedure.

[0044] The "normal control value" is determined by performing each method on multiple healthy subjects, measuring the amount of compound (if any) bound to TDP-43 aggregates in each healthy subject, and calculating the average value.

[0045] A "healthy control subject (or patient)" or "healthy subject (or patient)" is a human who does not show clinical evidence of a neurodegenerative disease. The human meets the following criteria: Healthy male and female subjects with no clinically relevant findings upon physical examination. No (family) history of TDP-43 proteinopathy, TDP-43 aggregate formation, or other early-onset neurological disorders associated with dementia. No (personal) history of clinically significant neurological (and / or human psychiatric) disorders. No clinical signs or symptoms of current neurological deficits, such as cognitive impairment or motor deficits must be met.

[0046] A "preclinical control value" is determined by performing each method on multiple subjects in a preclinical state, measuring the amount of compound (if any) bound to TDP-43 aggregates in each subject, and calculating the average value.

[0047] A "clinical control value" is determined by performing each method on multiple subjects in a clinical state, measuring the amount of compound (if any) bound to TDP-43 aggregates in each subject, and calculating the average value.

[0048] The term "predict" or "prediction" generally refers to the advance pronouncement, prognosis, or forecast of a disease or condition in a patient who does not have the disease, disorder, or disorder. For example, a prediction of a disease, disorder, or disorder in a patient can indicate the probability, likelihood, or risk that the patient will suffer from the disease, disorder, or disorder, for example, within a certain time period or by a certain age.

[0049] Detectable labels include suitable isotopes, such as radioisotopes, in particular positron- or gamma-emitters; 2 H, 3 H, 18 F, 123 I, 124 I, 125 I, 131I, 11 C. 13 N, 15 O. 99m Tc, and 77 Br, preferably 2 H, 3 H, 11 C. 13 N, 15 O, and 18 F, more preferably 2 H, 3 H, and 18 F, more preferably 3 H and 18 F, most preferably 18 F is one example.

[0050] The terms "Hal," "halogen," or "halo" mean F, Cl, Br, or I, particularly Br or I, more particularly Br.

[0051] The term "carbocycle" refers to, but is not limited to, a 5- or 6-membered carbon ring, including any 5- or 6-membered saturated or unsaturated carbocycle, which may be substituted or unsubstituted. Unsaturated carbocycles include, but are not limited to, aromatic rings. Examples of 5- or 6-membered carbocycles include, for example, phenyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. Phenyl is preferred.

[0052] The term "heterocycle" refers to a stable 5- or 6-membered heterocycle, including, but not limited to, any 5- or 6-membered saturated or unsaturated heterocycle, which may be substituted or unsubstituted. Unsaturated heterocycles include, but are not limited to, aromatic rings. The heterocycle contains one or more heteroatoms (e.g., one or two heteroatoms) selected from N, O, and S. The heteroatom is preferably N or S, more preferably N. Examples of 5- or 6-membered heterocycles include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, oxathiolidinyl, isoxthiolidinyl, oxathiolyl, isoxathiolyl, thiazolidinyl, isothiazolidinyl, thiazolyl, and isothiazolyl, preferably pyridinyl, pyrazinyl, pyrimidinyl, and isothiazolyl.

[0053] The term "leaving group" (LG) as used herein refers to any leaving group, meaning an atom or group of atoms that can be replaced by another atom or group of atoms. Examples are shown, for example, in Synthesis (1982), pp. 85-125, Table 2; Carey and Sundberg, Organische Synthese, (1995), pp. 279-281, Table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71-83, Schemes 1, 2, 10, and 15). (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger PA, Friebe M., Lehmann L., (eds), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50, explicitly Scheme 4, p. 25; Scheme 5, p. 28; Table 4, p. 30; Figure 7, p. 33). Preferably, the "leaving group" (LG) is C 1~4 Alkyl sulfonate, C 6~10 Preferably, the leaving group (LG) is selected from arylsulfonate or nitro. More preferably, the leaving group (LG) is mesylate, tosylate, nosylate, or nitro. Even more preferably, the leaving group (LG) is mesylate or nitro, most preferably mesylate.

[0054] As used herein, the term "detecting" encompasses quantitative and / or qualitative detection.

[0055] The compounds of the invention can be used as analytical standards or in vitro screening tools.

[0056] For example, an unlabeled compound of formula (I) according to the present invention can be converted to a corresponding labeled compound of the present invention, such as a compound of the corresponding formula (IV) or a derivative thereof. 18It can be used as an analytical standard for quality control and publication of F-labeled compounds. This quality control is performed by an in vitro method.

[0057] The compounds of the present invention can be used as in vitro screening tools for the characterization of tissues with TDP-43 pathology and for the testing of compounds that target TDP-43 pathology on such tissues.

[0058] Unless otherwise stated, the preferred definitions set forth in the "Definitions" section apply to all embodiments described below. Various embodiments of the invention are described herein. It will be recognized that the features defined in each embodiment can be combined with other defined features to realize further embodiments of the invention.

[0059] Detailed Description of the Invention Various embodiments of the present invention are described herein, and it will be recognized that features defined in each embodiment may be combined with other defined features to realize further embodiments of the present invention.

[0060] It will be understood that all definitions given with respect to formula (I) apply to all its derivative genera, including formulas (Ia), (Ib), (II), (II'), (III), (IIIa), (IIIb), (IV), and (IVa).

[0061] In a first aspect, the present invention provides a compound of formula (I):

[0062] [ka]

[0063] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R A is H or F; R 2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more (preferably 1 or 2, more preferably 1) heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof; and the derived formula (Ia):

[0064] [ka]

[0065] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R 2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof; Or the derived formula (Ib):

[0066] [ka]

[0067] (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R2 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with F, NH, CN, and / or CH. or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof.

[0068] The present invention is A is H or F. In some preferred embodiments, the present invention relates to compounds of formula (I) wherein R A is H. In another preferred embodiment, the present invention relates to compounds of formula (I) (derived formula (Ia)), wherein R A is F.

[0069] The present invention relates to compounds of formula (I) or derivative formulae (Ia) or (Ib), wherein n is 1 or 2. In a preferred embodiment, n is 1. In another embodiment, n is 2.

[0070] The present invention is 1 is H or F. In a preferred embodiment, R 1 is H. In another most preferred embodiment, R 1 is F.

[0071] The present invention relates to a compound in which n is 1 and X is N; Y is CH; Z is CH; or X is N; Y is CH; Z is N; or X is N; Y is N; Z is CH; or X is CH; Y is CH; and Z is CH; The present invention relates to compounds of formula (I) or derivative formula (Ia) or (Ib).

[0072] The present invention is 2is a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with F, NH2, CN, and / or CH3. Thus, one or more identical or different substituents may be present. The substituents may be present at any available position. The number of substituents is not particularly limited and may range from 1 to the maximum number of available positions. Preferably, the number of substituents, when present, is 1 or 2. The heterocyclic ring contains one or more heteroatoms selected from N, O, and S, preferably N or S. The heteroatoms may be the same or different.

[0073] In a different embodiment, R 2 teeth a 5- or 6-membered carbocyclic ring, preferably an aryl ring, optionally substituted with F, NH, CN, and / or CH; a 5-membered heteroaryl ring optionally substituted with F, NH2, CN, and / or CH3 and containing one or more heteroatoms selected from N, O, and / or S; or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms selected from O, N, and / or S, optionally substituted with F, NH2, CN, and / or CH3; is.

[0074] R 2 Preferred examples of rings are given in the "Definitions" section above. Preferably, R 2is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, or isothiazolyl, any of which may be optionally substituted with F, NH, CN, and / or CH, for example with F, NH, and / or CH, preferably with F, and optionally with NH. In a preferred embodiment, phenyl is substituted with F and may be optionally substituted with NH and / or CN. In a preferred embodiment, pyrimidinyl is substituted with F. In another embodiment, pyrimidinyl is unsubstituted. In a preferred embodiment, pyridyl is unsubstituted. In a preferred embodiment, pyridyl is substituted with F. In a preferred embodiment, isothiazolyl is unsubstituted. In a preferred embodiment, pyrazinyl is substituted with F.

[0075] In one embodiment, the present invention provides a compound comprising R 2 is a 5- or 6-membered carbocyclic or 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with F, NH, and / or CH. Preferably, the 5- or 6-membered carbocyclic or heterocyclic ring is substituted with one or more F, NH, and / or CH.

[0076] In a preferred embodiment, R 2 is a 6-membered heteroaryl ring substituted with F and / or NH and containing at least one heteroatom which is N. In a preferred embodiment, R 2 is a pyridinyl ring substituted with F.

[0077] In one embodiment, the present invention provides R 2 but

[0078] [ka]

[0079] (In the formula, R 3 is F and R4 is NH2 and R 7 is H and R 8 is H; or R 3 is NH2 and R 4 is F and R 7 is H and R 8 is H; or R 3 is CN and R 4 is NH2 and R 7 is H and R 8 is H; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is CN; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is F) The present invention relates to a compound of formula (I) or derivative formula (Ia) or (Ib) wherein:

[0080] In a preferred embodiment, R 3 is F and R 4 is NH2 and R 7 is H and R 8 is H.

[0081] In another embodiment, the present invention provides R 2 but

[0082] [ka]

[0083] (Wherein W1 is N, S, or O, and W2 is N) The present invention relates to a compound of formula (I) or derivative formula (Ia) or (Ib) wherein:

[0084] In another embodiment, the present invention provides a compound comprising R 2 but

[0085] [ka]

[0086] (where "----F" indicates that "F" may or may not be present); or

[0087] [ka]

[0088] The present invention relates to compounds of formula (I)

[0089] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y is N and the other is CH; Z is CH; R 2 but

[0090] [ka]

[0091] (In the formula, R 3 is F and R 4 is -NH2 and R 7 and R 8 is H or CH3, preferably H).

[0092] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y (preferably X) is N and the other is CH; Z is CH; R 2 but

[0093] [ka]

[0094] (wherein W1 is S and W2 is N).

[0095] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least two of X, Y, and Z are N and the other is CH (preferably, X and Y are N and Z is CH); R 2 but

[0096] [ka]

[0097] It is defined as:

[0098] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y (preferably X) is N and the other is CH; Z is CH; R 2 but

[0099] [ka]

[0100] It is defined as:

[0101] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y (preferably X) is N and the other is CH; Z is CH; R 2 but

[0102] [ka]

[0103] It is defined as:

[0104] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y (preferably X) is N and the other is CH; Z is CH; R 2 but

[0105] [ka]

[0106] It is defined as:

[0107] In one embodiment, the compound of formula (I) or derivative formula (Ia) or (Ib) has n=1; R 1 is F; X, Y, and Z are independently CH or N; preferably, at least one of X or Y (preferably X) is N and the other is CH; Z is CH; or, X, Y, and Z are CH; R 2 but

[0108] [ka]

[0109] (wherein "----F" indicates that "F" may or may not be present).

[0110] Preferred compounds of formula (I) include

[0111] [ka]

[0112] Examples include:

[0113] In one embodiment, preferred compounds of formula (I) are the following stereoisomers:

[0114] [ka]

[0115] can be selected from:

[0116] In one embodiment, the present invention relates to a compound of formula (I) or a derivative formula (Ia) or (Ib) comprising at least one detectable label, i.e., the compound of formula (I) or a derivative formula (Ia) or (Ib) comprises one or more detectable labels.

[0117] The type of detectable label is not particularly limited and depends on the detection method selected. Examples of possible detectable labels include isotopes, such as radioisotopes (i.e., radionuclides), particularly positron emitters or gamma emitters. Detectable labels, such as radioisotopes, particularly positron emitters or gamma emitters, should be present in an amount that is not identical to the natural amount of each isotope. Furthermore, the amount used should allow its detection by the detection method selected.

[0118] In a preferred embodiment, the detectable label is 3 H and / or 18 F, most preferably 18 The detectable label can be present at any available position. Typically, the detectable label is a radioisotope of one of the atoms present in the compound of formula (I). For example, any reference to "F" in the present invention is 19 F (stable) or 18 Covers F (detectable label). Any reference to "H" 1 H (stable) or 3 H (detectable label, also called tritium, represented herein as "T").

[0119] Generally, the isotopic variants of the compounds of the present invention can be prepared by conventional procedures, for example, by exemplary methods, or by the preparation methods described in the following examples and preparation examples, using the appropriate isotopic variants of suitable reagents that are commercially available or prepared by known synthetic techniques.Radioisotopes, particularly positron emitters or gamma emitters, can be incorporated into the compounds of the present invention by methods that are common in the field of organic synthesis.Usually, they are introduced using correspondingly labeled starting materials.Exemplary methods for introducing detectable labels are described, for example, in US 8,932,557, which is incorporated herein by reference.

[0120] 18 F can be attached at any position suitable for attaching fluorine. 18 F-labeled compounds are particularly suitable for imaging applications such as positron emission tomography (PET). 19 The corresponding compounds containing F are 18 It is also of special interest because of its potential use as an analytical standard during the manufacture, quality control, release, and clinical use of the F analogs.

[0121] In the compounds having formula (I), 18 F is, for example, R 2 as an F substituent in, or R 1 Preferably, it can exist as R 1 (R 1 teeth 18 F).

[0122] 3 When H is used as a detectable label, it is -CT3 (T is -CT3) at any position where a CH3 group can be attached. 3 H). 3Substitution with radioisotopes such as H can provide certain diagnostic advantages afforded by increased metabolic stability, for example, by reduced defluorination, increased in vivo half-life, or reduced dosage requirements, while maintaining or improving the intrinsic efficacy of the compound.

[0123] In one embodiment, the present invention provides a method for producing a compound in which at least one hydrogen (H) is replaced by a tritium ( 3 and tritium (III) having the above formula (I), and derivative formula (Ia) or (Ib), wherein the tritium (III) is replaced with a detectable label selected from the group consisting of: 3 1 to 3 hydrogens (H) are detectably labeled with tritium ( 3 Tritium (III) having the formula (I) 3 3H) are preferably defined as compounds detectably labeled with tritium ( 3 Tritium (III) having the formula (I) 3 3H) are more preferably defined as compounds detectably labeled with tritium ( 3 Tritium (III) having formula (I) and derivative formula (Ia) or (Ib) 3 H) detectably labeled compounds are further preferably defined.

[0124] In one embodiment, the present invention provides a compound of formula (IT):

[0125] [ka]

[0126] (where n, R A , R 1 , R 2 , X, and Z are as defined herein for compounds of formula (I); Y is CR 6 and R 6 is T or H, and R 2 is substituted with at least one CT3, and / or R 2at least one hydrogen atom in the tritium ( 3 H), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof. 3 It's H.

[0127] In one embodiment, the present invention provides a compound of formula (I-Ta):

[0128] [ka]

[0129] (where n, R 1 , R 2 , X, and Z are as defined herein for compounds of formula (I); Y is CR 6 and R 6 is T or H, and R 2 is substituted with at least one CT3, and / or R 2 at least one hydrogen atom in the tritium ( 3 H), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof. 3 It's H.

[0130] In another embodiment, the present invention provides a compound of formula (I-Tb):

[0131] [ka]

[0132] (where n, R 1 , R 2 , X, and Z are as defined herein for compounds of formula (I); Y is CR 6 and R 6 is T or H, and R 2is substituted with at least one CT3, and / or R 2 at least one hydrogen atom in the tritium ( 3 H), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof. 3 It's H.

[0133] In some embodiments, R 6 is T. In other embodiments, R 6 is H.

[0134] In a preferred embodiment, R 2 At least one hydrogen atom in R is replaced by T. In a preferred embodiment, R 6 is T and R 2 At least one hydrogen atom in is replaced by T.

[0135] In a preferred embodiment, the present invention comprises: R 2 but

[0136] [ka]

[0137] (In the formula, R 3 is F and R 4 is -NH2 and R 7 and R 8 at least one of R is T and, if applicable, the other is H; preferably, R 7 and R 8 is T;R 6 is T); or R 2 but

[0138] [ka]

[0139] (In the formula, W 1 is S and W 2 is N and R 9 is T and R 6 is T); or R 2 but

[0140] [ka]

[0141] (In the formula, R 10 is T and R 6 is T); or R 2 but

[0142] [ka]

[0143] (In the formula, R 10 is T and R 6 is T); or R 2 but

[0144] [ka]

[0145] (In the formula, R 10 is T and R 6 is T); or R 2 but

[0146] [ka]

[0147] (wherein "----F" indicates that "F" may or may not be present, and R 10 is T and R 6 is T); or R 2 but

[0148] [ka]

[0149] (In the formula, R 10 is T and R 6 is T); or R 2 but

[0150] [ka]

[0151] (In the formula, R 10 is T and R 6 is H; or R 2 but

[0152] [ka]

[0153] (wherein "----F" indicates that "F" may or may not be present, and R 10 is T and R 6 is H.

[0154] In one embodiment, the present invention provides R 1 is H; R 6 is T; R 2 but

[0155] [ka]

[0156] (In the formula, R 3 is F;R 4 is -NH2; R 7 and R8 and at least one of R is T and, if applicable, the other is H. Preferably, R 7 is T;R 8 is T.

[0157] In one embodiment, the present invention provides R 1 is F; R 6 is T; R 2 but

[0158] [ka]

[0159] (In the formula, W 1 is S and W 2 is N and R 9 is T).

[0160] In one embodiment, the present invention provides R 1 is H or F; R 6 is T; R 2 but

[0161] [ka]

[0162] (In the formula, R 10 is T).

[0163] In a preferred embodiment, the present invention provides a compound of formula (IT):

[0164] [ka]

[0165] (Wherein, T is3 H).

[0166] The tritium ( 3 Preferred detectably labeled compounds include:

[0167] [ka]

[0168] (wherein T is 3 (meaning H).

[0169] More preferably, the tritium ( 3 H) The detectably labeled compound is a stereoisomer.

[0170] [ka]

[0171] (Wherein, T is 3 H).

[0172] In one embodiment, the present invention provides a compound of formula (IF):

[0173] [ka]

[0174] (In the formula, R 1' teeth 18 F;n, X, Y, Z, R A , and R 2 is as defined herein for compounds of formula (I), and preferably n is 1. of 18 A compound detectably labeled with F, or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, is provided.

[0175] In one embodiment, the compound of formula (IF) 18 The compound detectably labeled with F has the formula (I-Fa):

[0176] [ka]

[0177] (In the formula, R 1' teeth 18 F; n, X, Y, Z, and R 2 is as defined herein for compounds of formula (I), and preferably n is 1. or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof.

[0178] In one embodiment, the compound of formula (IF) 18 The compound detectably labeled with F has the formula (I-Fb):

[0179] [ka]

[0180] (In the formula, R 1' teeth 18 F; n, X, Y, Z, and R 2 is as defined herein for compounds of formula (I), and preferably n is 1. or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof.

[0181] In one embodiment, (IF) is the following compound: (R 1 teeth 18 F (detectable label):

[0182] [ka]

[0183] (Wherein, n and R 2 is as defined herein for compounds of formula (I).

[0184] In another embodiment, (IF) is the following compound:

[0185] [ka]

[0186] (Wherein, n and R 2 is as defined herein for compounds of formula (I).

[0187] In preferred embodiments of formula (IF), (I-Fa), or (I-Fb), n is 1 or 2; R 2 teeth

[0188] [ka]

[0189] (In the formula, R 3 is F and R 4 is NH2 and R 7 is H and R 8 is H); or R 2 teeth

[0190] [ka]

[0191] wherein W1 is S and W2 is N; or R 2 teeth

[0192] [ka]

[0193] (wherein "----F" indicates that "F" may or may not be present); or

[0194] [ka]

[0195] is.

[0196] In a preferred embodiment, the present invention comprises: n is 1 or 2; R 1 teeth 18 F (detectable label); R 2 teeth

[0197] [ka]

[0198] The present invention relates to a compound of formula (IF),

[0199] In a preferred embodiment, n is 1.

[0200] The compound of the present invention, 18 Preferred compounds detectably labeled with F are

[0201] [ka]

[0202] is.

[0203] More preferably, the compound of the present invention is of formula (IF) 18 Compounds detectably labeled with F may be used to identify stereoisomers.

[0204] [ka]

[0205] It is possible.

[0206] Diagnostic Compositions In a second aspect, the present invention relates to a diagnostic composition comprising a compound of formula (I) as defined above and, optionally, at least one physiologically acceptable carrier, diluent, adjuvant, and / or excipient.

[0207] The compounds of the present invention are particularly suitable for imaging TDP-43 aggregates. Imaging can be performed in mammals, particularly humans. The imaging is preferably in vitro imaging, ex vivo imaging, or in vivo imaging. More preferably, the imaging is in vivo imaging. Even more preferably, the imaging is brain imaging. The imaging may be ocular / retinal imaging, or imaging of tissues of the central nervous system.

[0208] The compounds or compositions of the present invention are particularly suitable for use in diagnostic methods. Diagnostic methods can be performed on mammals, particularly humans. The tissue of interest on which the diagnostic method is performed can be the brain, tissue of the central nervous system, tissue of the eye (e.g., retinal tissue), or other tissues, or body fluids such as cerebrospinal fluid (CSF). The tissue is preferably brain tissue.

[0209] In the present invention, a "diagnostic composition" is defined as a composition comprising one or more compounds of the present invention in a form suitable for administration to a patient (e.g., a mammal such as a human) and suitable for use in diagnosing a particular disease, disorder, or abnormality in a tissue. In one embodiment, a diagnostic composition comprises a detectably labeled compound of the present invention as described above, and optionally at least one physiologically acceptable carrier, diluent, adjuvant, and / or excipient.

[0210] Preferred detectably labeled compounds of the present invention are compounds of formula (IT) or derivative formulae (I-Ta) and (I-Tb), or formula (IF) or derivative formulae (I-Fa) and (I-Fb).

[0211] The diagnostic composition or compound is particularly suitable for use in imaging TDP-43 aggregates by positron emission tomography.

[0212] The diagnostic composition is suitable for use in the diagnosis of a disease, disorder or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy, as defined below, in particular by positron emission tomography.

[0213] Preferably, the diagnostic composition further comprises a physiologically acceptable excipient, carrier, diluent, or adjuvant. Administration is preferably by injection of the composition as defined below, more preferably as an aqueous solution. The diagnostic composition may optionally contain additional components such as a buffer; a pharmaceutically acceptable solubilizing agent (e.g., a cyclodextrin, or a surfactant such as Pluronic, Tween, or a phospholipid); and a pharmaceutically acceptable stabilizer or antioxidant (e.g., ascorbic acid, gentisic acid, or p-aminobenzoic acid). Dosages of the compounds of the present invention will vary depending on the exact compound administered, the patient's weight, and other variables that will be apparent to a physician skilled in the art.

[0214] While the compounds of the present invention can be administered alone, they are preferably formulated as diagnostic compositions in accordance with standard pharmaceutical practice. Thus, diagnostic compositions comprising a diagnostically effective amount of a compound of the present invention in combination with a pharmaceutically acceptable carrier, diluent, adjuvant, and / or excipient are part of the present invention. Preferred pharmaceutically acceptable carriers, diluents, adjuvants, and / or excipients are those that are physiologically compatible with the diagnostic compositions of the present invention.

[0215] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 18 thEd. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990). Pharmaceutically acceptable excipients can be selected with regard to the intended route of administration and standard pharmaceutical practice. Excipients must be acceptable in the sense of not being harmful to the recipients thereof.

[0216] Pharmaceutically useful excipients, carriers, adjuvants, and diluents that can be used in formulating the diagnostic compositions of the present invention may include, for example, solvents; monohydric alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycol; edible oils such as soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil; oily esters such as ethyl oleate and isopropyl myristate; binders, adjuvants, solubilizers, thickeners, stabilizers, disintegrants, glidants, lubricants, buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorings, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and drug delivery enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, glucose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low-melting point waxes, and ion exchange resins.

[0217] Routes of administration (delivery) of the compounds of the present invention include, but are not limited to, one or more of intravenous, gastrointestinal, intraspinal, intraperitoneal, intramuscular, oral (e.g., as a tablet, capsule, or ingestible liquid), topical, mucosal (e.g., as a nasal spray or inhaled aerosol), intranasal, parenteral (e.g., in injectable form), intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, intraocular (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual. Preferably, the route of administration (delivery) of the compounds of the present invention is parenteral.

[0218] The compounds of the invention (e.g., detectably labeled compounds, e.g., detectably labeled 3 H or 18When a compound having F is administered parenterally, examples of such routes of administration include one or more of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, or subcutaneous, and / or by use of infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other excipients. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art.

[0219] A physician will generally determine the actual dosage that will be most suitable for an individual patient. 3 H or 18 The dosage of the compound having F will vary depending on the exact compound administered, the patient's weight, the size and type of sample, and other variables that will be apparent to a physician skilled in the art. In general, dosages may range from 0.001 μg / kg to 10 μg / kg, preferably 0.01 μg / kg to 1.0 μg / kg. The radiation dose may be, for example, 100 to 600 MBq, more preferably 150 to 450 MBq.

[0220] Due to their design and binding properties, the compounds of the invention defined herein can be used in the diagnosis of diseases, disorders, and conditions associated with TDP-43 aggregates. The compounds of the invention are particularly suitable for positron emission tomography imaging of TDP-43 aggregates.

[0221] The compounds or diagnostic compositions or methods of the invention disclosed herein may be used to treat diseases, disorders, or abnormalities associated with TDP-43 aggregates, or TDP-43 proteinopathies, such as frontotemporal dementia (FTD, e.g., sporadic or familial with or without motor neuron disease (MND), with progranulin (GRN) mutations, with C9orf72 mutations, with TARDBP mutations, with valosin-containing protein (VCP) mutations, chromosome 9p-linked, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) (previously unrelated). Frontotemporal lobar dementia (including TDP-43 or frontotemporal lobar degeneration with ubiquitin-positive TDP-43 inclusions (FTLD-TDP)), argyrophilic grain disease, Pick's disease, semantic primary progressive aphasia (svPPA), behavioral FTD (bvFTD), non-fluent primary progressive aphasia (e.g., nfvPPA), amyotrophic lateral sclerosis (ALS, e.g., sporadic ALS, those with TARDBP mutations, those with angiogenin (ANG) mutations), Alexander disease (AxD), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease, and Alzheimer's disease. Zheimer's disease (including sporadic and familial forms of AD), Down's syndrome, familial British dementia, polyglutamine diseases (Huntington's disease and spinocerebellar ataxia type 3 (SCA3; also known as Machado-Joseph disease)), hippocampal sclerosis dementia and myopathy (sporadic inclusion body myositis, inclusion body myopathy with mutations in valosin-containing protein (VCP), and Paget's disease of bone and frontotemporal dementia), oculopharyngeal muscular dystrophy with rimmed vacuoles, myotilin-associated myopathy with mutations in the myotilin (MYOT) gene or the gene encoding desmin (DES), It is particularly suitable for use in the diagnosis of a disease, disorder, or abnormality selected from, but not limited to, fibrillary myopathy, traumatic brain injury (TBI), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), and preferably, the TDP-43 aggregate-associated disease, disorder, or abnormality or TDP-43 proteinopathy is selected from frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and limbic-predominant late-life TDP-43 encephalopathy (LATE).

[0222] In one embodiment, the TDP-43 aggregate-associated disease, disorder, or condition or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

[0223] In one embodiment, the diagnosis of a disease, disorder, or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy is Alzheimer's disease (AD).

[0224] In one embodiment, the diagnosis of a disease, disorder, or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy is frontotemporal dementia (FTD), including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).

[0225] In one embodiment, the diagnosis of a disease, disorder, or condition associated with TDP-43 aggregates or TDP-43 proteinopathy is limbic-predominant late-life TDP-43 encephalopathy (LATE).

[0226] Methods and Uses In a third aspect, the present invention provides the following methods and uses: A method for diagnosing a disease, disorder, or condition associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, in a subject; · A method for positron emission tomography (PET) imaging of TDP-43 aggregates in tissue of a subject; A method for the detection and optionally quantification of TDP-43 aggregates in tissue of a subject; A method for determining the amount of TDP-43 aggregates in a sample or in a specific body part or body region; Methods of collecting data for the diagnosis of a disease, disorder, or abnormality associated with TDP-43 aggregates or for the diagnosis of a TDP-43 proteinopathy: · A method for collecting data to determine a disease, disorder, or abnormality associated with TDP-43 aggregates or a predisposition to a TDP-43 proteinopathy; A method of collecting data to monitor the progression of a disease, disorder, or abnormality associated with TDP-43 aggregates or to monitor the progression of a TDP-43 proteinopathy in a patient; A method of collecting data to predict the responsiveness of a patient suffering from a disease, disorder, or abnormality associated with TDP-43 aggregates or suffering from a TDP-43 proteinopathy to pharmaceutical treatment; Use of the compounds of the invention as biomarkers of TDP-43 aggregates or as biomarkers of TDP-43 proteinopathies, Use of the compounds of the invention as diagnostic agents or tools for TDP-43 proteinopathies, Use of the compounds of the present invention as in vitro analytical standards or in vitro screening tools Regarding.

[0227] Any compound of the present invention (e.g., compounds of formulae (IA)-(IJ), (I'-A)-(I'-J), (IT), and (IF)) can be used in the methods summarized above. Preferably, the compound is a detectably labeled compound (e.g., a detectable label 3 H or 18 F). The compounds of formula (II), (III), and (IV) are precursors of the compound of formula (I).

[0228] The methods of the present invention may include contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention or a diagnostic composition comprising a compound of the present invention.

[0229] The body is preferably a mammalian body, more preferably a human body, and includes the whole body or partial body regions / body parts of a patient suspected of containing TDP-43 aggregates.

[0230] The sample may be selected from tissues or body fluids suspected of containing TDP-43 aggregates, which are samples obtained from patients. Preferably, the tissue is selected from tissues of the central nervous system (CNS), eye tissue, or brain tissue, more preferably brain tissue. Examples of body fluids include cerebrospinal fluid (CSF) or blood. The sample may be obtained from a mammal, more preferably a human. Preferably, the sample is an in vitro sample derived from a patient.

[0231] An in vitro sample or a particular body part or area obtained from a patient can be contacted with a compound of the invention by direct incubation.

[0232] In the in vivo method, a specific body part or region can be contacted with a compound of the present invention by administering an effective amount of the compound of the present invention to a patient, the effective amount being an amount sufficient to allow the presence or absence of TDP-43 aggregates in the specific body part or region to be determined using a selected analytical technique.

[0233] The step of binding the compounds of the present invention to TDP-43 aggregates involves allowing sufficient time for this binding to occur. The amount of time required for binding depends on the type of test (e.g., in vitro or in vivo) and can be determined by one of ordinary skill in the art through routine experimentation. For in vitro methods, the amount of time depends on the sample or the specific body part or region and can range, for example, from about 30 minutes to about 120 minutes. For in vivo methods, the amount of time depends on the time required for the compounds of the present invention to reach the specific body part or region suspected of containing TDP-43 aggregates. The amount of time should not be too long to avoid washout and / or metabolism of the compounds of the present invention. The period can range, for example, from about 0 minutes to about 240 minutes (the duration of PET scans during initial compound characterization (NHP PET and subsequent FiH studies)).

[0234] The method for detecting the compound of the present invention bound to TDP-43 aggregates is not particularly limited and depends, inter alia, on the detectable level, the type of sample, the specific body part or region, and whether the method is an in vitro or in vivo method. Possible detection methods include, but are not limited to, fluorescent or nuclear imaging techniques such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). Fluorescent and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the compound of the present invention within a sample or body. The imaging system is a system that displays an image of a detectably bound label, such as a radioisotope, particularly a positron emitter or gamma emitter, as present in the examined sample, the examined specific body part, or the examined body region. Preferably, the compound of the present invention bound to TDP-43 aggregates is detected by an imaging device such as a PET or SPECT spacer. The amount of compound bound to TDP-43 can be determined by visual or quantitative analysis, for example, using a PET scan image.

[0235] In one embodiment, the presence or absence of a compound of the present invention bound to TDP-43 aggregates in a sample or a specific body part or region can be correlated with the presence or absence of TDP-43 aggregates. The correlation can be qualitative or quantitative. In a preferred embodiment, this step (d) comprises the following steps: - quantifying the amount of the compound of the invention bound to the TDP-43 aggregates, for example by measuring the radioactive signal of the compound bound to the TDP-43 aggregates; - correlating the amount of the compound of the invention bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - optionally comparing the amount of compound bound to TDP-43 aggregates in the sample or in a particular body part or region with a normal control value in a healthy control subject.

[0236] The amount of compound bound to TDP-43 aggregates can be determined by any suitable method, with a preferred method being positron emission tomography (PET).

[0237] In another embodiment, the presence or absence of a compound of the present invention bound to TDP-43 aggregates can be correlated with a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto. The correlation can be qualitative or quantitative. In a preferred embodiment, this step (d) comprises the following steps: - quantifying the amount of the compound of the invention bound to the TDP-43 aggregates, for example by measuring the radioactive signal of the compound bound to the TDP-43 aggregates; - correlating the amount of the compound of the invention bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - optionally comparing the amount of compound bound to TDP-43 aggregates in the sample or in a particular body part or region with a normal control value in a healthy control subject.

[0238] In any of the methods disclosed herein, steps (a)-(c), and optional steps (d) and (e), if present, can be repeated at least once. Repeating the steps is particularly useful in methods for collecting data to monitor progression and for predicting responsiveness. In these methods, it may be advantageous to monitor the patient over time and repeat the steps after a certain period of time. The time interval before repeating the steps can be determined by a physician depending on the severity of the disease, disorder, or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy.

[0239] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates. The present invention relates to a method for detecting a neurological disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, in a subject, comprising:

[0240] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention disclosed herein; or a diagnostic composition comprising a compound of the invention disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting and optionally quantifying the compound bound to the TDP-43 aggregates using positron emission tomography. The present invention relates to a method (e.g., an in vivo method or an in vitro method) for detecting and optionally quantifying TDP-43 aggregates in tissue of a subject, comprising:

[0241] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates by collecting positron emission tomography (PET) images of the subject's brain. The present invention relates to a method for diagnostic imaging of the brain of a subject, comprising:

[0242] Imaging: The present invention relates to methods for imaging TDP-43 aggregates using the compounds of the present invention. Imaging can be performed using, for example, any of the methods described above, in particular by PET.

[0243] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates. The present invention relates to a method for imaging TDP-43 aggregates in a sample or a patient, particularly in the brain, or in a sample taken from the brain of a patient, comprising:

[0244] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to TDP-43 aggregates in the brain of the subject. The present invention relates to a method for imaging or diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, in a subject, comprising:

[0245] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates. The present invention relates to a method for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, in a subject, comprising:

[0246] In one embodiment, a method for diagnosing a disease, disorder, or condition associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, comprises the steps of: (d) generating an image representing the location and / or amount of compound bound to the TDP-43 aggregates; (e) an optional step of comparing the generated image with a control image of a healthy control subject, wherein an increase in binding signal indicates that the subject is suffering from or at risk of developing a TDP-43 aggregate-associated disease, disorder, or condition, or a TDP-43 proteinopathy.

[0247] In one embodiment, the present invention provides a method for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, in a subject, comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to TDP-43 aggregates; (c) detecting the compound bound to the TDP-43 aggregate; and (d) generating an image representing the location and / or amount of compound bound to TDP-43 aggregates.

[0248] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) administering to a subject a compound of the invention; or a diagnostic composition comprising a compound of the invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates by collecting positron emission tomography (PET) images of the tissue of interest. The present invention relates to a method for positron emission tomography (PET) imaging of TDP-43 aggregates in tissue of a subject, comprising:

[0249] Preferably, the tissue is central nervous system (CNS) tissue, eye tissue, or brain tissue. More preferably, the tissue is brain tissue.

[0250] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting compounds bound to TDP-43 aggregates by imaging the sample, specific body part, or body region with an imaging system. The present invention relates to a method for imaging TDP-43 aggregates in a sample or a patient, comprising:

[0251] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) contacting an in vitro sample suspected of containing TDP-43 aggregates with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention, as disclosed herein; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates by imaging the in vitro sample with an imaging system. The present invention relates to a method for imaging TDP-43 aggregates in an in vitro patient sample, comprising:

[0252] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) contacting a sample, or a specific body part or region, suspected of containing TDP-43 aggregates, with a compound of the present invention, preferably a compound of formula (I-T) or derivative formula (I-Ta) or (I-Tb), or formula (I-Fa) or (I-Fb), as disclosed herein; or with a diagnostic composition comprising a compound of the present invention, preferably a compound of formula (I-T) or formula (I-Fa); (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates by imaging the sample or a specific body part or body region of the patient with an imaging system. The present invention relates to a method for imaging TDP-43 aggregates in a patient or in a specific body part or region of a patient, comprising:

[0253] The step of imaging the sample, patient, or specific body part or region of the patient with an imaging system includes detecting the compound of the present invention bound to TDP-43 aggregates using the imaging system disclosed herein. Detecting the compound of the present invention bound to TDP-43 aggregates by imaging allows for the identification of the distribution of TDP-43 aggregates in the tested sample, patient, specific body part, or region. PET imaging should be performed when the compound has entered the tissue and bound to the TDP-43 aggregates.

[0254] Determine the amount of TDP-43 aggregates: In one embodiment, the present invention relates to a method for determining the amount of TDP-43 aggregates in a sample, a particular body part, or a body region suspected of containing TDP-43 aggregates using the compounds of the present invention.

[0255] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention, as disclosed herein; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; (d) quantifying the amount of the compound of the invention bound to the TDP-43 aggregates by measuring the radioactive signal of the compound; and (e) Optional step of calculating the amount of TDP-43 aggregates in a sample, a specific body part, or a body region. The present invention provides a method for determining the amount of TDP-43 aggregates in a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates, comprising:

[0256] The amount of TDP-43 aggregates can be calculated, for example, by determining Bmax (maximum number of binding sites).

[0257] At least one radiolabeled atom (e.g. 3 H, 2 H, or 18 When a detectably labeled compound of the invention comprising F) binds to TDP-43 aggregates, a radioactive signal is observed.

[0258] Diagnose: In one embodiment, the present invention provides a method for producing a method comprising the steps of: (c) detecting a compound of the invention bound to TDP-43 aggregates; and (d) correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with a disease, disorder, or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy. The present invention relates to a method for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, comprising:

[0259] Preferably, the method for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, comprises the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention, as disclosed herein; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; and (d) correlating the presence or absence of a compound of the present invention bound to TDP-43 aggregates in a sample or in a particular body part or region with a disease, disorder, or condition associated with TDP-43 aggregates, or a TDP-43 proteinopathy.

[0260] In one embodiment, the present invention provides a method for producing a method comprising the steps of: (a) contacting a sample or a specific body part or region suspected of containing TDP-43 aggregates with a compound of the present invention; or a diagnostic composition comprising a compound of the present invention; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; and (d) an optional step of correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or in a particular body part or body region. The present invention relates to a method for collecting data for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, comprising:

[0261] After contacting a sample or a specific body part or region with the compound of the present invention, the compound binds to TDP-43 aggregates. The amount of time required for binding depends on the type of test (e.g., in vitro or in vivo) and can be determined by one skilled in the art through routine experimentation. The compound bound to the TDP-43 aggregates can then be detected by any suitable method. The specific method selected will depend on the selected detectable level. Examples of possible methods include, but are not limited to, fluorescent or nuclear imaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). Fluorescent and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the detectably labeled compound within a sample or a specific body part or region.

[0262] The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region, as mentioned above, comprises the following steps: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - an optional step of comparing the amount of compound bound to TDP-43 aggregates in the sample or in a specific body part or body region with a normal control value in a healthy control subject. Includes.

[0263] The amount of compound bound to TDP-43 aggregates can be compared to a normal control value established in a sample from healthy subjects or in a specific body part or region, and an increase in the amount of compound bound to TDP-43 aggregates compared to the normal control value can indicate that the patient is suffering from or at risk of developing a TDP-43 aggregate-associated disease, disorder, or condition, or a TDP-43 proteinopathy.

[0264] If the amount of compound bound to TDP-43 aggregates is greater than the normal control value defined herein, it can be predicted that the patient is suffering from or has a high probability of suffering from a disease, disorder, or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0265] Determine predisposing factors: A further aspect of the present invention relates to a method of collecting data to determine a predisposition to a disease, disorder, or condition associated with TDP-43 aggregates or a TDP-43 proteinopathy, the method comprising the steps of: (a) contacting a sample or a specific body part or region suspected of containing TDP-43 aggregates with a compound of the present invention; or a diagnostic composition comprising a compound of the present invention; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; and (d) an optional step of correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or in a particular body part or body region. Includes.

[0266] The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region, as mentioned above, comprises the following steps: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - an optional step of comparing the amount of compound bound to TDP-43 aggregates in the sample or in a specific body part or body region with a normal control value in a healthy control subject. Includes.

[0267] If the amount of compound bound to TDP-43 aggregates is higher than the normal control value for healthy subjects / reference subjects, this indicates that the patient / subject is suffering from or at risk of developing a TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy. In particular, if the amount of compound bound to TDP-43 aggregates is higher than expected in an individual who does not show clinical evidence of a neurodegenerative disease, the patient may be considered to have a predisposition to a TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy.

[0268] Monitor disease progression: In one embodiment, the present invention relates to a method for monitoring the progression of a TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy in a patient. Typically, the patient is undergoing or has undergone treatment for the TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy. In particular, the treatment may include administration of an anti-TDP-43 drug.

[0269] A method for collecting data to monitor the progression of a disease, disorder, or abnormality associated with TDP-43 aggregates or to monitor the progression of a TDP-43 proteinopathy in a patient, comprising the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; (d) an optional step of correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region; and (e) the optional step of repeating steps (a) through (c) and, if present, optional step (d) at least once. Includes.

[0270] Steps (a)-(c), and optional step (d), if present, can be repeated one or more times to monitor the progression of a TDP-43 aggregate-associated disease, disorder, or disorder or TDP-43 proteinopathy over time. Preferably, these steps should be repeated until no further progression of the disease is observed in the patient.

[0271] The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region, as mentioned above, comprises the following steps: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - an optional step of comparing the amount of compound bound to TDP-43 aggregates in the sample or in a specific body part or body region with a normal control value in a healthy control subject. Includes.

[0272] In methods for monitoring progression over time, the amount of a compound of the invention bound to TDP-43 aggregates may optionally be compared at various times during treatment, e.g., before and after initiation of treatment, and / or at various times after initiation of treatment. A change, particularly a decrease, in the amount of a compound of the invention bound to TDP-43 aggregates may indicate that the disease is not progressing.

[0273] Predicting disease: In one embodiment, the present invention relates to a method for prognosing a TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy in a patient. Typically, the patient is undergoing or has undergone treatment for a TDP-43 aggregate-associated disease, disorder, or disorder, or a TDP-43 proteinopathy. In particular, the treatment may include administration of an anti-TDP-43 drug.

[0274] A method for collecting data to predict a disease, disorder, or abnormality associated with TDP-43 aggregates or to predict a TDP-43 proteinopathy in a patient, comprising the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention; or a diagnostic composition of the present invention comprising a compound of the present invention; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; (d) an optional step of correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region; and (e) the optional step of repeating steps (a) through (c) and, if present, optional step (d) at least once.

[0275] Steps (a)-(c), and optional step (d), if present, can be repeated one or more times to predict the progression of a TDP-43 aggregate-associated disease, disorder, or disorder or TDP-43 proteinopathy over time. Preferably, these steps should be repeated until no further progression of the disease is observed in the patient.

[0276] The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region, as mentioned above, comprises the following steps: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - optionally comparing the amount of compound bound to TDP-43 aggregates in the sample or in a particular body part or region with a normal control value in a healthy control subject.

[0277] In methods for predicting progression over time, the amount of a compound of the invention bound to TDP-43 aggregates may optionally be compared at various time points during treatment, such as before and after initiation of treatment and / or at various time points after initiation of treatment. A change, particularly a decrease, in the amount of a compound of the invention bound to TDP-43 aggregates may indicate that the disease is not progressing.

[0278] Predict responsiveness: In one embodiment, the present invention relates to a method for predicting the responsiveness of a patient suffering from a TDP-43 aggregate-associated disease, disorder, or disorder or suffering from a TDP-43 proteinopathy to treatment of said TDP-43 aggregate-associated disease, disorder, or disorder or TDP-43 proteinopathy.

[0279] The method can be used to predict the most suitable treatment for a patient. In particular, the treatment may include the administration of an anti-TDP-43 drug.

[0280] A method for predicting the responsiveness of a patient suffering from a TDP-43 aggregate-associated disease, disorder, or disorder or suffering from a TDP-43 proteinopathy to a treatment for said TDP-43 aggregate-associated disease, disorder, or disorder or TDP-43 proteinopathy comprises the steps of: (a) contacting a sample, a specific body part, or a body region suspected of containing TDP-43 aggregates with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention, as disclosed herein; (b) binding a compound of the present invention to TDP-43 aggregates; (c) detecting a compound of the invention bound to TDP-43 aggregates; (d) an optional step of correlating the presence or absence of a compound of the invention bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region; and (e) the optional step of repeating steps (a) through (c) and, if present, optional step (d) at least once. may include:

[0281] Typically, the patient is undergoing / has undergone treatment for a disease, disorder, or disorder associated with TDP-43 aggregates or a TDP-43 proteinopathy. In particular, the treatment may include the administration of a medicament suitable for treating a disease, disorder, or disorder associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0282] This method makes it possible to predict a patient's responsiveness to a particular treatment. In one embodiment, responsiveness can be estimated, for example, by repeating steps (a) to (c) and, if present, optional step (d), and monitoring the amount of the compound of the present invention bound to TDP-43 aggregates over a period of time while the patient is undergoing treatment for a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. If the amount changes over time, one skilled in the art can estimate whether the patient will respond to the treatment. Generally, if the amount of the compound of the present invention bound to TDP-43 aggregates decreases over time, the patient can be considered responsive to the treatment. Generally, if the amount of the compound bound to TDP-43 aggregates remains essentially constant or increases over time, the patient can be considered non-responsive to the treatment.

[0283] Alternatively, responsiveness can be estimated by determining the amount of a compound of the present invention bound to TDP-43 aggregates. The amount of compound bound to TDP-43 aggregates can be compared to a control value, such as a normal control value, a preclinical control value, or a clinical control value. The control value may refer to a control value of a healthy control subject. Alternatively, the control value may refer to a control value of a subject known to be responsive to a particular treatment, or the control value may refer to a control value of a subject known to be non-responsive to a particular treatment. The result regarding responsiveness can be "responsive" to a particular treatment, "non-responsive" to a particular treatment, or "undetermined responsiveness" to a particular treatment. Response to treatment can vary from patient to patient.

[0284] The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region, as mentioned above, comprises the following steps: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - an optional step of comparing the amount of compound bound to TDP-43 aggregates in the sample or in a specific body part or body region with a normal control value in a healthy control subject. Includes.

[0285] A control value can be, for example, a normal control value, a preclinical control value, and / or a clinical control value. A "healthy control subject" or "healthy subject" is an individual who does not show clinical evidence of a neurodegenerative disease.

[0286] In any of the methods summarized above, if the amount of compound bound to TDP-43 aggregates is greater than the normal control value, it can be predicted that the patient is suffering from or has a high probability of suffering from a disease, disorder, or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy.

[0287] Any compound of the present invention can be used in the methods summarized above. Preferably, the detectably labeled compounds of the present invention disclosed herein can be used in the methods summarized above.

[0288] In a fourth aspect, the present invention relates to the use of the compounds of the present invention as diagnostic agents or tools for TDP-43 aggregates. In one embodiment, the present invention relates to the use of the compounds of the present invention as standards for in vitro analysis or as in vitro screening tools. The compounds of the present invention are also useful in in vivo diagnostic methods. In these cases, the compounds of the present invention may be detectably labeled or may contain non-radioactive isotopes.

[0289] In another embodiment, the present invention further relates to the use of the compounds of the invention as defined herein, more particularly the detectably labeled compounds of the invention, as diagnostic biomarkers that allow for more efficient and accurate patient selection, for example for long-term monitoring in clinical trials or to aid in the development of new therapeutics for the treatment of TDP-43 proteinopathies. In another embodiment, the present invention further relates to the use of the compounds of the invention as defined herein, more particularly the detectably labeled compounds of the invention, as biomarkers for TDP-43 aggregates or for TDP-43 proteinopathies.

[0290] In another embodiment, the compounds of the present invention can be used for research, particularly as analytical tools or reference molecules. The compounds can also be used to detect TDP-43 aggregates in vitro or in vivo. The compounds of the present invention can be used to stain TDP-43 aggregates. For example, the compounds of the present invention can be used for histochemical detection in postmortem tissues such as brain tissue. The compounds of the present invention are preferably detectably labeled compounds, and can be labeled directly or indirectly as described herein.

[0291] Kit of Parts In a fifth aspect, the present invention further relates to a kit for use in one or more methods of the present invention, comprising a compound of the present invention as described herein. Typically, the kit comprises a container holding a compound of the present invention and instructions for using the compound of the present invention. Preferably, the kit comprises a compound of formula (I) as disclosed herein. More preferably, the compound of the present invention is a detectably labeled compound (e.g., a compound of formula (IT) or derivative formula (I-Ta) or (I-Tb), or formula (IF) or derivative formula (I-Fa) or (I-Fb)).

[0292] The term "kit" generally refers to any diagnostic kit known in the art. More specifically, the latter term refers to the diagnostic kit described in Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.

[0293] Doses of detectably labeled compounds of the present invention will vary depending on the exact compound administered, the patient's weight, the size and type of sample, and other variables that will be apparent to a physician skilled in the art. In general, doses can range from 0.001 μg / kg to 10 μg / kg, preferably 0.01 μg / kg to 1.0 μg / kg. Radiation doses can range, for example, from 100 to 600 MBq, more preferably from 150 to 450 MBq.

[0294] In particular, these kits may be useful for performing the methods of the present invention (e.g., including, but not limited to, imaging, diagnostic, and monitoring methods), for example, for diagnosing a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. These kits may contain all of the components necessary to perform the methods provided herein. Typically, each component is stored separately in a single, complete package. Suitable additional components included in the kit include, for example, buffers, detectable dyes, laboratory equipment, reaction vessels, instructions, etc. The instructions can be adapted to the particular method in which the kit is to be used.

[0295] The present invention further relates to a kit for preparing the detectably labeled compounds of the present invention, wherein the detectable label is, in particular, a radioisotope. Thus, the kit comprises a precursor of the detectably labeled compound of formula (I) and a labeling agent that reacts with the precursor to introduce a detectable (e.g., radioactive) label. Preferred precursors include compounds of formula (II), (III), or (IV). The labeling agent that reacts with the precursor is 18 F or 3 The labeling agent can be an agent that introduces a detectable (e.g., radioactive) label, such as H. 18 F-can be a fluorinating agent.

[0296] The present invention further relates to a kit for preparing a radiopharmaceutical preparation comprising a precursor of a detectably labeled compound of formula (I), which is a compound of formula (II), or a compound of formula (III), or a compound of formula (IV).

[0297] Methods for preparing compounds of the present invention In a sixth aspect, the present invention further relates to a method for preparing a compound of formula (I).

[0298] Non-radioactive isotopic compounds: In one embodiment, the present invention provides a method for producing a method for manufacturing a semiconductor device comprising the steps of: Compound of formula (II) and R 13 by reacting with a compound of formula (Ia):

[0299] [ka]

[0300] (In the formula, n, R 1 , R 2 , and X, Y, and Z are as defined above; R 13 is a 5- or 6-membered carbocyclic compound substituted with NH2 and optionally further substituted with F, NH2, CN, and / or CH3, or a 5- or 6-membered heterocyclic compound, wherein the heterocycle contains one or more heteroatoms selected from N, O, and / or S.

[0301] Formula (II):

[0302] [ka]

[0303] (In the formula, n is 1 or 2; X, Y, and Z are independently CH or N; R 1 is H or F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, is an aspect of the present invention.

[0304] In a preferred embodiment, R 13 is the following compound:

[0305] [ka]

[0306] (In the formula, R 3 is F and R 4 is NH2 and R 7 is H and R 8 is H (preferred embodiment); or R 3 is NH2 and R 4 is F and R 7 is H and R 8 is H; or R 3 is CN and R 4 is NH2 and R 7 is H and R 8 is H; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is CN; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is F);

[0307] [ka]

[0308] (In the formula, W 1 is S and W2 is N);

[0309] [ka]

[0310] (wherein "----F" indicates that "F" may or may not be present).

[0311] A compound having formula (II) and R 13 The reaction can be carried out by any suitable method. In one alternative, the reaction can be carried out in the presence of a diamine chelating agent such as DMEDA, a base such as potassium carbonate, a catalyst such as CuI, and an aprotic solvent such as dioxane. In another alternative, the reaction can be carried out under Pd coupling conditions in the presence of a Pd catalyst such as Pd[P(Ph)] or Pd(OAc), and XantPhos.

[0312] In another embodiment, the present invention provides a method for producing a method for manufacturing a semiconductor device comprising the steps of: Compound of formula (II') and R 14 and reacting with a compound of formula (I):

[0313] [ka]

[0314] (In the formula, R 14 teeth

[0315] [ka]

[0316] and; n, R 1 , R 2 and X, Y, and Z are as defined for formula (I) above.

[0317] Formula (II'):

[0318] [ka]

[0319] (In the formula, R 2 is as specified above) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, is an aspect of the present invention.

[0320] In a preferred embodiment, R 14 teeth

[0321] [ka]

[0322] is.

[0323] Tritium ( 3 H) a compound detectably labeled with In one embodiment, the present invention provides a compound having formula (IT) wherein at least one leaving group of the precursor of the compound having formula (IT) is tritium ( 3 The method for producing a compound of the present invention having formula (IT) comprising the step of radiolabeling a precursor of the compound having formula (IT) with a radioactive isotope, wherein the precursor is replaced with tritium (H). 3 H) provides a method for preparing a compound detectably labeled with

[0324] At least 1 to 3 hydrogen (H) are tritium ( 3 Tritium (H) having the formula (IT) 3 3H) are preferably defined as compounds detectably labeled with one or two hydrogens (H) replaced by tritium ( 3 Tritium (H) having the formula (IT) 3H) detectably labeled compounds are more preferably defined.

[0325] In another embodiment, the present invention provides a compound of formula (III):

[0326] [ka]

[0327] (In the formula, n is 1 or 2; R 1 is H or F; Y 1 is selected from C—Br, CI, and CH; Z is selected from CH or N; R A is H or F, R 11 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with Br, I, F, NH, CN, and / or CH; Y 1 and / or R 11 At least one of these contains Br or I) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

[0328] In one embodiment, the present invention provides a compound of the derivative formula (IIIa):

[0329] [ka]

[0330] (In the formula, n is 1 or 2; R 1 is H or F; Y 1 is selected from C—Br, CI, and CH; Z is selected from CH or N; R 11 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with Br, I, F, NH, CN, and / or CH; Y 1 and / or R 11 At least one of these contains Br or I) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

[0331] In another embodiment, the present invention provides a compound of the derivative formula (IIIb):

[0332] [ka]

[0333] (In the formula, n is 1 or 2; R 1 is H or F; Y 1 is selected from C—Br, CI, and CH; Z is selected from CH or N; R 11 is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with Br, I, F, NH, CN, and / or CH; Y 1 and / or R 11 At least one of these contains Br or I) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

[0334] In a preferred embodiment, Y 1is C-Br or CI, where Br or I is replaced by T.

[0335] In another preferred embodiment, R 11 contains Br or I, and Br or I is replaced by T.

[0336] In one preferred embodiment, Y 1 is C-Br or CI, where Br or I is replaced by T; R 11 contains Br or I, and Br or I is replaced by T.

[0337] Preferably, the tritium (III) compound according to the present invention has the formula (IT) 3 H) Detectably labeled compounds include:

[0338] [ka]

[0339] (wherein T is 3 (meaning H).

[0340] In another embodiment, the present invention provides a compound of formula (III):

[0341] [ka]

[0342] (In the formula, n is 1 or 2; R 1 is H or F; R A is H or F; Y 1 is selected from C—Br, CI, and CH; Z is selected from CH or N; R 11is a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with Br, I, F, NH, CN, and / or CH; Y 1 and / or R 11 at least one of which contains Br or I; wherein at least one Br or I is replaced by T; or R 11 contains a 5- or 6-membered carbocyclic or heterocyclic ring containing an NH moiety; where the NH moiety is replaced by N-CT3, T is 3 H) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, is referred to as T (i.e. 3 H).

[0343] Preferably, the precursor according to the invention has formula (III)

[0344] [ka]

[0345] can be selected from:

[0346] 3 The methods used to introduce radioisotopes such as 3H are well known in the art and include those described below.

[0347] [ka]

[0348] In this scheme, the substituents Br, NH2, F, and CN are shown merely by way of example. The definition of formula (IT) applies in this regard. Further examples are shown in the following schemes:

[0349] [ka]

[0350] Regarding the introduction of T, 3 The H radiolabeling agent can be tritium gas. The method can be carried out in the presence of a catalyst such as palladium on carbon (Pd / C) or Lindlar's catalyst, a solvent such as N,N-dimethylformamide (DMF), and a base such as N,N-diisopropylethylamine (DIPEA).

[0351] In one embodiment, the present invention provides a method for producing a method for manufacturing a semiconductor device comprising the steps of: Compounds of formula (II) and R 13 to give a compound of formula (Ia), followed by NBS bromination or acid cleavage of the trimethylsilylethoxymethyl (SEM) protecting group. The following examples are given by way of illustration:

[0352] [ka]

[0353] (In the formula, n, R 1 , and R 13 is as specified above).

[0354] R with different ring structures 13 Compounds with can be prepared similarly.

[0355] In a preferred embodiment, R 13 is the following compound:

[0356] [ka]

[0357] wherein Hal is Br or I; and R 3 is F and R 4 is NH2 and R 7 is H and R 8 is H (preferred embodiment); or R 3 is NH2 and R 4 is F and R 7 is H and R 8 is H; or R 3 is CN and R 4 is NH2 and R 7 is H and R 8 is H; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is CN; or R 3 is H and R 4 is NH2 and R 7 is H and R 8 is F);

[0358] [ka]

[0359] (In the formula, W 1 is S and W 2 is N; Hal is Br or I);

[0360] [ka]

[0361] wherein Hal is Br or I; and

[0362] [ka]

[0363] (wherein Hal is Br);

[0364] [ka]

[0365] wherein Hal is Br; or

[0366] [ka]

[0367] wherein Hal is Br.

[0368] In all of the above, "----Hal" indicates that "Hal" may or may not be present.

[0369] A compound having formula (II) and R 13 The reaction can be carried out by any suitable method. In one alternative, the reaction can be carried out in the presence of a diamine chelating agent such as DMEDA, a base such as potassium carbonate, a catalyst such as CuI, and an aprotic solvent such as dioxane. In another alternative, the reaction can be carried out under Pd coupling conditions in the presence of a Pd catalyst such as Pd[P(Ph)] or Pd(OAc), and XantPhos.

[0370] Fluorine ( 18 F) A compound detectably labeled with: In one embodiment, the present invention provides a compound of formula (IV):

[0371] [ka]

[0372] (In the formula, n, R A , R 2and X, Y, and Z are as defined for formula (I) above; R 12 is used in the radiolabeling process. 18 A leaving group (LG) suitable for replacement with F, preferably a mesylate group. or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, in association with a radioactive isotope [ 18 The method of the present invention includes a step of radiolabeling with fluorine (F). 18 F) provides a method for preparing a detectably labeled compound.

[0373] In one embodiment, the present invention provides a compound of formula (IVa):

[0374] [ka]

[0375] (In the formula, n is 1 or 2; R 2 teeth

[0376] [ka]

[0377] and; R 12 is used in the radiolabeling process. 18 A leaving group (LG) suitable for replacement with F, preferably a mesylate group. or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, in association with a radioactive isotope [ 18 The method of the present invention includes a step of radiolabeling with fluorine (F). 18 F) provides a method for preparing a detectably labeled compound.

[0378] R having different ring structures as defined above2 Compounds with can be prepared similarly.

[0379] Fluorination is carried out by K[ 18 F], Cs 18 F, Na 18 F, Rb 18 F, Kryptofix

[0222] K 18 F, 18 F Tetra (C 1~6 alkyl) ammonium salts, and 18 F] tetrabutylammonium fluoride 18 It can be carried out in the presence of an F-fluorinating agent.

[0380] Preferably, the leaving group (LG) is C 1~4 Alkyl sulfonate or C 6~10 More preferably, the leaving group (LG) is mesylate, tosylate, or nosylate, or nitro. Even more preferably, the leaving group (LG) is mesylate or nitro.

[0381] 18 Suitable solvents for the F-fluorination step are known to those skilled in the art. The solvent may be selected from the group consisting of, for example, DMF, DMSO, acetonitrile, DMA, or a mixture thereof. Preferably, the solvent is acetonitrile or DMSO.

[0382] Preferably, fluorine ( 18 A method for preparing compound 1 detectably labeled with F) is shown below, where the leaving group (LG), in this case mesylate, of precursor L1 is reacted with K[ 18 F] or [ 18 F]TBAF etc. 18 F - fluorine ( 18 F).

[0383] [ka]

[0384] The compounds of the present invention can be prepared by one of the general methods shown in the following schemes, which are presented for illustrative purposes only and should not be construed as limiting.

[0385] Precursor compounds having formula (II), (III), or (IV) as defined above, or stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, or solvates thereof, are part of the present invention.

[0386] [Table 1A]

[0387] [Table 1B]

[0388] General synthetic scheme: Synthetic scheme for the preparation of (R)-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (compound 1)

[0389] [ka]

[0390] Synthetic scheme for the preparation of (R)-4-fluoro-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (compound 13)

[0391] [ka]

[0392] Synthetic scheme for the preparation of (R)-4-fluoro-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (compound 12)

[0393] [ka]

[0394] [ 3 [H] Synthetic scheme for the preparation of precursor compounds (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-N-(5-bromo-6-fluoropyridin-3-yl)thiazole-5-carboxamide ( 3 H. Synthetic scheme for the preparation of compound 2 (precursor of compound 1)

[0395] [ka]

[0396] (R)—N-(2,4-dibromo-5-fluoropyridin-3-yl)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide ( 3 H. Synthetic scheme for the preparation of compound 20 (precursor of compound 12)

[0397] [ka]

[0398] 3 H-labeled compounds can be prepared by catalytic tritium dehalogenation with tritium gas from suitable precursor compounds containing halogen atoms (M. Saljoughian Synthesis (2002), 1781-1801) or by the addition of methyl iodide [ 3H] (Y. Chen Chemistry 25 (2019):3405-3439). Preferably, 3 The solvent used in 3H-labeling is DMF or DMA, preferably the solvent is DMF.

[0399] 3 Synthetic scheme for preparation for H labeling Tritiated 2-[2-fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridyl]-5-(3-pyridyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4-one 3 Synthesis of H-compound 1

[0400] [ka]

[0401] T is 3 It means H.

[0402] 18 Synthetic scheme for the preparation of precursors for F labeling (S)-1-(5-(5-((6-fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate( 18 F. Synthetic scheme for the preparation of compound 3 (precursor of compound 1)

[0403] [ka]

[0404] The reaction is carried out in the presence of a fluorinating agent, and usually a solvent.

[0405] 18 F-labeled compounds were synthesized with precursor compounds containing LG. 18 The reaction with F-fluorinating agent is 18 It can be prepared by replacing with F. 18F-fluorination agent 18 Tetraalkylammonium salts of F (e.g. 18 F Tetra (C 1~6 alkyl)ammonium salts, for example [ 18 F]tetrabutylammonium fluoride), 18 Tetraalkylphosphonium salts of F (e.g. 18 F Tetra (C 1~6 Alkyl)phosphonium salt), K[ 18 F], Cs 18 F, Na 18 F, Rb 18 F, or Kryptofix

[0222] K 18 It can be F. Preferably, 18 F-fluorination agent is Cs 18 F, K 18 F, or [ 18 F] tetrabutylammonium fluoride. 18 Reagents, solvents, and conditions that can be used for F-fluorination are well known to those skilled in the art (L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem. 2008, 2853-2873; J. Fluorine Chem., 27 (1985):177-191; Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger PA, Friebe M., Lehmann L., (eds), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50). Preferably, 18 The solvent used in the F-fluorination is DMF, DMSO, acetonitrile, DMA, or a mixture thereof, preferably the solvent is acetonitrile or DMSO.

[0406] In the above 18 Although the reaction is shown using F as the radioactive label, other radioactive labels may be introduced following similar procedures.

[0407] This invention is illustrated by the following examples which should not be construed as limiting. [Example]

[0408] All reagents and solvents were obtained from commercial sources and used without further purification. 1 H NMR spectra were recorded on a Bruker DRX-400 MHz NMR spectrometer or a Bruker AV-400 MHz NMR spectrometer in deuterated solvents. Mass spectra (MS) were recorded on an Advion CMS mass spectrometer. Chromatography was performed using silica gel (Fluka: Silica gel 60, 0.063-0.2 mm) and the appropriate solvents indicated in the specific examples. Flash purification was performed on a Biotage Isolera One flash purification system using HP-Sil or KP-NH SNAP cartridges (Biotage) and the solvent gradients indicated in the specific examples. Thin-layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0409] Although some of the examples do not indicate that each compound is detectably labeled, a corresponding detectably labeled compound is contemplated, e.g., a detectably labeled starting material, e.g., C( 3 H)3, ( 11 C) H3, or 18 It will be appreciated that it can be readily prepared using starting materials containing F.

[0410] Example 1 Synthesis of (R)-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide compound 1

[0411] [ka]

[0412] Step 1: Methyl 2-(6-fluoropyridin-3-yl)thiazole-5-carboxylate (B) To an oven-dried round-bottom flask was added methyl 2-bromothiazole-5-carboxylate (3.0 g, 13 mmol), boronic acid (2.8 g, 20 mmol), NaHCO3 (5.6 g, 65 mmol), and (THF:HO) (1:1, 45 mL, 15 vol) under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Pd(PPh3)4 (1.5 g, 0.13 mmol) was then added, and the mixture was heated to 90 °C for 12 hours. The reactant was consumed as monitored by TLC. The reaction mixture was quenched with ice water (20 mL) and extracted into EtOAc (70 mL × 3). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (230-400 mesh) eluting with 20% EtOAc in hexane to give (B) as a light brown liquid (2.0 g, 62%). MS (ESI): 239.1 [M] + .1H NMR (CDCl3) δ 8.71 (s, 1H), 8.61 (m, 1H), 8.46 (s, 1H), 7.07 (dd, 1H), 3.95 (s, 3H).

[0413] Step 2: Methyl (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate (C) Compound (B) (2.0 g, 8.4 mmol), (R)-3-fluoropyrrolidine hydrochloride (1.37 g, 11 mmol), DIPEA (3.0 mL, 16.8 mmol), and NMP (20 mL, 10 volumes) were taken in an oven-dried microwave vial under an argon atmosphere. The reaction mixture was irradiated at 120 °C for 2 h. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with cold brine solution (20 mL × 2), dried over NaSO, and concentrated under reduced pressure. The resulting crude product mass was purified by silica gel (100-200 mesh) column chromatography eluting with 20% EtOAc in hexane to give (C) as a white solid (1.9 g, 76%). MS (ESI): 308.17 [M+H] + ; 1H NMR (CDCl3) δ 8.78 (m, 1H), 8.35 (s, 1H), 8.05 (dd, 1H), 6.45 (d, 1H), 5.41 (dt, 1H), 3.92 (s, 3H), 3.70 (m, 3H), 2.44 (m, 1H), 2.19 (m, 3H), 1.51 (m, 1H).

[0414] Step 3: (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (D) To a solution of (C) (1.5 g, 4.5 mmol) in (THF:MeOH:water) (2:2:1, 75 mL, 50 vol) was added lithium hydroxide (233 mg, 9.7 mmol), and the mixture was maintained at room temperature for 3 h. The mixture was then treated with 2 M HCl (aqueous) solution until the pH reached 2-3. The biphasic mixture was filtered through a Buchner funnel. The resulting mass was washed with hexane (5 mL x 3) and dried under high vacuum to give (D) as an off-white solid (1.4 g, 78%). MS (ESI): 294.15 [M+H] +; 1H NMR (DMSO-D6) δ 13.49 (s, 1H), 8.75 (d, 1H), 8.29 (s, 1H), 8.07 (dd, 1H), 6.63 (d, 1H), 5.54 (s, 1H), 3.73 (m, 3H), 3.49 (m, 1H), 2.23 (m, 2H).

[0415] Step 4: (R)-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (1) To a solution of (D) (150 mg, 0.5 mmol) in DMF (3.0 mL, 20 vol) was added HATU (380 mg, 1.0 mmol) followed by DIPEA (0.26 mL, 1.5 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. again, and to this was added 6-fluoropyridin-3-amine (68 mg, 0.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with ice-cold water (3.0 mL). A solid precipitate formed. The crude reaction mass was filtered through a Buchner funnel. The resulting mass was washed with hexane (3 mL×3) and dried under high vacuum to give (1) as an off-white solid (120 mg, 62%). LCMS (ESI): 387.8 [M] + ; 1H NMR (DMSO-D6) δ 10.68 (s, 1H), 8.77 (d, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.27 (m, 1H), 8.10 (dd, 1H), 7.24 (dd, 1H), 6.65 (d, 1H), 5.48 (d, 1H), 3.74 (m, 3H), 3.48 (m, 1H), 2.24 (m, 2H).

[0416] Example 2 Synthesis of 5-(3-amino-2,6-dibromo-4-fluorophenyl)-2-(5-bromo-6-(pyrrolidin-1-yl)pyridin-3-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one compound 2

[0417] [ka]

[0418] Step 1: Methyl 2-(5-bromo-6-fluoropyridin-3-yl)thiazole-5-carboxylate (E): To an oven-dried round-bottom flask was added (A) (0.6 g, 2.7 mmol), boronic ester (0.9 g, 2.9 mmol), Cs2CO3 (1.75 g, 5.4 mmol), and 1,4-dioxane:HO (4:1, 30 mL, 50 vol) under an argon atmosphere. The reaction mixture was degassed with argon for 15 min. Pd(dppf)Cl2.DCM (0.22 g, 0.27 mmol) was then added, and the mixture was heated to 90 °C for 3 h. The reactant was consumed, as monitored by TLC. The reaction mixture was then quenched with ice water (10 mL) and extracted into DCM (50 mL × 3). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel chromatography (100-200 mesh) eluting with 10% EtOAc in hexane to give (E) as a light brown liquid (120 mg, 14%). MS (ESI): 317.09 [M] + .1H NMR (CDCl3) δ 8.71 (s, 1H), 8.61 (m, 1H), 8.46 (s, 1H), 3.96 (s, 3H), 3.90 (s, 1H).

[0419] Step 2: Methyl (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate (F) Compound (E) (120 mg, 0.38 mmol), (R)-3-fluoropyrrolidine hydrochloride (72 mg, 0.56 mmol), DIPEA (0.2 mL, 1.1 mmol), and EtOH (2.0 mL, 17 volumes) were taken in an oven-dried microwave vial under an argon atmosphere. The reaction mixture was irradiated at 120 °C for 2 h. After completion, the reaction mixture was quenched with ice-cold water (4 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with cold brine solution (10 mL), dried over NaSO, and concentrated under reduced pressure. The resulting crude product mass was purified by silica gel (100-200 mesh) column chromatography, eluting with 20% EtOAc in hexane, to give (F) as a white solid (100 mg, 69%). MS (ESI): 387.96 [M+H] + ; 1H NMR (CDCl3) δ 8.65 (d, 1H), 8.36 (d, 1H), 8.33 (d, 1H), 5.34 (d, 1H), 4.06 (m, 1H), 3.92 (s, 3H), 2.37 (m, 1H), 2.07 (m, 1H).

[0420] Step 3: (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (G) To a solution of (F) (120 mg, 0.3 mmol) in (THF:MeOH:water) (2:2:1, 6.0 mL, 50 vol) was added lithium hydroxide monohydrate (15 mg, 0.6 mmol), and the mixture was maintained at room temperature for 2 h. The mixture was then treated with 2 M HCl (aqueous) solution until the pH reached 2-3. The biphasic mixture was stirred for 5 min, and the layers were separated. The aqueous layer was further extracted with 10% MeOH in DCM (2 × 20 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give (G) as a yellowish solid (100 mg, 86%). MS (ESI): 372.96 [M+H] +; 1H NMR (DMSO-D6) δ 13.52 (s, 1H), 8.74 (d, 1H), 8.35 (m, 2H), 5.43 (d, 1H), 4.06 (dd, 1H), 3.89 (m, 4H), 2.17 (m, 2H).

[0421] Step 4: (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-N-(5-bromo-6-fluoropyridin-3-yl)thiazole-5-carboxamide (2) To a solution of (G) (50 mg, 0.13 mmol) in DCM (2.5 mL, 50 vol) was added HATU (67 mg, 0.17 mmol) followed by DIPEA (0.07 mL, 0.4 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to 0 °C again, and 5-bromo-6-fluoropyridin-3-amine (33 mg, 0.17 mmol) was added to it. The resulting mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water, and the product was extracted with 10% MeOH in DCM (20 mL × 3). The extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (230-400 mesh) column chromatography eluting with 3% MeOH in DCM to give the title product (2) as a yellowish solid (35 mg, 47%).

[0422] Example 3 Synthesis of (S)-1-(5-(5-((6-fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate compound 3

[0423] [ka]

[0424] Step 1: Methyl 2-(6-fluoropyridin-3-yl)thiazole-5-carboxylate (B) To an oven-dried round-bottom flask was added (A) (3.0 g, 13 mmol), boronic acid (2.8 g, 20 mmol), NaHCO3 (5.6 g, 65 mmol), and (THF:HO) (1:1, 45 mL, 15 vol) under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Pd(dppf)Cl2.DCM (1.1 g, 13 mmol) was then added, and the mixture was heated to 90 °C for 16 hours. The reactant was consumed, as monitored by TLC. The reaction mixture was then quenched with ice water (30 mL) and extracted into DCM (60 mL × 3). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (230-400 mesh) eluting with 20% EtOAc in hexane to give (B) as an off-white solid (1.6 g, 50%). MS (ESI): 239.08 [M] + 1H NMR (CDCl3) δ 8.71 (s, 1H), 8.61 (m, 1H), 8.46 (s, 1H), 7.07 (dd, 1H), 3.95 (s, 3H).

[0425] Step 2: Methyl (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate(I) Compound (B) (1.0 g, 4.2 mmol), (S)-pyrrolidin-3-ol (440 mg, 5.0 mmol), DIPEA (2.3 mL, 12.6 mmol), and n-butanol (10 mL, 10 vol) were taken in an oven-dried microwave vial under an argon atmosphere. The reaction mixture was irradiated at 120 °C for 2 h. After completion, the solvent was removed under high vacuum. The resulting crude product mass was purified by silica gel (230-400 mesh) column chromatography eluting with 2% MeOH in DCM to give (I) as a white solid (100 mg, 69%). MS (ESI): 306.13 [M+H] +; 1H NMR (DMSO-D6) δ 8.75 (d, 1H), 8.39 (d, 1H), 8.04 (dd, 1H), 6.57 (d, 1H), 5.03 (d, 1H), 4.41 (s, 1H), 3.85 (s, 2H), 3.54 (m, 3H), 2.03 (m, 1H), 1.93 (m, 1H), 1.23 (d, 1H).

[0426] Step 3: (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (J) To a solution of (I) (1.3 g, 4.2 mmol) in (THF:MeOH:water) (2:2:1, 45 mL, 35 vol) was added lithium hydroxide (2.4 mg, 8.5 mmol), and the mixture was maintained at room temperature for 6 h. The mixture was then treated with 2 M HCl (aqueous) solution until a pH of 2-3 was reached. The biphasic mixture was stirred for 5 min, and the layers were separated. The aqueous layer was further extracted with 10% MeOH in DCM (3 × 50 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give (J) as a brown solid (1.0 g, 83%). MS (ESI): 292.14 [M+H] + ; 1H NMR (DMSO-D6) δ 13.54 (s, 1H), 8.74 (d, 1H), 8.30 (s, 1H), 8.03 (dd, 1H), 6.57 (d, 1H), 5.03 (s, 1H), 4.41 (s, 1H), 3.50 (m, 4H), 2.04 (m, 1H), 1.92 (m, 1H).

[0427] Step 4: (S)—N-(6-fluoropyridin-3-yl)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (K) To a solution of (J) (80 mg, 0.27 mmol) in DMF (1.6 mL, 20 vol) was added HATU (208 mg, 0.54 mmol) followed by DIPEA (0.14 mL, 0.82 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to 0 °C again, and 6-fluoropyridin-3-amine (36 mg, 0.33 mmol) was added to it. The resulting mixture was stirred at room temperature for 24 h. Upon completion, the reaction mixture was quenched with ice-cold water, and the product was extracted with 10% MeOH in DCM (20 mL × 3). The extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (230-400 mesh) column chromatography eluting with 5% MeOH in DCM to give product (K) as a yellowish solid (65 mg, 61%). LCMS (ESI): 386 [M] + ; 1H NMR (DMSO-D6) δ 10.66 (s, 1H), 8.74 (d, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.27 (m, 1H), 8.05 (dd, 1H), 7.23 (dd, 1H), 6.58 (d, 1H), 5.02 (d, 1H), 4.42 (s, 1H), 3.55 (dd, 3H), 3.41 (m, 1H), 2.04 (s, 1H), 1.94 (s, 1H)

[0428] Step 5: (S)-1-(5-(5-((6-fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate (3): To an ice-cold solution of (K) (65 mg, 0.16 mmol) in pyridine (2.0 mL, 33 vol) under N2 atmosphere at 0 °C, methanesulfonyl chloride (0.3 mL, 4.5 mmol) was added in several portions, and the mixture was stirred at room temperature for 2 h. The reaction time was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C, and saturated NaHCO3 (2 mL) was added. The solvent was extracted with DCM (15 mL × 3). The combined organic layers were washed with cold brine solution (7 mL × 2), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product mass was purified by silica gel (230-400 mesh) column chromatography, eluting with 4% MeOH in DCM, to give (3) as a yellow solid (35 mg, 44%). MS (ESI): 392.26 (M+H)+. 1H NMR (DMSO-D6) δ 10.68 (s, 1H), 8.77 (d, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.27 (m, 1H), 8.11 (dd, 1H), 7.24 (dd, 1H), 6.6 (d, 1H), 5.45 (m, 1H), 3.7 (m, 3H), 3.5 (m, 1H), 3.2 (s, 3H), 2.39 (m, 2H),

[0429] Example 4 Tritiated 2-[2-fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridyl]-5-(3-pyridyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4-one 3 Synthesis of H-compound 1

[0430] [ka]

[0431] T is 3 It means H.

[0432] 2.88 mg of the dibromo precursor (2), 2.97 mg of Pd / C (10% metal), and 50 μL of DIPEA were suspended in 0.3 mL of DMF. The suspension was degassed three times using a high-vacuum manifold and stirred under an atmosphere of tritium gas (5.3 Ci) at room temperature for 2.5 hours. The solvent was removed under reduced pressure, and the labile tritium was exchanged by adding 0.3 mL of methanol, stirring the solution, and removing the solvent again under reduced pressure. This process was repeated twice. The dried solid was extracted with 10 mL of methanol / DCM (1:1), and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear solution. The following HPLC conditions were used for compound purification: Waters Sunfire C18, 10 × 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); Solvent B: acetonitrile + 0.1% TFA. Purified product 3 H-Compound 1 was obtained (SA 49.1 Ci / mmol, purity 99%).

[0433] Example 5 Fluorinated 2-[2-fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridyl]-5-(3-pyridyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4-one 18 F - Synthesis of compound 1

[0434] [ka]

[0435] Drying 18A solution of (S)-1-(5-(5-((6-fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate (3) (1 mg in 1 mL of anhydrous DMSO) was added to the microwave vial containing [F] fluoride, and the vessel was heated at 110° C. for 20 min. The reaction vessel was cooled to 40° C., and the mixture was diluted with HPLC buffer (4 mL). The resulting mixture was passed through a Sep-Pak® Alumina-N Light cartridge. The crude material was purified by semi-preparative HPLC, and the collected purified fractions were passed through a Strata® C18-E cartridge. The final product, 18 F-Compound 1 was filtered through a sterile filter onto the final product vial inside the dispensing hot cell. The final product vial was assayed and a sample was removed for QC testing. The identity of the product was confirmed by 19 F—Confirmed by co-injection with a sample of the reference compound.

[0436] (Example Compounds 4 to 11) Following the coupling procedures reported for the preparation of Example 1, utilizing the building blocks and halogen derivatives shown in Table 1, the following compounds were prepared.

[0437] [Table 2A]

[0438] [Table 2B]

[0439] [Table 2C]

[0440] Example compounds 16 to 18 (respectively 3 Synthesis of H (precursor of compounds 4, 8, and 11) Following the coupling procedure reported for the preparation of Example 2, utilizing the building blocks and halogen derivatives shown in Table 2, the following compounds were prepared.

[0441] [Table 3]

[0442] Example 6 Synthesis of (R)-4-fluoro-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide Compound 12

[0443] [ka]

[0444] Step 1: Synthesis of 2-bromo-4-fluorothiazole-5-carbonyl chloride (R) To a solution of 2-bromo-4-fluorothiazole-5-carboxylic acid Q (0.3 g, 1.33 mmol) in THF (6 mL) were added (COCl) (0.34 g, 2.65 mmol) and DMF (102.12 μL, 1.33 mmol). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound R (0.3 g, 92% yield) as a yellow solid.

[0445] Step 2: Synthesis of 2-bromo-4-fluoro-N-(5-fluoropyridin-3-yl)thiazole-5-carboxamide (T) To a solution of 5-fluoropyridin-3-amine (165.08 mg, 1.47 mmol) and compound R (300 mg, 1.23 mmol) in THF (8 mL) was added pyridine (297.14 μL, 3.68 mmol). The mixture was stirred at 20 °C for 2 hours. The residue was poured into ice water (100 mL), and the aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE:EA = 1:1, Rf = 0.5) to give compound T (300 mg, 69% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.65 (s, 1H), 8.68 (s, 1H), 8.41 - 8.37 (m, 1H), 8.07 - 8.00 (m, 1H)

[0446] Step 3: Synthesis of (R)-4-fluoro-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (Compound 12) A mixture of compound 3 (200 mg, 624.78 μmol), (R)-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)boronic acid (182.53 mg, 624.78 μmol), XPhos Pd G2 (491.58 mg, 624.78 μmol), K3PO4 (397.86 mg, 1.87 mmol) in HO (0.2 mL) and toluene (1 mL) was degassed and purged with N2 three times. The mixture was then stirred under N2 atmosphere at 70 °C for 0.5 h. The residue was poured into saturated EDTA (100 mL) and stirred for 2 h. The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 15% to 55%, 8 min) to give compound 12 (50 mg, 19% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.65 (s, 1 H), 8.77 (s, 1 H), 8.68 - 8.61 (m, 1 H), 8.44 - 8.37 (m, 1 H), 8.23 ​​- 8.10 (m, 2 H), 6.86 (d, J= 9.2 Hz, 1 H), 5.63 - 5.41 (m, 1 H), 4.11 - 3.68 (m, 3 H), 3.65 - 3.52 (m, 1 H), 2.43 - 2.12 (m, 2 H) LCMS: 406.1 [M + H] +

[0447] Example 7 Synthesis of (R)-4-fluoro-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide Compound 13

[0448] [ka]

[0449] Step 1: Synthesis of tert-butyl (4-chloro-5-formylthiazol-2-yl)carbamate (M) To a solution of 2-amino-4-chlorothiazole-5-carbaldehyde L (10 g, 61.50 mmol) in dioxane (100 mL) were added DMAP (751.35 mg, 6.15 mmol) and (Boc)2O (15.54 mL, 67.65 mmol). The mixture was heated to 60 °C and stirred for 3 h. The mixture was cooled to 25 °C and poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (50 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 → 5 / 1) to give the title compound M (12 g, 74% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.85 (s, 1H), 1.50 (s, 9H) LCMS: 263.0 [M + H] +

[0450] Step 2: Synthesis of tert-butyl N-(4-fluoro-5-formylthiazol-2-yl)carbamate (N) To a solution of compound M (10 g, 38.06 mmol) in DMSO (100 mL) was added CsF (115.64 g, 761.29 mmol). The mixture was heated to 130 °C and stirred for 48 h. The reaction mixture was cooled to 25 °C and poured into ice-water (1000 mL). The aqueous phase was extracted with ethyl acetate (300 mL * 3). The combined organic phase was washed with brine (300 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75 * 30 mm * 3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10% to 40%, 8 min) to give the title compound N (2.5 g, 27% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 9.96 (s, 1 H), 9.23 - 9.17 (m, 1 H), 1.60 (s, 9 H) LCMS: 247.2 [M + H] +

[0451] Step 3: Synthesis of 2-amino-4-fluorothiazole-5-carbaldehyde (O) To a solution of compound N (2.5 g, 10.15 mmol) in DCM (50 mL) was added ZnBr (6.86 g, 30.46 mmol). The mixture was heated to 40 °C and stirred for 16 hours. The mixture was cooled to 25 °C, and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 10:1 to 1:1) to give the title compound O (1.1 g, 74% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.59 (s, 1H), 8.95 (s, 2H) LCMS: 147.2 [M + H] +

[0452] Step 4: Synthesis of 2-bromo-4-fluorothiazole-5-carbaldehyde (P) To a solution of compound O (1 g, 6.84 mmol) in ACN (40 mL) was added CuBr (1.53 g, 6.84 mmol) and a solution of isopentyl nitrite (1.45 g, 14.03 mmol) in ACN (20 mL). The mixture was stirred at 65 °C for 0.5 h. The reaction mixture was quenched by the addition of ice water (100 mL) at 25 °C. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 → 1 / 1) to give the title compound P (540 mg, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H)

[0453] Step 5: Synthesis of 2-bromo-4-fluorothiazole-5-carboxylic acid (Q) To a solution of compound P (500 mg, 2.38 mmol) in t-BuOH (4.2 mL) and HO (2.4 mL) were added 2-methylbut-2-ene (659.50 mg, 9.40 mmol), NaHPO (791.19 mg, 6.59 mmol), and NaClO (987 mg, 10.91 mmol). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was poured into ice-water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL * 3). The aqueous phase was then neutralized to pH = 5-6 with citric acid (saturated) and extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (100 mL * 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound Q (400 mg, 74% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 14.05 (brs, 1H)

[0454] Step 6: Synthesis of 2-bromo-4-fluorothiazole-5-carbonyl chloride (R) To a solution of compound Q (0.3 g, 1.33 mmol) in THF (6 mL) were added (COCl) (0.34 g, 2.65 mmol) and DMF (102.12 μL, 1.33 mmol). The mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound R (0.3 g, 92% yield) as a yellow solid.

[0455] Step 7: Synthesis of 2-bromo-4-fluoro-N-(6-fluoropyridin-3-yl)thiazole-5-carboxamide (S) To a solution of 6-fluoropyridin-3-amine (150 mg, 1.34 mmol) and compound R (270 mg, 1.10 mmol) in THF (2 mL) was added pyridine (647.99 μL, 8.03 mmol). The mixture was stirred at 20 °C for 0.5 hours. The residue was poured into ice water (100 mL), and the aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, PE:EA = 1:1, Rf = 0.5) to give compound S (300 mg, 70% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 8.46 (s, 1H), 8.23 ​​- 8.14 (m, 1H), 7.26 - 7.18 (m, 1H)

[0456] Step 8: Synthesis of (R)-4-fluoro-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (Compound 13) A mixture of Compound S (160 mg, 499.82 μmol), (R)-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)boronic acid (219.04 mg, 749.73 μmol), Pd(dppf)Cl (18.29 mg, 24.99 μmol), KPO (318.29 mg, 1.50 mmol) in HO (1 mL) and toluene (5 mL) was degassed and purged with N three times. The mixture was then stirred under a N atmosphere at 70 °C for 0.5 h. The residue was poured into saturated EDTA (100 mL) and stirred for 1 h. The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (30 mL * 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (HCl)-ACN]; B%: 20%~50%, 10 min) to give compound 13 (50 mg, yield 24.31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1 H), 8.71 (s, 1 H), 8.49 (s, 1 H), 8.27 - 8.19 (m, 1 H), 8.13 - 8.06 (m, 1 H), 7.23 - 7.15 (m, 1 H), 6.73 (d, J=9.2 Hz, 1 H), 5.60 - 5.40 (m, 1 H), 3.92 - 3.61 (m, 3 H), 3.60 - 3.48 (m, 1 H), 2.39 - 2.10 (m, 2 H) LCMS: 406.1 [M + H] +

[0457] Example Compounds 14-15 Following the coupling procedure reported for the preparation of Example 13, utilizing the building blocks and halogen derivatives shown in Table 3, the following compounds were prepared.

[0458] [Table 4]

[0459] Example 8 (R)-N-(2,4-dibromo-5-fluoropyridin-3-yl)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide Compound 19( 3 Synthesis of H-compound 12 (precursor)

[0460] [ka]

[0461] Step 1: Synthesis of (R)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (V) To a mixture of (R)-2-(3-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (775.60 mg, 2.65 mmol) and 2-bromo-4-fluorothiazole-5-carboxylic acid U (500 mg, 2.21 mmol) in dioxane (10 mL) and HO (1 mL) was added Pd(dppf)Cl (161.86 mg, 221.22 μmol) and CsCO (1.44 g, 4.42 mmol) at 25 °C. The reaction mixture was stirred at 110 °C under N for 2 h. LCMS showed that 41% of the desired product was detected. The reaction mixture was stirred with palladium scavenger (100 mg), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl conditions: column: Phenomenex Luna C18 80*40 mm*3 μm; mobile phase: [water(HCl)-ACN]; gradient: 15% to 45% B in 7 min) and then lyophilized to give the title compound V (200 mg, 29% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 13.56 (br s, 1H), 8.73 (s, 1H), 8.06 - 7.96 (m, 1H), 6.63 (d, J = 8.8 Hz, 1H), 5.59 - 5.36 (m, 1H), 3.85 - 3.48 (m, 4H), 2.33 - 2.15 (m, 2H) LCMS: 312.1 [M + H] +

[0462] Step 2: Synthesis of (R)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carbonyl chloride (W) To a mixture of compound V (200 mg, 642.46 μmol) in DCM was added SOCl (2 mL). The mixture was stirred at 70° C. for 1 hour. LCMS showed the reaction was 89% of the desired MS (quenched with MeOH). The reaction mixture was concentrated under reduced pressure to give compound W (200 mg, crude) as a yellow solid. LCMS: 326.2 (quenched with MeOH)

[0463] Step 3: Synthesis of (R)-N-(2,4-dibromo-5-fluoropyridin-3-yl)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (Compound 19) To a mixture of 2,4-dibromo-5-fluoropyridin-3-amine (163.70 mg, 606.52 μmol) in THF (2 mL) was added NaH (72.77 mg, 1.82 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Compound W (200 mg, 606.52 μmol) was then added, and the mixture was stirred at 25 °C for 1.5 h. LCMS showed the reaction was 32% of the desired MS. The reaction mixture was poured into saturated aqueous NH Cl (60 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, PE:EA = 2:1) to give compound 20 (30.12 mg, 8.55% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 10.34 (br s, 1H), 8.79-8.73 (m, 1H), 8.57 (s, 1H), 8.09-8.01 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.58-5.38 (m, 1H), 3.92-3.45 (m, 4H), 2.38-2.11 (m, 2H) LCMS: 563.9 [M + H] +

[0464] Example 9 Tritiated (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-N-(isothiazol-4-yl)thiazole-5-carboxamide 3 Synthesis of H-compound 4

[0465] [ka]

[0466] T is 3 It means H.

[0467] 3.54 mg of the dibromo precursor (16), 9.9 mg of Pd / C (10% metal), and 50 μL of DIPEA were suspended in 0.3 mL of DMF. The suspension was degassed three times using a high-vacuum manifold and stirred under an atmosphere of tritium gas (5.1 Ci) at room temperature for 16 h. The solvent was removed under reduced pressure, and the labile tritium was exchanged by adding 0.3 mL of methanol, stirring the solution, and removing the solvent again under reduced pressure. This process was repeated twice. The dried solid was extracted with 10 mL of methanol / DCM (1:1), and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear solution. The following HPLC conditions were used for the purification of the compound: Waters Sunfire C18, 10 × 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); Solvent B: acetonitrile + 0.1% TFA. Purified product 3 H-Compound 4 was obtained (SA 43.5 Ci / mmol, purity 99%).

[0468] Example 10 Tritiated (S)-2-(2-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-N-(pyridin-4-yl)thiazole-5-carboxamide 3 Synthesis of H-compound 8

[0469] [ka]

[0470] T is 3 It means H.

[0471] 2.56 mg of the dibromo precursor (17), 11.2 mg of Pd / C (10% metal), and 20 μL of DIPEA were suspended in 0.3 mL of DMF. The suspension was degassed three times using a high-vacuum manifold and stirred under an atmosphere of tritium gas (5.7 Ci) at room temperature for 50 min. The solvent was removed under reduced pressure, and the labile tritium was exchanged by adding 0.3 mL of methanol, stirring the solution, and removing the solvent again under reduced pressure. This process was repeated twice. The dried solid was extracted with 10 mL of methanol / DCM (1:1), and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear solution. The following HPLC conditions were used for the purification of the compound: Waters Sunfire C18, 10 × 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); Solvent B: acetonitrile + 0.1% TFA. Purified product 3 H-Compound 8 was obtained (SA 42.5 Ci / mmol, purity 99%).

[0472] Example 11 Tritiated (R)-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide 3 Synthesis of H-compound 11

[0473] [ka]

[0474] T is 3 It means H.

[0475] 2.95 mg of the dibromo precursor (18), 17 mg of Pd / C (10% metal), and 20 μL of DIPEA were suspended in 0.3 mL of DMF. The suspension was degassed three times using a high-vacuum manifold and stirred under an atmosphere of tritium gas (9.1 Ci) at room temperature for 15 min. The solvent was removed under reduced pressure, and the labile tritium was exchanged by adding 0.3 mL of methanol, stirring the solution, and removing the solvent again under reduced pressure. This process was repeated twice. The dried solid was extracted with 10 mL of methanol / DCM (1:1), and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear solution. The following HPLC conditions were used for the purification of the compound: Waters Sunfire C18, 10 × 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); Solvent B: acetonitrile + 0.1% TFA. Purified product 3 H-Compound 11 was obtained (SA 44.3 Ci / mmol, purity 99%).

[0476] Example 12 Tritiated (R)-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide 3 Synthesis of H-compound 12

[0477] [ka]

[0478] T is 3 It means H.

[0479] 2.48 mg of the dibromo precursor (19), 34 mg of Lindlar catalyst, and 50 μL of DIPEA were suspended in 0.3 mL of DMF. The suspension was degassed three times using a high-vacuum manifold and stirred under an atmosphere of tritium gas (5.7 Ci) at room temperature for 12 hours. The solvent was removed under reduced pressure, and the labile tritium was exchanged by adding 0.3 mL of methanol, stirring the solution, and removing the solvent again under reduced pressure. This process was repeated twice. The dried solid was extracted with 10 mL of methanol / DCM (1:1), and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear solution. The following HPLC conditions were used for the purification of the compound: Waters Sunfire C18, 10 × 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); Solvent B: acetonitrile + 0.1% TFA. Purified product 3 H-Compound 12 was obtained (SA 49.23 Ci / mmol, purity 99%).

[0480] Biological assay description 1. General method Human brain material for these studies was obtained from Professor William Seeley of the Neurodegenerative Disease Brain Bank, UCSF (funded by NIH grants P01AG019724 and P50AG023501, the Consortium for Frontotemporal Dementia Research, and the Tau Consortium), and Professor Tammarin Lashley of the Queen Square Brain Bank for Neurological Disorders, UCL. All material was collected from donors, who provided written informed consent for the brain bank to perform brain autopsies and use their material and clinical information for research purposes.

[0481] 1.1. Radioligand TDP-43 aggregates derived from FTD patient brains 3In all competitive assays described below, except when the [ H]-reference ligand (specific activity 80 Ci / mmol, 1.0 mCi / ml) was used, the above [ H]-reference ligand (specific activity 80 Ci / mmol, 1.0 mCi / ml) was used. 3 H]-Compound 1 was used. 3 H]-Compound 4 has a specific radioactivity of 44 Ci / mmol (1.0 mCi / mL). 3 H]-Compound 8 has a specific radioactivity of 37 Ci / mmol (1.0 mCi / mL). 3 H]-Compound 11 has a specific radioactivity of 44 Ci / mmol (1.0 mCi / mL). 3 H]-Compound 12 has a specific radioactivity of 29 Ci / mmol (1.0 mCi / mL).

[0482] 1.2. Preparation of human frontotemporal dementia (FTD) sarkosyl-insoluble brain extracts Human brain extracts were prepared as described in Laferriere et al., 2019, Nature Neurosc. Brain tissue samples (frontal or temporal cortex) were homogenized in homogenization-solubilization (HS) buffer at a 1:4 (w / v) ratio using a tissue homogenizer (Precellys) equipped with a CKmix homogenization tube at 4°C. The following sequence was used for homogenization: 5000 rpm for three 30-second cycles with a 15-second pause between each cycle. Homogenized samples were aliquoted and stored in 1.5 mL low-protein-binding tubes at -80°C.

[0483] Brain homogenates were thawed on ice and resuspended in HS buffer to a final concentration of 2% sarkosyl, 1 unit / μL Benzonase, and 1 mM MgCl2. The samples were then incubated at 37°C for 45 minutes with constant agitation at 600 rpm on a thermomixer. The supernatant was collected in a new tube (sarkosyl-soluble fraction, S1). The pellet was resuspended in 1,000 μL of myelin suspension buffer and centrifuged at 20,000 g for 60 minutes at 4°C. The supernatant was carefully removed to remove all floating lipids. This step was repeated if all lipids could not be removed in one step. The pellet was then washed with phosphate-buffered saline (PBS) and centrifuged at 20,000 g for 30 minutes at 4°C. The final pellet was resuspended in 200 μL of PBS and stored at -80°C (sarkosyl-insoluble fraction). Samples were analyzed by immunoblotting under denaturing conditions.

[0484] 2. Description of the biological assay and corresponding results 2.1 [ 3 H]-Determination of Kd for compounds 1, 4, 8, 11, and 12 in human FTD sarkosyl-insoluble brain extracts by microradiometric binding assay Human FTD sarkosyl-insoluble brain extract was spotted onto microarray slides. The slides were then individually coated with a range of [ 3 H]-Compound 1, [ 3 H]-Compound 4, [ 3 H]-Compound 8, [ 3 H]-compound 11, or [ 3 The slides were incubated with [H]-Compound 12. After incubation, the slides were washed and scanned using a real-time autoradiography system (BeaQuant, ai4R). Signal quantification was performed using Beamage image analysis software (ai4R). Nonspecific signals were determined with an excess of non-radiolabeled Compounds 1, 4, 8, 11, or 12 (2 μM), and specific binding was calculated by subtracting the nonspecific signals from the total signals.

[0485] Kd (dissociation constant) and R 2(a parameter ranging from 0.0 to 1.0 that quantifies the goodness of fit; the best curve fit is obtained with a value of 1.0) was obtained by fitting the specific binding data with nonlinear regression analysis using a one-site specific binding model in GraphPad's Prism 8.

[0486] result: [ 3 The dissociation constants (Kd) of [H]-compounds 1, 4, 8, 11, and 12 were determined with human FTD sarkosyl-insoluble brain extract in a microradiometric binding assay. 3 [H]-Compound 1 exhibited strong specific binding, yielding a large dynamic range, with a Kd value of 52 nM for human FTD sarkosyl-insoluble brain extract (Figure 1). Data from two independent experiments yielded an average Kd of 53 ± 10 nM. 3 H]-Compound 11 showed a Kd value of 80 nM (Fig. 2), and [ 3 [H]-Compound 12 exhibited a Kd value of 67 nM (Figure 3). The dissociation constants of compounds 4 and 8 were determined with different batches of FTD sarkosyl-insoluble brain extract. 3 H]-Compound 4 showed a Kd value of 51 nM (Figure 4). 3 H]-Compound 8 showed a Kd value of 75 nM (Figure 5).

[0487] These data demonstrate that compounds of the present invention bind with very good affinity to TDP-43 aggregates in human FTD sarkosyl-insoluble brain extracts.

[0488] 2.2. Microradiometric binding competition assay for determination of binding affinity Human FTD sarkosyl-insoluble brain extracts were spotted onto microarray slides. Three batches of extract were used. The slides were incubated with 25 nM tritiated reference ligand or with 40 nM or 50 nM tritiated Compound 1 ([ 3The slides were incubated with [H]-compound 1). Unlabeled example compounds were used at 1 μM and 125 nM (or 1 μM and 100 nM for compound 15). In some cases, non-radiolabeled example compounds were further evaluated at a series of different concentrations ranging from 0.24 nM to 2 μM for determination of the inhibition constant (Ki). After incubation, the slides were washed and scanned with a real-time autoradiography system (BeaQuant, ai4R). Signal quantification was performed using Beamage image analysis software (ai4R). Non-specific signal was determined with an excess of non-radiolabeled reference compound (2 μM), and specific binding was calculated by subtracting the non-specific signal from the total signal. Composition was calculated as a percentage, where 0% was defined as specific binding in the presence of vehicle and 100% was defined as the value obtained in the presence of an excess of non-radiolabeled reference compound. K i Values ​​were calculated in GraphPad Prism 8 by applying a nonlinear regression curve fit using a one-site specific binding model. Measurements were performed with at least two technical replicates in two-concentration competition experiments and one technical replicate in experiments involving a range of concentrations. For compounds tested in more than one experiment, replicates or K values ​​from independent experiments were used. i The average of the values ​​is reported.

[0489] result: Example compounds 1 to 10 were used to evaluate the activity of TDP-43 aggregates derived from the brains of FTD patients. 3 The results of the microradiometric binding competition assay for the example compounds are shown below in Table 2 as % competition at 1 μM and 125 nM. i The values ​​are also shown in Table 2.

[0490] Example compounds 11-15 were tested against two different batches of brain extract. 3H]-Compound 1 was evaluated for its ability to compete with the binding of Compound 1. The results of the microradiometric binding competition assay for the example compounds are shown in Table 3 below as % competition at 1 μM and 125 nM for Compounds 11-14 (competition with 50 nM Compound 1), or % competition at 1 μM and 100 nM for Compound 15 (competition with 40 nM Compound 1), respectively. i The values ​​are also shown in Table 3.

[0491] These data indicate that the compounds of the present invention can bind to TDP-43 aggregates with good affinity.

[0492] [Table 5]

[0493] [Table 6]

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R A is H or F; R 2 , F, NH 2 , CN, and / or CH 3 a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

2. Formula (Ia): 【Chemistry 2】 (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R 2 , F, NH 2 , CN, and / or CH 3 a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, having the formula:

3. f Formula (Ib): 【Transformation 3】 (In the formula, n is 1 or 2; R 1 is H or F; X, Y, and Z are independently CH or N; R 2 , F, NH 2 , CN, and / or CH 3 a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and / or S, optionally substituted with or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof, having the formula:

4. n is 1, and X is N; Y is CH; Z is CH; or X is N; Y is CH; Z is N; or X is N; Y is N; Z is CH; or X is CH; Y is CH; and Z is CH; A compound according to any one of claims 1 to 3.

5. R 2 but 【Chemistry 4】 (In the formula, R 3 is F and R 4 Ga-NH 2 and R 7 and R 8 is H); or 【Transformation 5】 (In the formula, W 1 is N, S, or O, and W 2 is N); or 【Transformation 6】 (where "----F" indicates that "F" may or may not be present); or 【Transformation 7】 The compound according to any one of claims 1 to 4, wherein 【Request Item 6】 【Chemistry 8】 2. The compound of claim 1, selected from:

7. The compound of any one of claims 1 to 6, comprising a detectable label.

8. Detectable label 3 H or 18 8. The compound of claim 7, wherein F.

9. Formula(IT): 【Chemistry 9】 (In the formula, n is 1 or 2; R 1 is H or F; X and Z are independently CH or N; Y is CR 6 and; R 6 is T or H; T is 3 H; R A is H or F; and, R 2 teeth 【Chemistry 10】 (In the formula, R 3 is F and R 4 Ha-NH 2 and R 7 and R 8 at least one of R is T and, if applicable, the other is H; preferably, R 7 and R 8 is T); or R 2 teeth 【Chemistry 11】 (In the formula, W 1 is N, S, or O (preferably S); W 2 is N and R 9 is T); or R 2 teeth 【Chemistry 12】 (In the formula, R 10 is T and R 6 is T); or R 2 teeth 【Chemistry 13】 (In the formula, R 10 is T and R 6 is T); or R 2 teeth 【Chemistry 14】 (In the formula, R 10 is T and R 6 is T); or R 2 teeth 【Chemistry 15】 (In the formula, R 10 is T and R 6 is T); or R 2 teeth 【Chemistry 16】 (In the formula, R 10 is T and R 6 is T); or R 2 teeth 【Chemistry 17】 (In the formula, R 10 is T and R 6 is H); or R 2 teeth [Chemistry 18] (In the formula, R 10 is T and R 6 is H); In the formula, "----F" indicates that "F" may or may not be present.

9. The compound of claim 8, or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula: 【Request Item 10】 【Chemistry 19】 (Wherein, T is 3 10. The compound of claim 9, wherein R is H.

11. Formula (IF): 【Chemistry 20】 (In the formula, R 1' teeth 18 F;n, X, Y, Z, R A , and R 2 is as defined in claim 1) 9. The compound of claim 8, or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, having the formula: 【Request Item 12】 【Chemistry 21】 12. The compound of claim 11, wherein:

13. A diagnostic composition comprising a compound according to any one of claims 7 to 12, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient.

14. A compound according to any one of claims 7 to 12 or a diagnostic composition according to claim 13 for use in a diagnostic method.

15. A compound according to any one of claims 7 to 12 or a diagnostic composition according to claim 13, in particular for use in imaging TDP-43 aggregates by positron emission tomography.

16. 14. A compound according to any one of claims 7 to 12, or a diagnostic composition according to claim 13, for use in the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates, in particular by positron emission tomography, or for use in the diagnosis of a TDP-43 proteinopathy or a predisposition thereto.

17. 1. A method for diagnosing a disease, disorder, or condition associated with TDP-43 aggregates, or a TDP-43 proteinopathy or predisposition thereto, in a subject, comprising the steps of: (a) administering to a subject a compound according to any one of claims 7 to 12; or a diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) binding the compound to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates. A method comprising:

18. The following stages: (d) generating an image representing the location and / or amount of compound bound to the TDP-43 aggregates; (e) an optional step of comparing the generated image with a control image of a healthy control subject, wherein an increase in binding signal indicates that the subject is suffering from or at risk of developing a TDP-43 aggregate-associated disease, disorder, or abnormality, or a TDP-43 proteinopathy.

18. The method of claim 17, further comprising:

19. The following stages: (a) administering to a subject a compound according to any one of claims 7 to 12; or a diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) allowing the compound to penetrate the tissue of the subject and bind to the TDP-43 aggregates; and (c) detecting the compound bound to the TDP-43 aggregates by collecting positron emission tomography (PET) images of the tissue of interest.

1. A method for positron emission tomography (PET) imaging of TDP-43 aggregates in tissue of a subject, comprising:

20. 20. The method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject according to claim 19, wherein the tissue is a tissue of the central nervous system (CNS), an eye tissue, or a brain tissue, preferably the tissue is a brain tissue.

21. The following stages: (a) contacting a sample or a specific body part or region suspected of containing TDP-43 aggregates with a compound according to any one of claims 7 to 12 or with the diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) binding the compound to TDP-43 aggregates; (c) detecting the compound bound to the TDP-43 aggregates using positron emission tomography; and (d) Optionally, quantifying the amount of compound bound to TDP-43 aggregates.

1. A method for detecting and optionally quantifying TDP-43 aggregates in tissue of a subject, comprising:

22. 1. A method of collecting data for the diagnosis of a disease, disorder, or abnormality associated with TDP-43 aggregates, or for the diagnosis of a TDP-43 proteinopathy or predisposition thereto, comprising the steps of: (a) contacting a sample or a specific body part or region suspected of containing TDP-43 aggregates with a compound according to any one of claims 7 to 12 or with the diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) binding the compound to TDP-43 aggregates; (c) detecting the compound bound to the TDP-43 aggregate; and (d) an optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or in a particular body part or body region. A method comprising:

23. The following stages: (a) contacting a sample, a specific body part or a body area suspected of containing TDP-43 aggregates with a compound according to any one of claims 7 to 12 or with the diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) binding the compound to TDP-43 aggregates; (c) detecting compounds bound to TDP-43 aggregates; (d) an optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region; and (e) the optional step of repeating steps (a) to (c) and, if present, optional step (d) at least once.

1. A method of collecting data to monitor the progression of a disease, disorder, or abnormality associated with TDP-43 aggregates, or to monitor the progression of a TDP-43 proteinopathy in a patient, comprising:

24. 1. A method of collecting data to predict the responsiveness of a patient suffering from a TDP-43 aggregate-associated disease, disorder, or disorder or suffering from a TDP-43 proteinopathy to a pharmaceutical treatment of the TDP-43 aggregate-associated disease, disorder, or disorder or a TDP-43 proteinopathy, comprising the steps of: (a) contacting a sample, a specific body part or a body area suspected of containing TDP-43 aggregates with a compound according to any one of claims 7 to 12 or with the diagnostic composition according to claim 13 comprising a compound according to any one of claims 7 to 12; (b) binding the compound to TDP-43 aggregates; (c) detecting compounds bound to TDP-43 aggregates; (d) an optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region; and (e) the optional step of repeating steps (a) to (c) and, if present, optional step (d) at least once. A method comprising:

25. The optional step of correlating the presence or absence of a compound bound to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region comprises the steps of: - quantifying the amount of compound bound to the TDP-43 aggregates; - correlating the amount of compound bound to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or in a particular body part or body region; and - an optional step of comparing the amount of compound bound to TDP-43 aggregates in the sample or in a specific body part or body region with a normal control value in a healthy control subject. The method according to any one of claims 22 to 24, comprising:

26. 13. Use of a compound according to any one of claims 7 to 12 as a biomarker for TDP-43 aggregates or a biomarker for a TDP-43 proteinopathy.

27. 13. Use of a compound according to any one of claims 7 to 12 as a diagnostic agent or tool for TDP-43 proteinopathies.

28. A compound according to any one of claims 7 to 12 for use as an in vitro analytical standard or an in vitro screening tool.

29. Diseases, disorders, or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathy include frontotemporal dementia (FTD, e.g., sporadic or familial with or without motor neuron disease (MND), with progranulin (GRN) mutations, with C9orf72 mutations, with TARDBP mutations, with valosin-containing protein (VCP) mutations, chromosome 9p-linked, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) (frontotemporal lobar dementia TDP-43 or frontotemporal lobar dementia with TDP-43 inclusions) Temporal lobar degeneration (FTLD-TDP), argyrophilic grain disease, Pick's disease, semantic primary progressive aphasia (svPPA), behavioral FTD (bvFTD), non-fluent primary progressive aphasia (e.g., nfvPPA), amyotrophic lateral sclerosis (ALS, e.g., sporadic ALS, those with TARDBP mutations, and those with angiogenin (ANG) mutations), Alexander disease (AxD), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease (AD, including sporadic and familial forms of AD), Down's disease syndrome, familial British dementia, polyglutamine diseases (Huntington's disease and spinocerebellar ataxia type 3 (SCA3; also known as Machado-Joseph disease)), hippocampal sclerosis dementia and myopathy (sporadic inclusion body myositis, inclusion body myopathy with mutations in valosin-containing protein (VCP), and Paget's disease of bone and frontotemporal dementia), oculopharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathy with mutations in the myotilin (MYOT) gene or the gene encoding desmin (DES), traumatic brain injury (TBI), Lewy bodies 28. The compound for use or the diagnostic composition for use according to claim 16, or the method according to any one of claims 17 to 27, wherein the disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy is selected from frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and limbic-predominant late-life TDP-43 encephalopathy (LATE).

30. 30. The compound for use, or diagnostic composition for use, or method according to claim 29, wherein the disease, disorder, or abnormality associated with TDP-43 aggregates, or TDP-43 proteinopathy, is amyotrophic lateral sclerosis (ALS).

31. 30. The compound for use, or diagnostic composition for use, or method according to claim 29, wherein the disease, disorder, or abnormality associated with TDP-43 aggregates, or TDP-43 proteinopathy, is Alzheimer's disease (AD).

32. 30. The compound for use, or diagnostic composition for use, or method according to claim 29, wherein the disease, disorder, or abnormality associated with TDP-43 aggregates, or TDP-43 proteinopathy, is frontotemporal dementia (FTD), including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).

33. 30. The compound for use, or diagnostic composition for use, or method according to claim 29, wherein the disease, disorder, or abnormality associated with TDP-43 aggregates, or TDP-43 proteinopathy, is limbic-predominant late-life TDP-43 encephalopathy (LATE).

34. Formula (II): 【Chemistry 22】 (In the formula, n is 1 or 2; X, Y, and Z are independently CH or N; R 1 is H or F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

35. Formula (II'): 【Chemistry 23】 (In the formula, R 2 is as defined in claim 1) A compound having the formula:

36. Formula (III): 【Chemistry 24】 (In the formula, n is 1 or 2; R 1 is H or F; Z is CH or N; Y 1 is selected from C—Br, CI, and CH; R A is H or F; R 11 Br, I, F, NH 2 , CN, and / or CH 3 a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, optionally substituted with Y 1 and / or R 11 At least one of these contains Br or I) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

37. Formula (IV): 【Chemistry 25】 (In the formula, n is 1 or 2; X, Y, and Z are independently CH or N; R A is H or F; R 2 teeth 【Chemistry 26】 and; R 12 is a leaving group (LG), preferably a mesylate group or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a mixture thereof.

38. 37. A kit for preparing a radiopharmaceutical preparation comprising a precursor of a detectably labeled compound as defined in any one of claims 7 to 12, which is a compound of formula (III) as defined in claim 36 or a compound of formula (IV) as defined in claim 37.

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