Novel compounds for diagnosis of TDP-43 proteinopathies

Abstract

The present invention relates to compounds suitable for the imaging of TDP-43 (trans-activation response (TAR) DNA binding protein 43kDa) aggregates. The compounds are useful, for example, in the diagnosis of 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 edge system dominated age-related TDP-43 encephalopathy (LATE).

Description

Field of the Invention

[0001] The present invention relates to compounds suitable for imaging TDP-43 (transactivation 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 age-related 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 their uses. Background of the Invention

[0003] Worldwide, age-related brain disorders characterized by pathological aggregation of proteins in the central nervous system (CNS) (proteinopathies) and peripheral organs represent one of the leading causes of disability and death. The best-characterized protein that forms extracellular aggregates is beta-amyloid (Aβ) in Alzheimer's disease (AD) and Aβ-related disorders. Other aggregation-prone proteins associated with neurodegenerative diseases include, but are not limited to, Tau protein, alpha-synuclein (a-syn), huntingtin, fused in sarcoma (FUS), dipeptide repeat proteins (DPRs) produced by unconventional translation of C9orf72 repeat expansions, superoxide dismutase 1 (SOD1), and TDP-43. Diseases involving TDP-43 aggregates are generally referred to as TDP-43 proteinopathies, and include, but are not limited to, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), including frontotemporal dementia with TDP-43 pathology (FTLD-TDP, frontotemporal lobar degeneration with TDP-43 inclusions) and limbic-predominant age-related TDP-43 encephalopathy (LATE).

[0004] Introduction of TDP-43

[0005] The trans-activation response (TAR) DNA-binding protein 43 kDa (TDP-43) is a 414-amino acid protein encoded by the TARDBP gene on chromosome 1p36.2 (ALS10). TARDBP consists of six exons (exon 1 is non-coding; exons 2-6 are protein-coding). TDP-43 belongs to the heterogeneous ribonucleoprotein (hnRNP) RNA-binding protein family (Wang et al., Trends in Molecular Medicine, Vol. 14, no. 11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 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 that enable it to shuttle between the nucleus and cytoplasm, a nuclear export signal (NES) and a nuclear localization signal (NLS) that bind 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 and ubiquitously expressed protein with tightly regulated expression levels, continuously shuttling between the nucleus and cytoplasm but generally mainly localized in the nucleus. In 2006, TDP-43 was identified as the protein that accumulates in the vast majority of frontotemporal lobar degeneration (FTLD) cases with tau-negative, ubiquitin-positive inclusions (subsequently called FTLD-TDP), as well as 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).

[0006] Thirty-eight TDP-43 negative dominant mutations (K263E, N267S) have been identified in sporadic and familial ALS patients and in patients with hereditary FTD, mainly located in the glycine-rich domain (Lagier-Tourenne and Cleveland, Cell, 136, 2009, 1001-1004 Figure 1 ). TDP-43 has an inherent tendency to aggregate, as shown by sedimentation assays, and this tendency is increased by some ALS-related TARDBP mutations (Ticozzi et al., CNS Neurol Disord Drug Targets, 2010, 9(3), 285-296).

[0007] TDP-43 in Neurodegeneration

[0008] TDP-43 aggregates have been identified in an increasing number of pathological conditions (Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64), including but not limited to: frontotemporal dementia (sporadic or familial, with or without motor neuron disease (MND), with progranulin (GRN) mutations, with TARDBP mutations, with valosin-containing protein (VCP) mutations, associated with chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration with ubiquitin-positive inclusions, argyrophilic grain disease, Pick's disease, etc.), amyotrophic lateral sclerosis (sporadic ALS, with TARDBP mutations, with ANG mutations), Alzheimer's disease (sporadic and familial), Down syndrome, familial British dementia, polyglutamine diseases (Huntington's disease and SCA3), hippocampal sclerosis dementia, and myopathies (sporadic inclusion body myositis, inclusion body myositis with VCP mutations, oculopharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathy with MYOT or DES mutations).

[0009] Aggregated TDP-43 from the patient's brain shows many abnormal modifications, including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragments by 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, Vol 64 No 1, 60-70; Cohen et al., Nat Commun.; 2015, 6:5845). Another feature 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 (NCI) and glial cytoplasmic inclusions (GCI), respectively) and dystrophic neurites (DN), which are immunoreactive to TDP-43 as well as ubiquitin and p62, but negative for proteins associated with other neurodegenerative diseases. Differences in inclusion morphology and their tissue distribution are associated with specific mutations and / or clinical manifestations. So far, four types of TDP-43 pathology have been described by histological methods (Mackenzie and Neumann, J. Neurochem., (2016), 138 (Suppl 1), 54-70). Type A FTLD-TDP cases are characterized by abundant short DNs and dense oval or crescent-shaped NCIs mainly located in layer II of the neocortex ( Figure 2 f) of Mackenzie et al., J. Neurochem., 2016, 138 (Suppl 1), 54-70). Cases with this pathology typically present clinically as behavioral variant frontotemporal dementia (bvFTD) or non-fluent / agrammatic variant primary progressive aphasia (nfvPPA) and are associated with progranulin (GRN) mutations. Type B cases show moderate numbers of dense or granular NCIs, relatively few DNs and NIIs in both the superficial and deep cortical layers ( Figure 2 g) of Mackenzie et al., J. Neurochem., 2016, 138 (Suppl 1), 54-70). Most cases presenting with both FTD and ALS symptoms are found to have the pathology of type B FTLD-TDP. Type C cases mainly have a large number of long, tortuous neurites in the superficial cortical layer and few or no NCIs ( Figure 2j). This pathology is particularly seen in cases presenting svPPA (semantic variant primary progressive aphasia). Type D FTLD-TDP shows abundant intranuclear inclusions (NII) and short DNs in the neocortex, and rare NCIs (in Mackenzie et al., J. Neurochem., 2016, 138 (Suppl 1), 54-70) Figure 2 k). This pathological pattern is found only in cases with VCP associated with inclusion body myositis.

[0010] TDP-43 in FTD

[0011] Frontotemporal dementia (FTD) is a clinical term that encompasses a broad spectrum of disorders based on frontal and temporal lobe degeneration (pathological features known as frontotemporal lobar degeneration (FTLD)). FTD is the second most common cause of early degenerative dementia in the age group under 65 years (Le Ber, Revue Neurologique, 169 (2013), 811-819). FTD presents as a variety of 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; corticobasal syndrome (CBS), progressive supranuclear palsy syndrome, and motor neuron disease characterized by motor dysfunction (FTD-MND). The diagnosis of these syndromes is complex and can only be finalized by immunohistochemistry-based postmortem tissue analysis to detect aggregated proteins and the description of affected brain regions. In terms of pathological, proteinaceous inclusions, approximately 45% of cases show pathological accumulation of misfolded Tau, 45% of cases 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, which is mainly found as cytoplasmic or neuritic protein aggregates in neurons and glial cells, containing misfolded, insoluble, phosphorylated, and truncated TDP-43.

[0012] TDP-43 in ALS

[0013] Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by the premature loss of upper and lower motor neurons. The progression of ALS is characterized by fatal paralysis and respiratory failure, with a disease course from diagnosis to death of 1 to 5 years. In most cases of sporadic ALS, the 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 with dementia involves the accumulation of TDP-43 in the motor cortex and hippocampus. The role of TDP-43 phosphorylation in patients with ALS has been explored with the help of phospho-specific antibodies that strongly bind to nuclear and cytoplasmic TDP-43 inclusions. Amino acids S379, S403, S404, S409, and S410 have been identified as the major sites of TDP-43 phosphorylation (Hasegawa et al., Ann Neurol., 2008; 64:60-70; Neumann et al., Acta Neuropathol., 2009, 117:137-149).

[0014] TDP-43 in LATE

[0015] Limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologic change (LATE-NC) is defined as a TDP-43 proteinopathy typical in the elderly, with or without coexistent hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy associated with an amnestic dementia syndrome mimicking Alzheimer-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology by its epidemiology (LATE typically affects older individuals) and the relatively limited neuroanatomic distribution of the TDP-43 proteinopathy. There are no molecularly specific biomarkers for LATE. The discovery of TDP-43 PET tracers could enable accurate, potentially early diagnosis and monitoring of disease progression to facilitate longitudinal measurement of drug efficacy in patients during clinical trials (including as a potential exclusion criterion in Alzheimer's disease clinical trials) and longitudinal studies of the clinical and pathologic progression of LATE (Nelson et al., Brain, 2019, volume 142; issue 6, 1503-1527).

[0016] TDP-43 in AD and Other Diseases

[0017] TDP-43 pathology occurs in the brains of up to 57% 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; McAleece 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 individuals. TDP-43 appears to represent a secondary or independent pathology that shares overlapping features with AD by targeting the medial temporal lobe. Pathological TDP-43 follows a typical deposition pattern captured by the staging scheme for TDP-43 in AD (TAD): TDP-43 first deposits in the amygdala (stage I), then the hippocampus, limbic, temporal lobe, and finally 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).

[0018] Diagnosis of FTD and ALS

[0019] Diagnosing FTD based on clinical manifestations is insufficient because the clinical presentation can overlap with other diseases, especially in the early stages. Therefore, developing sensitive and specific biomarkers to distinguish the pathological types within the FTD spectrum is an urgent task. Such tools will help better detect and understand the specific types of pathology leading to neurodegeneration. Ultimately, this will lead to the development of diagnostic biomarkers, enabling more efficient and precise patient selection for longitudinal monitoring in clinical studies to support the development of new therapies for ALS and FTD.

[0020] Many approaches aim to develop biochemical biomarkers to distinguish different types of FTD pathology. Some studies have shown increased concentrations of TDP-43 in the cerebrospinal fluid (CSF) of clinically defined FTD or FTD-MND populations, although there is significant overlap with controls or AD individuals, and it is currently unclear whether such approaches will be 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 Tau phosphorylated at Thr181 do not distinguish FTLD-Tau from controls. A diagnostic tool that may distinguish FTLD-Tau from FTLD-TDP is a 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 are positively correlated with the Tau brain burden in FTD and may help distinguish TDP-43 proteinopathies from tau proteinopathies (Irwin et al., Ann. Neurol., 2017 Aug; 82(2):247-258).

[0021] Concurrent with the development of biochemical biomarkers, the development of biomarker imaging will enable early and specific detection of the pathology of FTD, ALS, and other neurodegenerative diseases. The ability to image TDP-43 deposition in the brain would be an important achievement for the diagnosis and drug development of FTD, ALS, and other neurodegenerative disorders. Progressive TDP-43 accumulation in the CNS is associated with disease progression and represents an obvious target for the development of new therapies and for studying pharmacodynamics and disease progression diagnostic tools. Given that TDP-43 is a relatively new target, the development of PET tracers targeting this protein has only just begun. However, most of the compounds reported to date are not specific for TDP-43, and none of these compounds have been shown to bind directly to the target.

[0022] The development of TDP-43 specific PET tracers poses many challenges, including the low abundance and heterogeneous distribution of the target in the patient's brain, as well as the lack of reference compounds. To reduce background signal interference caused by non-specific off-target binding and to lower the dose requirements, TDP-43 imaging compounds should bind to the target with high affinity and selectivity. For imaging of TDP-43 aggregates associated with neurological disorders such as FTD and ALS, the imaging compounds need to penetrate the blood-brain barrier and enter the relevant regions of the brain. For targeting intracellular amyloid-like inclusions (such as TDP-43 aggregates), a further requirement for imaging compounds is cell permeability. To avoid the accumulation of compounds in tissues, which may lead to an increased risk of unwanted side effects, another prerequisite is the rapid clearance of the compounds from the brain (or other target organs).

[0023] The object of the present invention is to provide compounds capable of binding to TDP-43 aggregates. In particular, the compounds of the present invention should be useful for the identification and differentiation of patients or patient groups with TDP-43 proteinopathies (such as FTD, FTLD-TDP, LATE, and ALS), as well as for differentiating TDP-43 proteinopathies from other proteinopathies.

[0024] The inventors have surprisingly found that compounds having the structure of formula (I) can recognize and bind to TDP-43 aggregates. Summary of the Invention

[0026] The present invention is outlined in the appended claims. In particular, the present invention relates to compounds having the structure of formula (I)

[0027]

[0028] or their detectably labeled compounds, stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof;

[0029] wherein

[0030] n is 1 or 2;

[0031] R 1 is H or F;

[0032] X, Y and Z are independently CH or N;

[0033] R A is H or F; and

[0034] R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and / or S,

[0035] and relates to compounds having sub-formula (Ia)

[0036]

[0037] or a compound thereof which is detectably labeled, a stereoisomer, a polymorph, a racemic mixture, a tautomer, a pharmaceutically acceptable salt, a hydrate or a solvate or a mixture thereof;

[0038] wherein

[0039] n is 1 or 2;

[0040] R 1 is H or F;

[0041] X, Y and Z are independently CH or N; and

[0042] R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which may optionally be substituted by F, NH2, CN and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

[0043] or a compound having sub-formula (Ib)

[0044]

[0045] or a compound thereof which is detectably labeled, a stereoisomer, a polymorph, a racemic mixture, a tautomer, a pharmaceutically acceptable salt, a hydrate or a solvate or a mixture thereof;

[0046] wherein

[0047] n is 1 or 2;

[0048] R 1 is H or F;

[0049] X, Y and Z are independently CH or N; and

[0050] R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which may optionally be substituted by F, NH2, CN and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

[0051] In another aspect, the present invention provides a diagnostic composition comprising a compound of formula (I) or a sub-formula thereof as defined herein, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient. The compound can be used for imaging of TDP-43 aggregates, particularly where the imaging is performed by positron emission tomography, or for the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies, particularly where the diagnosis is performed by positron emission tomography.

[0052] In another aspect, the present invention provides a compound of formula (I) or a sub-formula thereof, which can be used in the following methods:

[0053] · A method for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, or a predisposition thereto, in an individual;

[0054] · A method for performing positron emission tomography (PET) imaging of TDP-43 aggregates in the tissue of an individual;

[0055] · A method for detecting and optionally quantifying TDP-43 aggregates in the tissue of an individual;

[0056] · A method for collecting data for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;

[0057] · A method for collecting data for determining a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;

[0058] · A method for collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates in a patient or for monitoring the progression of a TDP-43 proteinopathy; and

[0059] · A method for collecting data for predicting the response of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy to drug treatment.

[0060] In another aspect, the present invention provides a compound of formula (I) or a sub-formula thereof, which can be used as a biomarker for TDP-43 aggregates or a TDP-43 proteinopathy, as a diagnostic reagent or diagnostic tool for a TDP-43 proteinopathy, or as a reference for in vitro analysis or an in vitro screening tool.

[0061] Precursors of the compound of formula (I) or a sub-formula thereof having the structures of formula (II), (III) and (IV) or sub-formulas thereof are also aspects of the present invention.

[0062] 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 sub-formula thereof. Brief Description of the Drawings

[0064] Figure 1 : 3 Saturation binding curve of [3H] Compound 1 to human FTD tau insoluble brain extract. Each point represents the mean of two independent experiments ± standard error of the mean (SEM).

[0065] Figure 2 : 3 Saturation binding curve of [3H] Compound 11 to human FTD tau insoluble brain extract.

[0066] Figure 3 : 3 Saturation binding curve of [3H] Compound 12 to human FTD tau insoluble brain extract.

[0067] Figure 4 : 3 Saturation binding curve of [3H] Compound 4 to human FTD tau insoluble brain extract.

[0068] Figure 5 : 3 Saturation binding curve of [3H] Compound 8 to human FTD tau insoluble brain extract.

[0069] Definitions

[0070] Unless otherwise defined, within the meaning of this application, the following definitions apply, and where appropriate, terms used in the singular also include the plural and vice versa:

[0071] The compounds of the present invention may have one or more optically active carbons, which may exist in the following forms: racemates and racemic mixtures, stereoisomers (including mixtures of diastereoisomers and single diastereoisomers, mixtures of enantiomers and single enantiomers, mixtures of conformational isomers and single conformational isomers), tautomers, atropisomers and rotamers. All isomeric forms are included in the present invention. Compounds described in this specification containing an olefinic double bond include E and Z geometric isomers. The present invention also includes all salt forms such as pharmaceutically acceptable salts, polymorphs, hydrates, solvates and mixtures thereof. Unless otherwise specified, the term "compound of formula (X)" or "(the) compound of the invention" means "a compound of formula (X) or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof". Unless otherwise specified, the term "compound of formula (X)" or "(the) compound of the invention" means a compound of formula (X) or a sub-formula thereof, and its isotopically labeled compound (including but not limited to 18 F and 3 H substitution). The term "compound of formula (X)" or "(the) compound of the invention" means a compound as defined in any of the embodiments mentioned hereinafter

[0072] Unless otherwise specified, "----X" means that "X" is an optional substituent, i.e., "X" may be present or absent.

[0073] The term "polymorph" refers to the various crystalline structures of the compounds of the present invention. This may include but is not limited to crystal forms (and amorphous substances) and all lattice forms. Salts may also be crystalline and may exist as more than one polymorph.

[0074] The present invention also includes solvates, hydrates and anhydrous forms of salts. 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).

[0075] "Pharmaceutically acceptable salts" are defined as derivatives of the compounds of the present invention, wherein the parent compound is modified by preparing its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of basic residues such as amines; base salts or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such 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, etc.; 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, etc. Pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. Organic solvents include, but are not limited to, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, page 1445, the disclosure of which is incorporated herein by reference. Generally, pharmaceutically acceptable salts are salts of the amine residues in the compounds of the present invention.

[0076] The "patient" or "individual" in the present invention is generally an animal, particularly a mammal, more particularly a human and a mouse, and even more particularly a human.

[0077] The "diagnostic composition" as defined in the present invention is a composition comprising a compound of the present invention in a form suitable for administration to a patient, wherein the patient is, for example, a mammal such as a human.

[0078] "TDP-43 aggregates" are TDP-43 positive multimeric enriched assemblies of TDP-43. They can be found in intracellular deposits in a range of diseases termed TDP-43 proteinopathies, particularly in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 aggregates can be found in the following morphologies: dense oval or crescent-shaped neuronal cytoplasmic inclusions (NCIs), lentiform neuronal intranuclear inclusions (NIIs), glial cytoplasmic inclusions (GCIs), dystrophic neurites (DNs), and long tortuous neurites. In pathological aggregates, TDP-43 often exhibits a large increase in post-translational modifications such as phosphorylation, ubiquitination, acetylation, SUMOylation, and proteolytic cleavage to generate C-terminal fragments.

[0079] The "preclinical state" of a disease is defined as the disease stage in which disease-related changes at the molecular level do not result in overt clinical manifestations in the patient.

[0080] The "clinical state" of a disease is defined as the disease stage in which disease-related changes at the molecular level result in overt clinical manifestations in the patient.

[0081] The term "diagnosis" generally refers to the process or act of identifying, determining, or characterizing a patient's disease or disorder based on symptoms, signs, and / or the results of diagnostic procedures.

[0082] "Normal control values" are determined by measuring the amount (if any) of the compound that binds to TDP-43 aggregates in each healthy individual by the respective method for a large number of healthy individuals and calculating their average.

[0083] A "healthy control individual (or patient)" or "healthy individual (or patient)" is a person who does not show clinical evidence of a neurodegenerative disease. The person needs to meet the following criteria:

[0084] · Healthy male and female individuals with no clinically relevant findings on physical examination.

[0085] · No (family) history of TDP-43 proteinopathy, TDP-43 aggregate formation, or other early-onset neurodegenerative diseases associated with dementia.

[0086] · No (personal) history of clinically significant neurological (and / or psychiatric disorders, for humans).

[0087] · Currently no clinical signs or symptoms of neurological deficits such as cognitive impairment or motor deficits.

[0088] "Pre-clinical control value" is determined by measuring the amount of the compound (if any) that binds to the TDP-43 aggregate in each of a large number of pre-clinical individuals by their respective methods and calculating the average value thereof.

[0089] "Clinical control value" is determined by measuring the amount of the compound (if any) that binds to the TDP-43 aggregate in each of a large number of clinical individuals by their respective methods and calculating the average value thereof.

[0090] The term "prediction" generally refers to the pre-statement, indication or prediction of a disease or condition in a patient without a disease, disorder or abnormality. For example, the prediction of a disease, disorder or abnormality in a patient can indicate the probability, chance or risk that the patient will develop a disease, disorder or abnormality, such as within a certain time period or at a certain age.

[0091] Detectable labels include suitable isotopes such as radioisotopes, especially positron emitters or gamma emitters, and include 2 H, 3 H, 18 F, 123 I, 124 I, 125 I, 131 I, 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, even more preferably 3 H and 18 F, most preferably 18 F.

[0092] The terms "Hal", "halogen" or "halo" refer to F, Cl, Br or I, especially Br or I, more especially Br.

[0093] The term "carbocyclic ring" refers to a 5- or 6-membered carbocyclic ring, without particular limitation, and includes any 5- or 6-membered, saturated or unsaturated carbocyclic ring, which may be substituted or unsubstituted. Unsaturated carbocyclic rings include, but are not limited to, aromatic rings. Examples of 5- or 6-membered carbocyclic rings include, for example, phenyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. Phenyl is preferred.

[0094] The term "heterocycle" refers to a stable 5- or 6-membered heterocycle, without particular limitation, including 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 selected from N, O and S (e.g., one or two heteroatoms). The heteroatom is preferably N or S, more preferably N. Examples of 5- or 6-membered heterocycles include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, furyl, tetrahydrofuryl, thienyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, oxathiolanyl, isoxathiolanyl, oxathiolenyl, isoxathiolenyl, thiazolidinyl, isothiazolidinyl, thiazolyl and isothiazolyl, preferably pyridyl, pyrazinyl, pyrimidinyl and isothiazolyl.

[0095] The term "leaving group" (LG) as used herein is any leaving group and refers to an atom or group of atoms that can be replaced by another atom or group of atoms. Examples are given, for example, in: Synthesis (1982), pages 85-125, Table 2, Carey and Sundberg, Organische Synthese, (1995), pages 279-281, Table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71-83, Schemes 1, 2, 10 and 15 and others). (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), in: Schubiger P.A., Friebe M., Lehmann L. (eds.), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pages 15-50, specifically: page 25 Scheme 4, page 28 Scheme 5, page 30 Table 4, page 33 Figure 7). Preferably, the "leaving group" (LG) is selected from C 1-4 alkylsulfonate groups, C 6-10 arylsulfonate groups or nitro. More preferably, the leaving group (LG) is a mesylate group, a tosylate group, a p-nitrobenzenesulfonate group (nosylate) or nitro. Even more preferably, the leaving group (LG) is a mesylate group or nitro, most preferably a mesylate group.

[0096] The term "detection" as used herein includes quantitative detection and / or qualitative detection.

[0097] The compounds of the present invention can be used as analytical references or in vitro screening tools.

[0098] For example, the unlabeled compounds of formula (I) of the present invention can be used as analytical references for quality control and release of the corresponding labeled compounds of the present invention (e.g., the corresponding 18 compounds of formula (IV) or its sub-formulae labeled with

[0099] The compounds of the present invention can be used as in vitro screening tools for characterizing tissues with TDP-43 pathology and testing compounds targeting TDP-43 pathology on such tissues.

[0100] Unless otherwise specified, the preferred definitions given in the "Definitions" section apply to all embodiments described below. Multiple embodiments of the present invention are described herein, and it should be recognized that the features specified in each embodiment can be combined with other specified features to provide additional embodiments of the present invention. Detailed Description of the Invention

[0102] Multiple embodiments of the present invention are described herein, and it should be recognized that the features specified in each embodiment can be combined with other specified features to provide additional embodiments of the present invention.

[0103] It should be understood that all definitions given for formula (I) apply to all its sub-formulae, including formulae (I-a), (I-b), (II), (II’), (III), (IIIa), (IIIb), (IV), and (IVa).

[0104] In a first aspect, the present invention relates to compounds having the structure of formula (I)

[0105]

[0106] or their detectably labeled compounds, stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof;

[0107] Wherein

[0108] n is 1 or 2;

[0109] R 1 is H or F;

[0110] X, Y, and Z are independently CH or N;

[0111] R A is H or F; and

[0112] R 2is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more (preferably one or two, more preferably one) heteroatoms selected from N, O and / or S,

[0113] and compounds having the structure of formula (Ia)

[0114]

[0115] or a detectable labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof or a mixture thereof;

[0116] wherein

[0117] n is 1 or 2;

[0118] R 1 is H or F;

[0119] X, Y and Z are independently CH or N; and

[0120] R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

[0121] or a compound having the structure of formula (Ib)

[0122]

[0123] or a detectable labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof or a mixture thereof;

[0124] wherein

[0125] n is 1 or 2;

[0126] R 1 is H or F;

[0127] X, Y and Z are independently CH or N; and

[0128] R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

[0129] The present invention relates to compounds of formula (I), wherein R A is H or F. In some preferred embodiments, the present invention relates to compounds of formula (I), wherein RA is H (sub-formula (Ia)). In other preferred embodiments, the present invention relates to a compound of formula (I), wherein R A is F (sub-formula (Ib)).

[0130] The present invention relates to a compound of formula (I) or sub-formula (Ia) or (Ib), wherein n is 1 or 2. In a preferred embodiment, n is 1. In another embodiment, n is 2.

[0131] The present invention relates to a compound of formula (I) or sub-formula (Ia) or (Ib), wherein R 1 is H or F. In a preferred embodiment, R 1 is H. In another most preferred embodiment, R 1 is F.

[0132] The present invention relates to a compound of formula (I) or sub-formula (Ia) or (Ib), wherein n is 1, and wherein

[0133] X is N; Y is CH; and Z is CH; or

[0134] X is N; Y is CH; and Z is N; or

[0135] X is N; Y is N; and Z is CH; or

[0136] X is CH; Y is CH; and Z is CH.

[0137] The present invention relates to a compound of formula (I) or sub-formula (Ia) or (Ib), wherein R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by 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 be from 1 to the maximum number of available positions. Preferably, the number of substituents, if present, is 1 or 2. The heterocyclic ring contains one or more heteroatoms selected from N, O and S, preferably N or S, and the heteroatoms may be the same or different.

[0138] In different embodiments, R 2 is

[0139] a 5- or 6-membered carbocyclic ring, preferably an aryl ring, which may optionally be substituted by F, NH2, CN and / or CH3,

[0140] a 5-membered heteroaryl ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the 5-membered heteroaryl ring contains one or more heteroatoms selected from N, O and / or S, or

[0141] A 6 - heteroaryl ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein said 6 - heteroaryl ring contains one or two heteroatoms selected from O, N and / or S.

[0142] R 2 Preferred examples of the ring are given in the above definition section. Preferably, R 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl or isothiazolyl, any of which may optionally be substituted by F, NH2, CN and / or CH3, for example, substituted by F, NH2 and / or CH3, preferably substituted by F, and optionally substituted by NH2. In a preferred embodiment, the phenyl is substituted by F and may optionally be substituted by NH2 and / or CN. In a preferred embodiment, the pyrimidinyl is substituted by F. In another embodiment, the pyrimidinyl is unsubstituted. In a preferred embodiment, the pyridyl is unsubstituted. In a preferred embodiment, the pyridyl is substituted by F. In a preferred embodiment, the isothiazolyl is unsubstituted. In a preferred embodiment, the pyrazinyl is substituted by F.

[0143] In one embodiment, the present invention relates to a compound of formula (I) or sub - formula (Ia) or (Ib), wherein R 2 is a 5 - or 6 - membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2 and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and S. Preferably, the 5 - or 6 - membered carbocyclic or heterocyclic ring is substituted by one or more of F, NH2 and / or CH3.

[0144] In a preferred embodiment, R 2 is a 6 - heteroaryl ring substituted by F and / or NH2, wherein said 6 - heteroaryl ring contains at least one heteroatom which is N. In a preferred embodiment, R 2 is a pyridyl ring substituted by F.

[0145] In one embodiment, the present invention relates to a compound of formula (I) or sub - formula (Ia) or (Ib), wherein

[0146] R 2 is (i) wherein

[0147] R 3 is F, R 4 is NH2, R 7 is H, and R 8 is H; or

[0148] R 3 is NH2, R 4 is F, R 7 is H, and R 8 is H; or

[0149] R 3 is CN, R 4 is NH2, R 7 is H, and R 8 is H; or

[0150] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is CN; or

[0151] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is F.

[0152] In a preferred embodiment, R 3 is F, R 4 is NH2, R 7 is H, and R 8 is H.

[0153] In another embodiment, the present invention relates to a compound of formula (I) or sub-formula (Ia) or (Ib), wherein

[0154] R 2 is (ii) wherein W1 is N, S or O and W2 is N.

[0155] In another embodiment, the present invention relates to a compound of formula (I), wherein R 2 is

[0156] (iii) or

[0157] (iv) or

[0158] (v) or

[0159] (vi) wherein "----F" indicates that "F" may be present or absent; or

[0160] (vii)

[0162] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 1; R 1 is F; and X, Y and Z are independently CH or N; preferably at least one of X or Y is N and the other is CH; and Z is CH; and R 2 is

[0163] (i) wherein R 3 is F, R 4 is NH2, R 7 and R 8 are H or CH3, preferably H.

[0164] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 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; and Z is CH; and R 2 is (ii) wherein W1 is S and W2 is N.

[0165] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 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); and R 2 is (iii)

[0166] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 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; and Z is CH; and R 2 is (iv)

[0167] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 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; and Z is CH; and R 2 is (vii)

[0168] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 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; and Z is CH; and R 2 is (v)

[0169] In one embodiment, the compound of formula (I) or sub-formula (Ia) or (Ib) is defined as n is 1; R 1is 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; and Z is CH; or X, Y, and Z are CH; and R 2 is (vi) wherein "----F" indicates that "F" may be present or absent.

[0170] Preferred compounds of formula (I) include:

[0171]

[0172]

[0173] In one embodiment, preferred compounds of formula (I) may be selected from the following stereoisomers:

[0174]

[0175] In one embodiment, the invention relates to a compound of formula (I) or sub-formulae (Ia) or (Ib) which comprises at least one detectable label, which means that the compound of formula (I) or sub-formulae (Ia) or (Ib) comprises one or more detectable labels.

[0176] The type of detectable label is not particularly limited and will depend on the detection method selected. Examples of possible detectable labels include isotopes such as radioisotopes (i.e., radionuclides), in particular, positron emitters or gamma emitters. The detectable label, such as a radioisotope, in particular a positron emitter or gamma emitter, should be present in an amount that is not equivalent to the natural amount of each isotope. In addition, the amount used should be capable of being detected by the detection method selected.

[0177] In a preferred embodiment, the detectable label is selected from 3 H and / or 18 F, most preferably 18 F. The detectable label may be present at any available position. Generally, the detectable label is a radioisotope of an atom present in the compound of formula (I). For example, any mention of "F" in the present invention includes 19 F (stable) or 18 F (detectable label). Any mention of "H" includes 1 H (stable) or 3 H (detectable label, called tritium, denoted herein as "T").

[0178] Isotope variants of the compounds of the present invention can generally be prepared by conventional methods, for example, by the exemplary methods or by the preparation methods described in the Examples and Preparation Examples below, using appropriate isotope variants of suitable reagents, which are commercially available or prepared by known synthetic techniques. Radionuclides, particularly positron emitters and gamma emitters, can be included in the compounds of the present invention by methods commonly used in the field of organic synthesis. Generally, they are introduced by using the corresponding labeled starting materials. Exemplary methods for introducing detectable labels are described, for example, in US 8,932,557, which is incorporated herein by reference.

[0179] 18 F can be attached at any position suitable for attaching F. 18 F-labeled compounds are particularly suitable for imaging applications, such as in positron emission tomography (PET). The corresponding compounds containing the natural fluorine isotope 19 F are also of particular interest because they can be used as 18 analytical standards and references during the preparation, quality control, release, and clinical use of F-analogues.

[0180] In the compounds having the structure of formula (I), 18 F can be present, for example, as an F substituent of R 2 or as an R 1 substituent. Preferably, it is present as an R 1 substituent (R 1 is 18 F).

[0181] If 3 H is used as a detectable label, it is preferably attached at any position where a CH3 group can be attached in the form of -CT3 (T refers to 3 H). Substitution with a radioactive isotope such as 3 H can provide certain diagnostic advantages due to greater metabolic stability obtained by, for example, reducing defluorination, increasing the in vivo half-life, or reducing the dose requirement, while maintaining or improving the efficacy of the original compound.

[0182] In one embodiment, the present invention relates to compounds having the structure of formula (I) and sub-formulae (Ia) or (Ib) that are detectable labeled with tritium ( 3 H), as described above, wherein at least one hydrogen (H) is replaced by a detectable label selected from tritium ( 3 H). Compounds having the structure of formula (I) that are detectable labeled with tritium ( 3 H) are preferably defined as those in which 1 to 3 hydrogens (H) are replaced by tritium ( 3 H). Compounds having the structure of formula (I) that are detectable labeled with tritium ( 3H) The tritium ([ 3 H])-detectable labeled compound is more preferably defined as one in which 2 or 3 hydrogens (H) are replaced by tritium ([ 3 H]). The tritium ([ 3 H])-detectable labeled compound having the structure of formula (I) and sub-formulas (Ia) or (Ib) is even more preferably defined as one in which 2 hydrogens (H) are replaced by tritium ([ 3 H]) 3 H) 3 H) and the tritium ([ 3 H])-detectable labeled compound is even more preferably defined as one in which 2 hydrogens (H) are replaced by tritium ([ 3 H]) 3 H).

[0183] In one embodiment, the present invention relates to a tritium ([ 3 H])-detectable labeled compound having the structure of formula (I-T) 3 H)

[0184]

[0185] or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof; wherein n, R A , R 1 , R 2 , X and Z are as defined herein for the compound of formula (I); Y is CR 6 , R 6 is T or H, and wherein R 2 is substituted with at least one CT3 and / or at least one hydrogen atom in R 2 is replaced by T. T is 3 H.

[0186] In one embodiment, the present invention relates to a tritium ([ 3 H])-detectable labeled compound having the structure of formula (I-Ta) 3 H)

[0187]

[0188] or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof; wherein n, R 1 , R 2 , X and Z are as defined herein for the compound of formula (I); Y is CR 6 , R 6 is T or H, and wherein R 2 is substituted with at least one CT3 and / or at least one hydrogen atom in R 2 is replaced by T. T is 3 H.

[0189] In another embodiment, the present invention relates to a tritium ([ 3 H])-detectable labeled compound having the structure of formula (I-Tb) 3 H)

[0190]

[0191] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof or a mixture thereof; wherein n, R 1 , R 2 , X and Z are as defined herein for the compounds of formula (I); Y is CR 6 , R 6 is T or H, and wherein R 2 is substituted by at least one C T3 and / or at least one hydrogen atom in R 2 is replaced by T. T is 3 H.

[0192] In some embodiments, R 6 is T. In other embodiments, R 6 is H.

[0193] In a preferred embodiment, at least one hydrogen atom in R 2 is replaced by T. In a preferred embodiment, R 6 is T, and at least one hydrogen atom in R 2 is replaced by T.

[0194] In a preferred embodiment, the present invention relates to a compound of formula (I-T), wherein

[0195] wherein

[0196] R 2 is (i’) wherein R 3 is F, R 4 is -NH2, and at least one of R 7 and R 8 is T, and, where applicable, the other is H; preferably R 7 and R 8 are T; and R 6 is T; or wherein

[0197] R 2 is (ii’) wherein W 1 is S, and W 2 is N, and R 9 is T, and R 6 is T; or wherein

[0198] R 2 is (iii’) wherein R 10 is T, and R 6 is T; or wherein

[0199] R 2 is (iv’) wherein R 10 is T, and R 6 is T; or wherein

[0200] R 2 is (v’) wherein R 10 is T, and R 6 is T; or wherein

[0201] R 2 is (vi’) wherein “----F” indicates that “F” may be present or absent, and wherein R 10 is T, and R 6 is T; or wherein

[0202] R 2 is (vii’) wherein R 10 is T, and R 6 is T; or wherein

[0203] R 2 is (viii‘) wherein R 10 is T, and R 6 is H; or wherein;

[0204] R 2 is (ix’) wherein “----F” indicates that “F” may be present or absent, and wherein R 10 is T, and R 6 is H.

[0205] In one embodiment, the present invention relates to a compound of formula (I-T), wherein

[0206] R 1 is H;

[0207] R 6 is T; and

[0208] R 2 is (i’) wherein R 3 is F; R 4 is -NH2; and R 7 and R 8 at least one of which is T, and, if applicable, the other is H. Preferably R 7 is T; and R 8 is T.

[0209] In one embodiment, the present invention relates to a compound of formula (I-T), wherein

[0210] R 1 is F;

[0211] R 6 is T; and

[0212] R 2 is (ii’) wherein W 1 is S, and W 2 is N, and R 9 is T.

[0213] In one embodiment, the present invention relates to a compound of formula (I-T), wherein

[0214] R 1 is H or F;

[0215] R 6 is T; and

[0216] R 2 is (vi’) wherein R 10 is T.

[0217] In a preferred embodiment, the present invention relates to a compound of formula (I-T)

[0218] wherein T is 3 H.

[0219] Preferred tritium ([[]] 3 H) detectable labeled compounds according to the present invention include (wherein T means 3 H):

[0220]

[0221] More preferably, the tritium ([[]] 3 H) detectable labeled compounds according to the present invention may be stereoisomers (wherein T means 3 H)

[0222]

[0223]

[0224] In one embodiment, the present invention provides a 18 F detectable labeled compound of formula (I-F)

[0225]

[0226] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof;

[0227] wherein

[0228] R 1’ is 18 F; and n, X, Y, Z, R A and R 2 are as defined herein for the compounds of formula (I), and preferably n is 1.

[0229] In one embodiment, the compound of formula (I-F) 18 having an F-detectable label has the formula (I-Fa):

[0230]

[0231] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof or a mixture thereof;

[0232] wherein

[0233] R 1’ is 18 F; and n, X, Y, Z and R 2 are as defined herein for the compounds of formula (I), and preferably n is 1.

[0234] In one embodiment, the compound of formula (I-F) 18 having an F-detectable label has the formula (I-Fb):

[0235]

[0236] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof or a mixture thereof;

[0237] wherein

[0238] R 1’ is 18 F; and n, X, Y, Z and R 2 are as defined herein for the compounds of formula (I), and preferably n is 1.

[0239] In one embodiment, (I-F) is a compound in which (R 1 is 18 F (a detectable label);

[0240]

[0241] wherein n and R 2 are as defined herein for the compounds of formula (I).

[0242] In another embodiment, (I-F) is a compound

[0243]

[0244] wherein n and R 2 as defined herein for the compounds of formula (I).

[0245] In a preferred embodiment of formula (I-F), (I-Fa) or (I-Fb), n is 1 or 2; and

[0246] R 2 is (i) wherein R 3 is F, R 4 is NH2, R 7 is H, and R 8 is H; or wherein

[0247] R 2 is (ii) wherein W1 is S and W2 is N; or wherein

[0248] R 2 is (iii) or

[0249] (iv) or

[0250] (v) or

[0251] (vi) wherein "----F" indicates that "F" may be present or absent; or

[0252] (iv)

[0253] In a preferred embodiment, the present invention relates to a compound of formula (I-F), wherein

[0254] n is 1 or 2;

[0255] R 1 is 18 F (detectable label);

[0256] R 2 is (vi)

[0257] In a preferred embodiment n is 1.

[0258] Preferred compounds of formula (I-F) according to the present invention 18 with an F detectable label are

[0259]

[0260] More preferably, the compound of formula (I-F) according to the present invention 18 with an F-detectable label may be a stereoisomer

[0261]

[0262] Diagnostic Compositions

[0263] In a second aspect, the present invention relates to a diagnostic composition comprising a compound of formula (I) as described above and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient.

[0264] The compounds of the present invention are particularly suitable for imaging of TDP-43 aggregates. The imaging can be carried out in mammals, preferably in 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 can also be eye / retinal imaging or imaging of tissues of the central nervous system.

[0265] The compounds or compositions of the present invention are particularly suitable for diagnosis. The diagnosis can be carried out in mammals, preferably in humans. In the diagnosis carried out, the tissue of interest can be the brain, tissues of the central nervous system, tissues of the eye (such as retinal tissue) or other tissues, or body fluids, such as cerebrospinal fluid (CSF). The preferred tissue is brain tissue.

[0266] The "diagnostic composition" as defined in the present invention is a composition comprising one or more compounds of the present invention in a form suitable for administration to a patient (such as a mammal, such as a human), and which is suitable for diagnosing a specific disease, disorder or abnormal problem in a tissue. In one embodiment, the diagnostic composition comprises a detectable-labeled compound of the present invention as described above and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient.

[0267] Preferred detectable-labeled compounds of the present invention are compounds of formula (I-T) or sub-formulas (I-Ta) and (I-Tb) or (I-F) or sub-formulas (I-Fa) and (I-Fb).

[0268] The diagnostic composition or compound is suitable for imaging of TDP-43 aggregates, especially by positron emission tomography.

[0269] The diagnostic composition is suitable for the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies, especially where the diagnosis is carried out by positron emission tomography as defined below.

[0270] Preferably, the diagnostic composition further comprises a physiologically acceptable excipient, carrier, diluent or adjuvant. Administration is preferably carried out as defined below, and more preferably the composition is injected as an aqueous solution. The diagnostic composition may optionally contain additional ingredients, such as buffers; pharmaceutically acceptable solubilizers (e.g., cyclodextrins or surfactants such as pluronics, tweens or phospholipids); and pharmaceutically acceptable stabilizers or antioxidants (e.g., ascorbic acid, gentisic acid or para-aminobenzoic acid). The dosage of the compounds of the present invention will vary depending on the specific compound administered, the weight of the patient and other variables obvious to a skilled clinician in the art.

[0271] Although it is possible to administer the compounds of the present invention alone, they are preferably formulated into diagnostic compositions according to standard pharmaceutical practice. Thus, the diagnostic composition, which is part of the present invention, comprises a diagnostically effective amount of a compound of the present invention in combination with a pharmaceutically acceptable carrier, diluent, adjuvant and / or excipient. Preferred pharmaceutically acceptable carriers, diluents, adjuvants and / or excipients are physiologically compatible with the diagnostic composition according to the present invention.

[0272] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition (edited by Alfonso R. Gennaro; Mack Publishing Company, Easton, PA, 1990). Pharmaceutically acceptable excipients can be selected according to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense that it is harmless to its recipient.

[0273] Pharmaceutically useful excipients, carriers, adjuvants and diluents that can be used in the formulation of the diagnostic composition of the present invention can include, for example, solvents such as monohydric alcohols such as ethanol, isopropanol, and polyhydric alcohols such as diols, and edible oils such as soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, fatty acid esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickeners, stabilizers, disintegrants, glidants, lubricants, buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavoring agents, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

[0274] The administration (delivery) routes of the compounds of the present invention include, but are not limited to, one or more of the following: intravenous, gastrointestinal, intraspinal, intraperitoneal, intramuscular, oral (e.g., as tablets, capsules or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by an injectable form), intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. Preferably, the administration (delivery) route of the compounds of the present invention is parenteral.

[0275] If the compounds of the present invention (e.g., detectably labeled compounds, e.g., those having 3 H or 18 F detectably labeled) are administered parenterally, then examples of such administration routes include one or more of the following: intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous and / or using infusion techniques. For parenteral administration, the compounds are preferably used in the form of a sterile aqueous solution which may contain other excipients. If necessary, the aqueous solution should be suitably buffered (preferably to a pH of 3 - 9). Preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0276] Generally, a physician will determine the actual dose most appropriate for an individual patient. The dose of the compounds of the present invention (e.g., detectably labeled compounds, e.g., those having 3 H or 18 F detectably labeled compounds) will vary depending on the particular compound being administered, the weight of the patient, the size and type of the sample and other variables which will be apparent to a skilled physician in the art. Generally, the dose preferably ranges from 0.001 μg / kg to 10 μg / kg, more preferably 0.01 μg / kg to 1.0 μg / kg. The radioactive dose can be, for example, 100 to 600 MBq, more preferably 150 to 450 MBq.

[0277] Due to the design and binding properties of the compounds of the present invention as defined herein, they can be used for the diagnosis of diseases, disorders and abnormalities associated with TDP-43 aggregates. The compounds of the present invention are particularly suitable for positron emission tomography imaging of TDP-43 aggregates.

[0278] As disclosed herein, the compounds or diagnostic compositions or methods of the present invention are particularly suitable for the diagnosis of diseases, disorders, and abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies, such as diseases, disorders, or abnormalities selected from, but not limited to, 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, associated with chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) including frontotemporal dementia TDP-43 or frontotemporal lobar degeneration with ubiquitin-positive TDP-43 inclusions (FTLD-TDP), argyrophilic grain disease, Pick's disease, semantic variant primary progressive aphasia (svPPA), behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (e.g., nfvPPA), amyotrophic lateral sclerosis (ALS, e.g., sporadic ALS, with TARDBP mutations, with angiogenin (ANG) mutations), Alexander disease (AxD), limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease (AD, including sporadic and familial forms of AD), Down 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 myopathies (sporadic inclusion body myositis, inclusion body myopathy with valosin-containing protein (VCP) mutations; also known as Paget's bone disease and frontotemporal dementia), oculopharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathy with myotilin (MYOT) gene mutations or desmin (DES)-encoding gene mutations, traumatic brain injury (TBI), Lewy body dementia (DLB), and Parkinson's disease (PD). Preferably, the diseases, disorders, or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies are selected from frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and limbic-predominant age-related TDP-43 encephalopathy (LATE).

[0279] In one embodiment, the disease, disorder, or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

[0280] In one embodiment, the diagnosis of the disease, disorder, or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy is Alzheimer's disease (AD).

[0281] In one embodiment, the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy is frontotemporal dementia (FTD), including frontotemporal dementia with TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).

[0282] In one embodiment, the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy is limbic-predominant age-related TDP-43 encephalopathy (LATE).

[0283] Methods and Uses

[0284] In a third aspect, the present invention relates to the methods and uses listed below

[0285] · A method for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, or a predisposition thereto, in an individual;

[0286] · A method for performing positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of an individual;

[0287] · A method for detecting and optionally quantifying TDP-43 aggregates in a tissue of an individual;

[0288] · A method for determining the amount of TDP-43 aggregates in a sample or a specific body part or body region;

[0289] · A method for collecting data for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;

[0290] · A method for collecting data for determining a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;

[0291] · A method for collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates in a patient or for monitoring the progression of a TDP-43 proteinopathy,

[0292] · A method for collecting data for predicting the response of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy to drug treatment;

[0293] · Use of a compound of the present invention as a biomarker for TDP-43 aggregates or as a biomarker for a TDP-43 proteinopathy,

[0294] · Use of a compound of the present invention as a diagnostic reagent or diagnostic tool for a TDP-43 proteinopathy,

[0295] · Use of the compounds of the present invention as in vitro analysis reference or in vitro screening tool.

[0296] Any compound of the present invention (e.g., compounds of formula (I-A) to (I-J), (I'-A) to (I'-J), (I-T) and (I-F)) can be used in the methods outlined above. Preferably, the compound is a detectably labeled compound (e.g., those having 3 H or 18 F detectable labels). Compounds of formula (II), (III), and (IV) are precursors of compounds of formula (I).

[0297] The method of the present invention may include the step of contacting a sample, a specific body part or body region suspected of containing TDP-43 aggregates with a compound of the present invention or a diagnostic composition comprising a compound according to the present invention.

[0298] The body is preferably mammalian, more preferably human, including the whole body or a partial body region / part of a patient suspected of containing TDP-43 aggregates.

[0299] The sample can be selected from tissues or body fluids suspected of containing TDP-43 aggregates, and the sample is obtained from a patient. Preferably, the tissue is selected from tissues of the central nervous system (CNS), eye tissues or brain tissues, more preferably brain tissues. Examples of body fluids include cerebrospinal fluid (CSF) or blood. The sample can be obtained from a mammalian, more preferably human. Preferably, the sample is an in vitro sample obtained from a patient.

[0300] An in vitro sample obtained from a patient or a specific body part or body region can be contacted with a compound of the present invention by direct incubation.

[0301] In an in vitro method, the compound of the present invention is contacted with a specific body part or body region by administering a therapeutically effective amount of the compound of the present invention to the patient. The effective amount of the compound of the present invention is an amount suitable for allowing the presence or absence of TDP-43 aggregates in a specific body part or body region to be determined using the selected analytical technique.

[0302] The step of allowing the compound of the present invention to bind to TDP-43 aggregates includes allowing the binding to occur for a sufficient amount of time. The amount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and can be determined by those skilled in the art through routine experimentation. In an in vitro method, the amount of time will depend on the sample or the specific body part or body region, and the range can be, for example, from about 30 minutes to about 120 minutes. In an in vivo method, the amount of time will depend on the time required for the compound of the present invention to reach the specific body part or body region suspected of containing TDP-43 aggregates. The amount of time should not be too long to avoid washout and / or metabolism of the compound of the present invention. The duration range can be, for example, from about 0 minutes to about 240 minutes (PET scan duration during initial compound characterization (NHP PET and subsequent FiH-studies)).

[0303] The method for detecting the compound of the present invention that binds to TDP-43 aggregates is not particularly limited and depends on the detectable label, sample type, specific body part or body region, and whether the method is an in vitro or in vivo method, etc. Possible detection methods include, but are not limited to, fluorescence imaging techniques 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). Fluorescence imaging techniques and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the compound of the present invention in a sample or the body. The imaging system thus provides an image of the detectable label (e.g., a radioisotope, especially a positron emitter or a γ emitter) of the binding present in the test sample, the specific body part being tested, or the body region being tested. Preferably, the compound of the present invention that binds to TDP-43 aggregates is detected by an imaging device such as a PET or SPECT scanner. The amount of the compound that binds to TDP-43 can be determined by visual or quantitative analysis, such as using PET scan images.

[0304] In one embodiment, the presence or absence of the compound of the present invention that binds to TDP-43 aggregates can be correlated with the presence or absence of TDP-43 aggregates in a sample or a specific body part or body region. The correlation can be qualitative or quantitative. In a preferred embodiment, step (d) includes:

[0305] - determining the amount of the compound of the present invention that binds to TDP-43 aggregates, for example, by measuring the radioactive signal of the compound that binds to TDP-43 aggregates;

[0306] - correlating the amount of the compound of the present invention that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or the specific body part or body region; and

[0307] - Optionally, compare the amount of the compound that binds to TDP-43 aggregates in a sample or a specific body part or body region with the normal control value in healthy control individuals.

[0308] The amount of the compound that binds to TDP-43 aggregates can be determined by any suitable method. A preferred method is positron emission tomography (PET).

[0309] In another embodiment, the presence or absence of the compound of the invention that binds to TDP-43 aggregates can be correlated with a disease, disorder or abnormality associated with TDP-43 aggregates or with a TDP-43 proteinopathy, or a predisposition thereto. The correlation can be qualitative or quantitative. In a preferred embodiment, step (d) includes:

[0310] - Determine the amount of the compound of the invention that binds to TDP-43 aggregates; for example, by measuring the radioactive signal of the compound that binds to TDP-43 aggregates;

[0311] - Correlate the amount of the compound of the invention that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in a sample or a specific body part or body region; and

[0312] - Optionally, compare the amount of the compound that binds to TDP-43 aggregates in a sample or a specific body part or body region with the normal control value in healthy control individuals.

[0313] In any of the methods disclosed herein, steps (a) to (c) and, if present, optional steps (d) and (e) can be repeated at least once. The repetition of steps is particularly useful in methods for collecting data for monitoring progress and methods for collecting data for predicting responsiveness. In these methods, it may be advantageous to monitor the patient over time and repeat the above steps after a certain period of time. The time interval before repeating the above steps can be determined by the physician according to the differences in the severity of the disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy.

[0314] In one embodiment, the invention relates to a method for detecting a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, or a predisposition thereto, in an individual, the method comprising the steps of:

[0315] (a) Administer to the individual a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein;

[0316] (b) Allow the compound to bind to TDP-43 aggregates; and

[0317] (c) Detect the compound that binds to TDP-43 aggregates.

[0318] In one embodiment, the present invention relates to a method for detecting and optionally quantifying TDP-43 aggregates in an individual's tissue (e.g., in vivo or in vitro method), the method comprising the steps of:

[0319] (a) administering to the individual a compound of the present invention as disclosed herein; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0320] (b) allowing the compound to bind to the TDP-43 aggregates; and

[0321] (c) detecting and optionally quantifying the compound bound to the TDP-43 aggregates using positron emission tomography.

[0322] In one embodiment, the present invention relates to a method for diagnosing the imaging of an individual's brain, the method comprising the steps of:

[0323] (a) administering to the individual a compound of the present invention; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0324] (b) allowing the compound to bind to the TDP-43 aggregates; and

[0325] (c) detecting the compound bound to the TDP-43 aggregates by collecting positron emission tomography (PET) images of the individual's brain.

[0326] Imaging:

[0327] The present invention relates to a method for imaging TDP-43 aggregates using a compound of the present invention. For example, any of the above methods can be used, particularly imaging by PET.

[0328] In one embodiment, 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 patient's brain, the method comprising the steps of:

[0329] (a) administering to the individual a compound of the present invention; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0330] (b) allowing the compound to bind to the TDP-43 aggregates; and

[0331] (c) detecting the compound bound to the TDP-43 aggregates.

[0332] In one embodiment, 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 an individual, the method comprising the following steps:

[0333] (a) Administering a compound of the present invention to an individual; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0334] (b) Allowing the compound to bind to TDP-43 aggregates; and

[0335] (c) Detecting the compound that binds to TDP-43 aggregates in the brain of the individual.

[0336] In one embodiment, 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 an individual, the method comprising the steps of:

[0337] (a) Administering a compound of the present invention to an individual; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0338] (b) Allowing the compound to bind to TDP-43 aggregates; and

[0339] (c) Detecting the compound that binds to TDP-43 aggregates.

[0340] In one embodiment, a method for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a predisposition thereto, the method further comprising the steps of:

[0341] (d) Generating an image representative of the location and / or amount of the compound that binds to TDP-43 aggregates,

[0342] (e) Optionally comparing the generated image with a control image of a healthy control individual, wherein an increase in the binding signal indicates that the individual is suffering from a disease, disorder or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or is at risk of developing the disease, disorder or abnormality, or TDP-43 proteinopathy.

[0343] In one embodiment, 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 an individual, the method comprising the steps of:

[0344] (a) Administering a compound of the present invention to an individual; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0345] (b) Allowing the compound to bind to TDP-43 aggregates;

[0346] (c) Detecting the compound that binds to TDP-43 aggregates; and

[0347] (d) Generate an image representative of the location and / or amount of a compound that binds to TDP-43 aggregates.

[0348] In one embodiment, the present invention relates to a method for positron emission tomography (PET) imaging of TDP-43 aggregates in the tissue of an individual, the method comprising the steps of:

[0349] (a) Administering to the individual a compound of the present invention; or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0350] (b) Allowing the compound to bind to the TDP-43 aggregates; and

[0351] (c) Detecting the compound that binds to the TDP-43 aggregates by collecting a positron emission tomography (PET) image of the tissue of the individual.

[0352] Preferably, the tissue is tissue of the central nervous system (CNS), eye tissue or brain tissue. More preferably, the tissue is brain tissue.

[0353] In one embodiment, the present invention relates to a method for imaging TDP-43 aggregates in a sample or a patient, the method comprising the steps of:

[0354] (a) Contacting a sample suspected of containing TDP-43 aggregates or a specific body part or body region with a compound of the present invention, or a diagnostic composition comprising a compound of the present invention as disclosed herein;

[0355] (b) Allowing the compound to bind to the TDP-43 aggregates; and

[0356] (c) Detecting the compound that binds to the TDP-43 aggregates by imaging the sample, specific body part or body region using an imaging system.

[0357] In one embodiment, the present invention relates to a method for imaging TDP-43 aggregates in an in vitro sample of a patient, the method comprising the steps of:

[0358] (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;

[0359] (b) Allowing the compound to bind to the TDP-43 aggregates; and

[0360] (c) Detecting the compound that binds to the TDP-43 aggregates by imaging the in vitro sample using an imaging system.

[0361] In one embodiment, the present invention relates to a method for imaging TDP-43 aggregates in a patient or a specific body part or body region of a patient, the method comprising the following steps:

[0362] (a) contacting a sample or a specific body part or body region suspected of containing TDP-43 aggregates with a compound of the present invention, preferably a compound of formula (I-T) or sub-formula (I-Ta) or (I-Tb) or formula (I-F) or sub-formula (I-Fa) or (I-Fb); or a diagnostic composition comprising a compound of the present invention, preferably a compound of formula (I-T) or formula (I-F) as disclosed herein;

[0363] (b) allowing the compound to bind to the TDP-43 aggregates; and

[0364] (c) detecting the compound bound to the TDP-43 aggregates by imaging the sample or the specific body part or body region of the patient using an imaging system.

[0365] The step of imaging the sample, patient, specific body part or body region of the patient using an imaging system comprises detecting the compound of the present invention bound to the TDP-43 aggregates using an imaging system as disclosed herein. Detecting the compound of the present invention bound to the TDP-43 aggregates, and identifying the distribution of the TDP-43 aggregates in the test sample, patient, specific body part or body region by imaging. PET imaging should be performed when the compound has penetrated the tissue and the compound has bound to the TDP-43 aggregates.

[0366] Determining the Amount of TDP-43 Aggregates:

[0367] In one embodiment, the present invention relates to a method for determining the amount of TDP-43 aggregates in a sample, specific body part or body region suspected of containing TDP-43 aggregates using a compound of the present invention.

[0368] In one embodiment, the present invention provides a method for determining the amount of TDP-43 aggregates in a sample, specific body part or body region suspected of containing TDP-43 aggregates, wherein the method comprises the following steps:

[0369] (a) contacting a sample or a specific body part or 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;

[0370] (b) allowing the compound of the present invention to bind to the TDP-43 aggregates;

[0371] (c) detecting the compound of the present invention bound to the TDP-43 aggregates;

[0372] (d) Determining the amount of the compound of the invention that binds to TDP-43 aggregates by measuring the radioactive signal of the compound; and

[0373] (e) Optionally calculating the amount of TDP-43 aggregates in a sample, a particular body part or body region.

[0374] The amount of TDP-43 aggregates can be calculated, for example, by determining Bmax (the maximum number of binding sites).

[0375] When a detectable-labeled compound of the invention comprising at least one radio-labeled atom (e.g., 3 H, 2 H or 18 F) binds to TDP-43 aggregates, a radioactive signal is observed.

[0376] Diagnosis:

[0377] In one embodiment, the 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, the method comprising the steps of:

[0378] (c) Detecting the compound of the invention that binds to TDP-43 aggregates; and

[0379] (d) Correlating the presence or absence of the compound of the invention that binds to TDP-43 aggregates with the presence or absence of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0380] Preferably, a method for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, or a predisposition thereto, comprises the steps of:

[0381] (a) Contacting a sample, a particular body part or body region suspected of containing TDP-43 aggregates with the compound of the invention, or a diagnostic composition comprising the compound of the invention as disclosed herein;

[0382] (b) Allowing the compound of the invention to bind to TDP-43 aggregates;

[0383] (c) Detecting the compound of the invention that binds to TDP-43 aggregates; and

[0384] (d) Correlating the presence or absence of the compound of the invention that binds to TDP-43 aggregates with the presence or absence of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy in the sample or the particular body part or body region.

[0385] In one embodiment, the present invention relates to a method of collecting data for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy, or a predisposition thereto, the method comprising the steps of:

[0386] (a) contacting a sample or a specific body part or 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;

[0387] (b) allowing the compound of the present invention to bind to the TDP-43 aggregates;

[0388] (c) detecting the compound of the present invention that has bound to the TDP-43 aggregates; and

[0389] (d) optionally correlating the presence or absence of the compound of the present invention that has bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the specific body part or body region.

[0390] After contacting the sample or the specific body part or body region with the compound of the present invention, the compound is allowed to bind to the TDP-43 aggregates. The amount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and can be determined by those skilled in the art through routine experimentation. Subsequently, the compound that has bound to the TDP-43 aggregates can be detected by any suitable method. The particular method selected will depend on the detectable label selected. Examples of possible methods include, but are not limited to, fluorescence imaging techniques 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). Fluorescence imaging techniques and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the compound with the detectable label in the sample or the specific body part or body region.

[0391] As described above, the step of optionally correlating the presence or absence of the compound that has bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the specific body part or body region comprises the steps of:

[0392] - determining the amount of the compound that has bound to the TDP-43 aggregates;

[0393] - correlating the amount of the compound that has bound to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or the specific body part or body region; and

[0394] - optionally comparing the amount of the compound that has bound to the TDP-43 aggregates in the sample or the specific body part or body region with a normal control value in a healthy control individual.

[0395] The amount of the compound that binds to the TDP-43 aggregates can be compared to a normal control value determined in a sample from a healthy individual or a particular body part or body region, wherein an increase in the amount of the compound that binds to the TDP-43 aggregates compared to the normal control value can indicate that the patient has, is suffering from, or is at risk of developing a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0396] If the amount of the compound that binds to the TDP-43 aggregates is higher than the normal control value, as defined herein, then it can be expected that the patient has or may have a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0397] Determining Predisposition:

[0398] Another aspect of the invention relates to a method of collecting data for determining the propensity for a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. The method comprises the steps of:

[0399] (a) contacting a sample or a particular body part or body region suspected of containing TDP-43 aggregates with a compound of the invention or a diagnostic composition comprising a compound of the invention as disclosed herein;

[0400] (b) allowing the compound of the invention to bind to the TDP-43 aggregates;

[0401] (c) detecting the compound of the invention that binds to the TDP-43 aggregates; and

[0402] (d) optionally correlating the presence or absence of the compound of the invention that binds to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the particular body part or body region.

[0403] As described above, the step of optionally correlating the presence or absence of the compound that binds to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the particular body part or body region comprises the steps of:

[0404] - determining the amount of the compound that binds to the TDP-43 aggregates;

[0405] - correlating the amount of the compound that binds to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or the particular body part or body region; and

[0406] - Optionally, compare the amount of a compound that binds to TDP-43 aggregates in a sample or a specific body part or body region with a normal control value in a healthy control individual.

[0407] If the amount of a compound that binds to TDP-43 aggregates is higher than the normal control value in a healthy / reference individual, this indicates that the patient / individual has a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy or is at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. In particular, if the amount of a compound that binds to TDP-43 aggregates is higher than the value in individuals who do not show clinical evidence of neurodegenerative disease, the patient can be considered to have a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0408] Monitoring Disease Progression:

[0409] In one embodiment, the present invention relates to a method for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-4 proteinopathy in a patient. Generally, the patient is undergoing or has undergone treatment for a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. In particular, the treatment can involve the administration of an anti-TDP-43 drug.

[0410] A method for collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy in a patient, the method comprising the steps of:

[0411] (a) contacting a sample, a specific body part or body region suspected of containing TDP-43 aggregates with a compound of the present invention;

[0412] (b) allowing the compound of the present invention to bind to the TDP-43 aggregates;

[0413] (c) detecting the compound of the present invention that binds to the TDP-43 aggregates;

[0414] (d) optionally correlating the presence or absence of the compound of the present invention that binds to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the specific body part or body region; and

[0415] (e) optionally repeating at least once: steps (a) to (c) and, if present, the optional step (d).

[0416] To monitor the progression over time of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, steps (a) to (c) and optional step (d) (if present) can be repeated one or more times. Preferably, the steps should be repeated until no further progression of the disease is observed in the patient.

[0417] As described above, the optional step of correlating the presence or absence of a compound that binds to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or a particular body part or body region includes the following steps:

[0418] - Determining the amount of a compound that binds to TDP-43 aggregates;

[0419] - Correlating the amount of a compound that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or a particular body part or body region; and

[0420] - Optionally comparing the amount of a compound that binds to TDP-43 aggregates in the sample or a particular body part or body region with a normal control value in a healthy control individual.

[0421] In the method of monitoring progression over time, the amount of the compound of the invention that binds to TDP-43 aggregates can optionally be compared at multiple time points during treatment, e.g., before and after the start of treatment and / or at multiple time points after the start of treatment. A change, particularly a decrease, in the amount of the compound of the invention that binds to TDP-43 aggregates can indicate that the disease is not progressing.

[0422] Disease Prognosis :

[0423] In one embodiment, the invention relates to a method of prognosticating a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy in a patient. Generally, the patient is undergoing or has undergone treatment for a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. In particular, the treatment can involve the administration of an anti-TDP-43 agent.

[0424] A method of collecting data for prognosticating a disease, disorder or abnormality associated with TDP-43 aggregates in a patient or prognosticating a TDP-43 proteinopathy in a patient includes the following steps:

[0425] (a) Contacting a sample, a particular body part or body region suspected of containing TDP-43 aggregates with the compound of the invention; or with a diagnostic composition according to the invention comprising a compound according to the invention;

[0426] (b) Allowing the compound of the invention to bind to TDP-43 aggregates;

[0427] (c) Detecting a compound of the present invention that binds to TDP-43 aggregates;

[0428] (d) Optionally correlating the presence or absence of a compound of the present invention that binds to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or a particular body part or body region; and

[0429] (e) Optionally repeating at least once: steps (a) to (c) and, if present, the optional step (d).

[0430] For prognosticating the progression over time of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, steps (a) to (c) and the optional step (d) (if present) may be repeated one or more times. Preferably, the steps should be repeated until no further progression of the disease is observed in the patient.

[0431] As described above, the optional step of correlating the presence or absence of a compound that binds to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or a particular body part or body region includes the following steps

[0432] - Determining the amount of the compound that binds to TDP-43 aggregates;

[0433] - Correlating the amount of the compound that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or a particular body part or body region; and

[0434] - Optionally comparing the amount of the compound that binds to TDP-43 aggregates in the sample or a particular body part or body region with a normal control value in a healthy control individual.

[0435] In a method for prognosticating progression over time, the amount of a compound of the present invention that binds to TDP-43 aggregates may optionally be compared at multiple time points during treatment, for example, before and after the start of treatment and / or at multiple time points after the start of treatment. A change, particularly a decrease, in the amount of a compound of the present invention that binds to TDP-43 aggregates may indicate that the disease is not progressing.

[0436] Predicting Responsiveness:

[0437] In one embodiment, the present invention relates to a method for predicting the responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy to treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy.

[0438] The method can be used to predict the treatment most suitable for a patient. In particular, the treatment can involve the administration of an anti-TDP-43 drug.

[0439] A method for predicting the responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy to treatment of said disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy may comprise the steps of:

[0440] (a) contacting a sample or a specific body part or body region suspected of containing TDP-43 aggregates with a compound of the invention or a diagnostic composition comprising a compound of the invention as disclosed herein;

[0441] (b) allowing the compound of the invention to bind to the TDP-43 aggregates;

[0442] (c) detecting the compound of the invention that binds to the TDP-43 aggregates;

[0443] (d) optionally correlating the presence or absence of the compound of the invention that binds to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or the specific body part or body region; and

[0444] (e) optionally repeating at least once: steps (a) to (c) and, if present, the optional step (d).

[0445] Typically, the patient is undergoing / has undergone treatment for a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. In particular, the treatment can involve the administration of a drug suitable for treating a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0446] The method can predict the responsiveness of a patient to a certain treatment. In one embodiment, for example, the responsiveness is estimated by repeating steps (a) to (c) and, if present, the optional step (d) and monitoring the amount of the compound of the invention that binds to the TDP-43 aggregates over a period of time during which 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, a skilled physician can infer whether the patient is responsive to the treatment. Typically, if the amount of the compound of the invention that binds to the TDP-43 aggregates decreases over time, the patient can be considered responsive to the treatment. Typically, if the amount of the compound that binds to the TDP-43 aggregates remains substantially constant or increases over time, the patient can be considered non-responsive to the treatment.

[0447] Alternatively, responsiveness can be estimated by determining the amount of the compound of the invention that binds to TDP-43 aggregates. The amount of the compound that binds 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 can refer to the control value of a healthy control individual. Alternatively, the control value can refer to the control value of an individual known to respond to a certain therapy, or to the control value of an individual known not to respond to a certain therapy. The result regarding responsiveness can be "responsive" to a certain therapy, "non-responsive" to a certain therapy, or "undetermined response" to a certain therapy. For different patients, the response to treatment may be different.

[0448] As described above, the step of optionally correlating the presence or absence of the compound that binds to TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or a particular body part or body region includes the following steps:

[0449] - Determining the amount of the compound that binds to TDP-43 aggregates;

[0450] - Correlating the amount of the compound that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or a particular body part or body region; and

[0451] - Optionally comparing the amount of the compound that binds to TDP-43 aggregates in the sample or a particular body part or body region with the normal control value in a healthy control individual.

[0452] The control value can be, for example, a normal control value, a preclinical control value, and / or a clinical control value. A "healthy control individual" or "healthy individual" is a person who does not exhibit clinical evidence of a neurodegenerative disease.

[0453] If, in any of the methods outlined above, the amount of the compound that binds to TDP-43 aggregates is higher than the normal control value, then it can be expected that the patient has or may have a disease, disorder, or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.

[0454] Any compound of the invention can be used in any of the methods outlined above. Preferably, the detectable labeled compounds of the invention as disclosed herein are used in the methods outlined above.

[0455] In a fourth aspect, the invention relates to the use of the compounds of the invention as diagnostic reagents or diagnostic tools for TDP-43 aggregates. In one embodiment, the invention relates to the use of the compounds of the invention as in vitro assay references or in vitro screening tools. The compounds of the invention can also be used in in vivo diagnostic methods. In this case, the compounds of the invention can be detectable labeled compounds or contain cold isotopes.

[0456] In another embodiment, the invention also relates to the use of the compounds of the invention, and more particularly, the detectable labeled compounds of the invention as defined herein as diagnostic biomarkers to enable more efficient and precise patient selection, for example, for longitudinal monitoring in clinical studies or to support the development of new therapies for treating TDP-43 proteinopathies. In another embodiment, the invention also relates to the use of the compounds of the invention, and more particularly, the detectable labeled compounds of the invention as defined herein as biomarkers of TDP-43 aggregates or biomarkers of TDP-43 proteinopathies.

[0457] In another embodiment, the compounds of the invention can be used in research applications, particularly as analytical tools or reference molecules. The compounds can be used for the detection of TDP-43 aggregates in vitro or in vivo. The compounds of the invention can be used for the staining of TDP-43 aggregates. For example, the compounds of the invention can be used for histochemical detection in autopsy tissues such as brain tissues. The compounds of the invention are preferably detectable labeled compounds and can be labeled directly or indirectly as discussed herein.

[0458] Kit

[0459] In a fifth aspect, the invention also relates to a kit for one or more methods of the invention, wherein the kit comprises a compound of the invention as described herein. The kit generally comprises a container for holding the compound of the invention and instructions for using the compound of the invention. Preferably, the kit comprises a compound of formula (I) as disclosed herein. More preferably, the compound of the invention is a detectable labeled compound (e.g., a compound of formula (I-T) or sub-formula (I-Ta) or (I-Tb), or (I-F) or sub-formula (I-Fa) or (I-Fb)).

[0460] The term "kit" generally refers to any diagnostic kit known in the art. More particularly, the latter term refers to the diagnostic kits described by Zrein et al. in Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.

[0461] The dose of the detectable labeled compound of the invention will vary depending on the particular compound administered, the patient's body weight, the size and type of the sample, and other variables that will be apparent to a skilled physician in the art. Generally, the dose is preferably in the range of 0.001 μg / kg to 10 μg / kg, more preferably 0.01 μg / kg to 1.0 μg / kg. The radioactive dose can be, for example, 100 to 600 MBq, more preferably 150 to 450 MBq.

[0462] In particular, such kits can be used to perform the methods of the present invention (which include, for example but not limited to, imaging, diagnostic, and monitoring methods), for example, for diagnosing diseases, disorders, or abnormalities associated with TDP-43 aggregates or TDP-43 proteinopathies. Such kits can contain all the necessary components for performing the methods provided herein. Typically, each component is stored separately in a single integral package. Suitable additional components included in the kit are, for example, buffers, detectable dyes, test devices, reaction vessels, instructions, etc. The instructions for use can be customized according to the specific method of using the kit.

[0463] The present invention also relates to a kit for preparing a detectable labeled compound of the present invention, in particular, wherein the detectable label is a radioisotope. Thus, the kit contains a precursor of the detectable labeled compound of formula (I) and a labeling reagent that reacts with the precursor to introduce a detectable (e.g., radioactive) label. Preferred precursors are compounds of formula (II), (III), or (IV). The labeling reagent that reacts with the precursor can be a reagent that introduces a detectable (e.g., radioactive) label such as 18 F or 3 H. The labeling reagent can be 18 an F-fluorinating agent.

[0464] The present invention also relates to a kit for preparing a radiopharmaceutical preparation, which contains a precursor of the detectable labeled compound of formula (I), wherein the precursor is a compound of formula (II), or a compound of formula (III), or a compound of formula (IV).

[0465] Methods for Preparing Compounds of the Invention

[0466] In a sixth aspect, the present invention further relates to a method for preparing a compound of formula (I).

[0467] Cold Isotope Compounds:

[0468] In one embodiment, the present invention relates to a method for preparing a compound of formula (Ia), as described above, the method comprising the steps of:

[0469] Reacting a compound of formula (II) with R 13 to provide a compound of formula (Ia)

[0470]

[0471] wherein

[0472] n, R 1 , R 2 and X, Y, and Z are as defined above;

[0473] R 13is a 5- or 6-membered carbocyclic or heterocyclic compound, which is substituted by NH2 and may optionally be further substituted by F, NH2, CN, and / or CH3, wherein the heterocycle contains one or more heteroatoms selected from N, O, and / or S.

[0474] One aspect of the present invention is a compound having the structure of formula (II) or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, or solvates, or mixtures thereof:

[0475]

[0476] wherein

[0477] n is 1 or 2;

[0478] X, Y, and Z are independently CH or N; and

[0479] R 1 is H or F.

[0480] In a preferred embodiment, R 13 is selected from the following compounds:

[0481] (i) wherein

[0482] R 3 is F, R 4 is NH2, R 7 is H, and R 8 is H (preferred embodiment); or

[0483] R 3 is NH2, R 4 is F, R 7 is H, and R 8 is H; or

[0484] R 3 is CN, R 4 is NH2, R 7 is H, and R 8 is H; or

[0485] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is CN; or

[0486] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is F;

[0487] (ii) wherein W 1 is S, and W 2 is N;

[0488] (iii) and

[0489] (iv)

[0490] (v) or

[0491] (vi) wherein "----F" indicates that "F" may be present or absent.

[0492] The method of reacting a compound having the structure of formula (II) with R 13 can be carried out by any suitable method. In one option, 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 option, the reaction can be carried out under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph)3]4 or Pd(OAc)2, and XantPhos.

[0493] In another embodiment, the present invention relates to a method for preparing a compound of formula (Ib) as described above, the method comprising the steps of:

[0494] Reacting a compound of formula (II') with R 14 to provide a compound of formula (I)

[0495]

[0496] wherein

[0497] R 14 is

[0498] and

[0499] n, R 1 , R 2 and X, Y and Z are as defined above for formula (I).

[0500] One aspect of the present invention is a compound having the structure of formula (II') or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof:

[0501]

[0502] wherein

[0503] R 2As defined above.

[0504] In a preferred embodiment, R 14 is

[0505]

[0506] A tritium ( 3 H)-detectable labeled compound

[0507] In one embodiment, the present invention provides a method for preparing a tritium ([ 3 H)-detectable labeled compound of the present invention having the structure of formula (I-T), the method comprising the step of radioactively labeling a precursor of a compound having the structure of formula (I-T) with a radioisotope, wherein at least one leaving group in the precursor of the compound having the structure of formula (I-T) is replaced by tritium ([ 3 H).

[0508] The tritium ([ 3 H)-detectable labeled compound having the structure of formula (I-T) is preferably defined as one in which at least 1 to 3 hydrogens (H) are each replaced by tritium ([ 3 H). The tritium ([ 3 H)-detectable labeled compound having the structure of formula (I-T) is more preferably defined as one in which 1 or 2 hydrogens (H) are replaced by tritium ([ 3 H).

[0509] In another embodiment, the present invention provides a compound of formula (III)

[0510]

[0511] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof,

[0512] wherein

[0513] n is 1 or 2;

[0514] R 1 is H or F;

[0515] Y 1 is selected from C-Br, C-I and C-H,

[0516] Z is selected from CH or N,

[0517] R A is H or F,

[0518] R 11is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted with Br, I, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S;

[0519] and Y 1 and / or R 11 at least one of which contains Br or I.

[0520] In one embodiment, the present invention provides a compound of formula (III) having the sub-formula (IIIa):

[0521]

[0522] or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof,

[0523] wherein

[0524] n is 1 or 2;

[0525] R 1 is H or F;

[0526] Y 1 is selected from C-Br, C-I and C-H,

[0527] Z is selected from CH or N,

[0528] R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted with Br, I, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S;

[0529] and Y 1 and / or R 11 at least one of which contains Br or I.

[0530] In another embodiment, the present invention provides a compound of formula (III) having the sub-formula (IIIb):

[0531]

[0532] or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof,

[0533] wherein

[0534] n is 1 or 2;

[0535] R 1 is H or F;

[0536] Y1 Selected from C-Br, C-I, and C-H,

[0537] Z is selected from CH or N.

[0538] R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted with Br, I, F, NH2, CN, and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O, and S;

[0539] and Y 1 and / or R 11 at least one of which contains Br or I.

[0540] In a preferred embodiment, Y 1 is C-Br or C-I, and Br or I is replaced by T.

[0541] In another preferred embodiment, R 11 contains Br or I, and Br or I is replaced by T.

[0542] In a preferred embodiment, Y 1 is C-Br or C-I, and Br or I is replaced by T; and R 11 contains Br or I, and Br or I is replaced by T.

[0543] Preferably, the tritium ( 3 H)-detectable labeled compounds having the structure of formula (I-T) according to the present invention include (wherein T means 3 H)

[0544]

[0545] In another embodiment, the present invention provides a method for preparing a compound of formula (I-T), the method comprising the steps of:

[0546] Radioactively labeling a precursor compound having formula (III) with T (i.e., 3 H) by using T2 (preferably using a catalyst, such as Pd / C catalyst) to exchange Br or I with T or by introducing a CT3-group,

[0547]

[0548] or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof,

[0549] wherein

[0550] n is 1 or 2;

[0551] R1 is H or F;

[0552] R A is H or F;

[0553] Y 1 is selected from C-Br, C-I and C-H,

[0554] Z is selected from CH or N,

[0555] R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted with Br, I, F, NH2, CN and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and S;

[0556] and Y 1 and / or R 11 at least one of which contains Br or I,

[0557] wherein said at least one Br or I is replaced by T; Or

[0558] R 11 contains a 5- or 6-membered carbocyclic or heterocyclic ring containing an NH structure;

[0559] wherein said NH-structure is replaced by N-CT3,

[0560] and wherein T is 3 H.

[0561] Preferably, the precursor having the structure of formula (III) according to the present invention may be selected from

[0562]

[0563]

[0564] Methods for introducing radioisotopes such as 3 H are well known in the art and include the methods described below.

[0565]

[0566] In this process, the substituents Br, NH2, F and CN are shown only as examples. The definition of formula (I-T) applies to this aspect. Further examples are shown in the following process:

[0567]

[0568] For the introduction of T, 3The H radioactive labeling reagent 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 catalyst, a solvent such as N,N-dimethylformamide (DMF), and a base such as N,N-diisopropylethylamine (DIPEA).

[0569] In one embodiment, the present invention relates to a method for preparing a precursor compound of formula (III) as described above, the method comprising the steps of:

[0570] Reacting a compound of formula (II) as defined above with R 13 to provide a compound of formula (Ia), and then subjecting the trimethylsilylethoxymethyl (SEM) protecting group to NBS bromination or acid cleavage. The following examples are given by way of illustration:

[0571]

[0572] wherein

[0573] n, R 1 and R 13 are as defined above.

[0574] Compounds having different ring structures with R 13 can be prepared in a similar manner.

[0575] In a preferred embodiment, R 13 is selected from the following compounds:

[0576] (i) wherein Hal is Br or I; and

[0577] R 3 is F, R 4 is NH2, R 7 is H, and R 8 is H (preferred embodiment); or

[0578] R 3 is NH2, R 4 is F, R 7 is H, and R 8 is H; or

[0579] R 3 is CN, R 4 is NH2, R 7 is H, and R 8 is H; or

[0580] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is CN; or

[0581] R 3 is H, R 4 is NH2, R 7 is H, and R 8 is F;

[0582] (ii) wherein W 1 is S, and W 2 is N; and wherein Hal is Br or I;

[0583] (iii) wherein Hal is Br or I; and

[0584] (iv) wherein Hal is Br;

[0585] (v) wherein Hal is Br; or

[0586] (vi) wherein Hal is Br.

[0587] In all of the above, "----Hal" indicates that "Hal" may be present or absent.

[0588] The method of reacting the compound of formula (II) with R 13 can be carried out by any suitable method. In one option, 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 option, the reaction can be carried out under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph)3]4 or Pd(OAc)2, and XantPhos.

[0589] Compound labeled with fluorine ( 18 F) that is detectable:

[0590] In one embodiment, the present invention provides a method for preparing a fluorine ( 18 F)-detectable labeled compound of the present invention, the method comprising radioactively labeling a precursor having formula (IV) with a radioisotope 18 F]:

[0591]

[0592] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof,

[0593] wherein

[0594] n, R A 、R 2X, Y, and Z are as defined above for formula (I);

[0595] R 12 is a leaving group (LG), preferably a mesylate group, which is suitable for being 18 replaced by

[0596] In one embodiment, the present invention provides a method for preparing a fluorine-( 18 F) detectable labeled compound of the present invention, the method comprising radioactively labeling a precursor of formula (IV) having the structure of formula (IVa) with a radioisotope 18

[0597]

[0598] or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof,

[0599] wherein

[0600] n is 1 or 2;

[0601] R 2 is

[0602] R 12 is a leaving group (LG), preferably a mesylate group, which is suitable for being 18 replaced by

[0603] Compounds having different ring structures with R 2 can be prepared in a similar manner.

[0604] Fluorination can be carried out in the presence of a 18 F-fluorinating agent, 18 The F-fluorinating agent can be selected from K 18 F], Cs 18 F, Na 18 F, Rb 18 F, Kryptofix

[222] K 18 F, 18 tetra(C 1-6 alkyl)ammonium salts of 18 F and tetrabutyl

[0605] Preferably, the leaving group (LG) is a C 1-4 alkylsulfonate group or a C 6-10 ​an arylsulfonate group or a nitro group. More preferably, the leaving group (LG) is a mesylate group, a benzenesulfonate group, a m-nitrobenzenesulfonate group or a nitro group. Even more preferably, the leaving group (LG) is a mesylate group or a nitro group.

[0606] Suitable solvents known to those skilled in the art for 18 the F-fluorination step. The solvent can be, for example, selected from DMF, DMSO, acetonitrile, DMA or mixtures thereof. Preferably, the solvent is acetonitrile or DMSO.

[0607] Preferably, the method for preparing the fluorine( 18 F)-detectable labeled compound 1 includes a radiolabeling step, in which the leaving group (LG) of the precursor L1 (in this case, a mesylate group) is 18 substituted by fluorine( 18 F]) in the presence of an F-fluorination reagent such as K 18 F] or 18 F]TBAF, as shown below:

[0608]

[0609] The compounds of the present invention can be prepared by one of the general methods shown in the following schemes. These methods are given for illustrative purposes only and should not be construed as limiting.

[0610] Precursor compounds having formula (II), (III) or (IV) as defined above, or their stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates are part of the present invention.

[0611] Abbreviations

[0612]

[0613]

[0614] General Synthetic Procedures:

[0615] For the Preparation of (R)-N-(6-Fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5- Synthetic Procedure for Formamide (Compound 1)

[0616]

[0617] For the Preparation of (R)-4-Fluoro-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)Thi Synthetic Procedure for Azole-5-Carboxamide (Compound 13)

[0618]

[0619] For the Preparation of (R)-4-Fluoro-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)Thi Synthetic Procedure for Azole-5-Carboxamide (Compound 12)

[0620]

[0621] Synthesis process for preparing 3 precursor compounds of H

[0622] For the Preparation of (R)-2-(5-Bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-N-(5-bromo-6-fluoropyridin-3- Base) thiazole-5-carboxamide( 3 Synthetic route of the precursor of Compound 1 (Compound 2)

[0623]

[0624] For the Preparation of (R)-N-(2,4-Dibromo-5-fluoropyridin-3-yl)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)Pyr Pyridin-3-yl)thiazole-5-carboxamide( 3 Synthesis process of precursor 2) (Compound 20) of Compound 1

[0625]

[0626] 3 The H-labeled compound can be prepared from a suitable precursor compound containing a halogen atom and tritium gas through catalytic tritium dehalogenation (M. Saljoughian Synthesis (2002), 1781 - 1801), or from a suitable precursor compound containing an NH structure and methyl iodide 3 H] through methylation (Y. Chen Chemistry 25 (2019): 3405 - 3439). Preferably, 3 The solvent used in the H-labeling is DMF or DMA, and the preferred solvent is DMF.

[0627] Preparation 3 Synthesis process of H-labeled

[0628] Tritium-Labeled 2-[2-Fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridinyl]-5-(3-pyridinyl)-6,7- Dihydrothiazolo[5,4-c]pyridin-4-one 3 Synthesis of H-Compound 1

[0629]

[0630] T means 3 H.

[0631] Preparation for 18 Synthesis process of F-labeled precursor

[0632] For the Preparation of (S)-1-(5-(5-((6-Fluoropyridin-3-yl)Carbamoyl)Thiazol-2-yl)Pyridin- 2-yl)pyrrolidin-3-yl ester( 18 Synthetic route of precursor of Compound 1 (Compound 3)

[0633]

[0634] The reaction takes place in the presence of a fluorinating reagent and a common solvent.

[0635] 18 The F-labeled compound can be prepared by reacting a precursor compound containing LG with 18 an F-fluorinating reagent, so that LG is 18 replaced by F. 18 The F-fluorinating reagent can be 18Tetraalkylammonium salts of F (e.g., 18 tetra(C 1-6 alkyl)ammonium salts of F, e.g., tetrabutyl 18 F]ammonium fluoride), 18 tetraalkylphosphonium salts of F (e.g., 18 tetra(C 1-6 alkyl)phosphonium salts of F), K 18 F, Cs 18 F, Na 18 F, Rb 18 F, or Kryptofix

[222] K 18 F. Preferably, 18 the F-fluorinating agent is Cs 18 F, K 18 F or tetrabutyl 18 F]ammonium fluoride. Reagents, solvents and conditions that can be used for 18 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), Schubiger P.A., Friebe M., Lehmann L., (eds.), PET-Chemistry-The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15 - 50). Preferably, the solvent used for 18 F-fluorination is DMF, DMSO, acetonitrile, DMA or a mixture thereof, and the preferred solvent is acetonitrile or DMSO.

[0636] Although the reactions shown above are carried out with 18 F as the radioisotope label, other radioisotope labels can be introduced by following a similar method.

[0637] The following examples illustrate the invention, however, they should not be construed as limiting. Examples

[0638] All reagents and solvents were obtained from commercial sources and used without further purification. Proton ([[]] 1H) NMR spectrum. The mass spectrum (MS) was recorded using an Advion CMS mass spectrometer. Chromatography was performed using silica gel (Fluka: silica gel 60, 0.063 - 0.2 mm) and suitable solvents as shown in the specific examples. Flash purification was carried out using a Biotage Isolera One flash purification system, using HP - SIL or KP - NH SNAP columns (Biotage) and the solvent gradient shown in the specific examples. Thin - layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0639] Although some embodiments do not indicate that the compounds are detectably labeled, it should be understood that the corresponding detectably labeled compounds are expected and can be readily prepared, for example, by using detectably labeled starting materials, such as starting materials containing C( 3 H)3, ( 11 C)H3 or 18 F.

[0640] Example 1 (R)-N-(6 - fluoropyridin - 3 - yl)-2-(6-(3 - fluoropyrrolidin - 1 - yl)pyridin - 3 - yl)thiazole - 5 - carboxamide Compound 1 Synthesis

[0641]

[0642] Step - 1: Methyl 2-(6 - fluoropyridin - 3 - yl)thiazole - 5 - carboxylate (B)

[0643] Under an argon atmosphere, methyl 2 - bromothiazole - 5 - carboxylate (3.0 g, 13 mmol), boric acid (2.8 g, 20 mmol), NaHCO3 (5.6 g, 65 mmol) and (THF:H2O) (1:1, 45 mL, 15 vol) were added to a dried round - bottom flask. The reaction mixture was degassed with argon for 15 minutes. Then Pd(PPh3)4 (1.5 g, 0.13 mmol) was added, and the mixture was heated to 90 °C for 12 hours. The consumption of the reactants was monitored by TCL. The reaction mixture was quenched with ice - water (20 mL) and extracted with EtOAc (70 mL x 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 slightly brownish 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).

[0644] Step - 2: Methyl (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate (C)

[0645] Under an argon atmosphere, 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 vol) were added to a dried microwave vial. The reaction mixture was irradiated at 120 °C for 2 hours. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with cold brine solution (20 mL x 2), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (100 - 200 mesh) 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).

[0646] Step - 3: (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (D)

[0647] 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 hours. The mixture was then treated with 2M HCl (aqueous) solution until the pH reached 2 - 3. The biphasic mixture was filtered through a Büchner funnel. The resulting material 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).

[0648] Step - 4: (R)-N-(6-Fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (1).

[0649] At 0 °C, HATU (380 mg, 1.0 mmol) was added to a solution of (D) (150 mg, 0.5 mmol) in DMF (3.0 mL, 20 vol), followed by the addition of DIPEA (0.26 mL, 1.5 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled again to 0 °C, and 6-fluoropyridin-3-amine (68 mg, 0.6 mmol) was added thereto. 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 material was filtered through a Büchner funnel. The resulting material was washed with hexane (3 mL x 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).

[0650] Example 2 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 Synthesis

[0651]

[0652] Step - 1: Methyl 2-(5-bromo-6-fluoropyridin-3-yl)thiazole-5-carboxylate (E):

[0653] In an argon atmosphere, (A) (0.6 g, 2.7 mmol), borate ester (0.9 g, 2.9 mmol), Cs2CO3 (1.75 g, 5.4 mmol) and (1,4-dioxane: H2O) (4:1, 30 mL, 50 vol) were added to a dried round-bottom flask. The reaction mixture was degassed with argon for 15 minutes. Then Pd(dppf)Cl2.DCM (0.22 g, 0.27 mmol) was added, and the mixture was heated to 90 °C for 3 hours. The consumption of the reactants was monitored by TCL. The reaction mixture was then quenched with ice water (10 mL) and extracted in DCM (50 mL x 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 slightly brownish 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).

[0654] Step - 2: Methyl (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate (F)

[0655] Under an argon atmosphere, 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 vol) were added to a dried microwave vial. The reaction mixture was irradiated at 120 °C for 2 hours. After completion, the reaction mixture was quenched with ice-cold water (4 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with a cold brine solution (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (100 - 200 mesh) 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).

[0656] Step - 3: (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (G)

[0657] Lithium hydroxide monohydrate (15 mg, 0.6 mmol) was added to a solution of (F) (120 mg, 0.3 mmol) in (THF:MeOH:water) (2:2:1, 6.0 mL, 50 vol), 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 extracted again with 10% MeOH in DCM (2 x 20 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give (G) as a pale yellow 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).

[0658] 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)

[0659] HATU (67 mg, 0.17 mmol) was added to a solution of (G) (50 mg, 0.13 mmol) in DCM (2.5 mL, 50 vol) at 0 °C, followed by DIPEA (0.07 mL, 0.4 mmol). The resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled again to 0 °C, and 5-bromo-6-fluoropyridin-3-amine (33 mg, 0.17 mmol) was added thereto. The resulting mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with ice-cold water and the product was extracted with 10% MeOH in DCM (20 mL x 3). The extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (230 - 400 mesh) eluting with 3% MeOH in DCM to give the title product (2) as a pale yellow solid (35 mg, 47%).

[0660] Example 3 (S)-1-(5-(5-((6-Fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate Compound 3 Synthesis

[0661]

[0662] Step - 1: Methyl 2-(6-fluoropyridin-3-yl)thiazole-5-carboxylate (B)

[0663] In a dried round-bottom flask under an argon atmosphere, (A) (3.0 g, 13 mmol), boric acid (2.8 g, 20 mmol), NaHCO3 (5.6 g, 65 mmol) and (THF:H2O) (1:1, 45 mL, 15 vol) were added. The reaction mixture was degassed with argon for 15 minutes. Then Pd(dppf)Cl2.DCM (1.1 g, 13 mmol) was added, and the mixture was heated to 90 °C for 16 hours. The consumption of the reactants was monitored by TCL. The reaction mixture was then quenched with ice water (30 mL) and extracted in DCM (60 mL x 3). The organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography (230 - 400 mesh) eluting in 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).

[0664] Step - 2: Methyl (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylate (I)

[0665] Under an argon atmosphere, 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 added to a dried microwave vial. The reaction mixture was irradiated at 120 °C for 2 hours. After completion, the solvent was removed under high vacuum. The resulting crude material was purified by silica gel column chromatography (230 - 400 mesh) eluting in 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).

[0666] Step - 3: (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (J)

[0667] To a solution of (I) (1.3 g, 4.2 mmol) in (THF:MeOH:water) (2:2:1, 45 mL, 35 volumes) was added lithium hydroxide (2.4 mg, 8.5 mmol), and the mixture was kept at room temperature for 6 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 extracted again with 10% MeOH in DCM (3 x 50 mL), and the combined organic layers were dried over Na2SO4 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).

[0668] Step - 4: (S)-N-(6-Fluoropyridin-3-yl)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide (K)

[0669] To a solution of (J) (80 mg, 0.27 mmol) in DMF (1.6 mL, 20 volumes) at 0 °C was added HATU (208 mg, 0.54 mmol), followed by DIPEA (0.14 mL, 0.82 mmol). The resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled again to 0 °C, and 6-fluoropyridin-3-amine (36 mg, 0.33 mmol) was added thereto. The resulting mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was quenched with ice-cold water, and the product was extracted with 10% MeOH in DCM (20 mL x 3). The extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (230 - 400 mesh) eluting with 5% MeOH in DCM to give the product (K), as a pale yellow 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)

[0670] Step 5: (S)-1-(5-(5-((6-Fluoropyridin-3-yl)carbamoyl)thiazol-2-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate (3):

[0671] To a cold solution of (K) (65 mg, 0.16 mmol) in pyridine (2.0 mL, 33 volumes) at 0 °C under N2 atmosphere was added methanesulfonyl chloride (0.3 mL, 4.5 mmol) portionwise, 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 x 3). The combined organic layers were washed with cold brine solution (7 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (230 - 400 mesh) 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),

[0672] Example 4 Tritium-labeled 2-[2-Fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridinyl]-5-(3-pyridinyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4-one 3 H-compound 1 Synthesis

[0673] T means 3 H.

[0674] Suspend 2.88 mg of the dibromo precursor (2), 2.97 mg of Pd / C (10% metal), and 50 μl of DIPEA in 0.3 ml of DMF. Degas the suspension three times in a high-vacuum apparatus and stir it for 2.5 hours at room temperature under a deuterium atmosphere (5.3 Ci). Remove the solvent under vacuum and exchange the labile deuterium by adding 0.3 ml of methanol. Stir the solution and remove the solvent again under vacuum. Repeat this process twice. Extract the dried solid with 10 ml of methanol / DCM (1:1) and filter the suspension through a 0.2-μm nylon membrane to obtain a clear solution. For the purification of the compound, use the following HPLC conditions: Waters Sunfire C18, 10 x 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); B: acetonitrile + 0.1% TFA. Obtain the purified product 3 H-Compound 1 (SA 49.1 Ci / mmol, 99% purity).

[0675] Example 5 Fluorinated 2-[2-fluoro-6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridinyl]-5-(3-pyridinyl)-6,7-dihydrothiazolo[5,4-c]pyridin-4-one 18 F-compound 1 Synthesis

[0676]

[0677] Add a 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) to a microwave vial containing dry 18 F]fluoride and heat the container at 110 °C for 20 minutes. Cool the reaction vessel to 40 °C and dilute the mixture with HPLC buffer (4 mL). Pass the resulting mixture through Alumina-N Light Cartridge. Purify the crude material by semi-preparative HPLC and pass the collected purified fractions through C18-E column. Filter the final product 18 F-Compound 1 through a sterile filter onto the final product vial inside the dispensing hot cell. Analyze the final product vial and take samples for QC testing. Determine the identity of the product by co-injecting samples with 19 F-reference compound

[0678] Example Compounds 4 to 11

[0679] Prepare the following compounds according to the coupling method reported in Preparation Example 1 and using the structural units and halogen derivatives shown in Table 1.

[0680] Table 1

[0681]

[0682]

[0683]

[0684] Synthesis of Example Compounds 16 to 18 ( 3 Precursors corresponding to Compounds 4, 8, and 11 of H)

[0685] Prepare the following compounds according to the coupling method reported in the preparation of Example 2 and using the structural units and halogen derivatives shown in Table 2.

[0686] Table 2

[0687]

[0688]

[0689] Example 6 Synthesis of (R)-4-Fluoro-N-(5-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)Thi Azole-5-Carboxamide Compound 12

[0690]

[0691] Step - 1: Synthesis of 2 - bromo - 4 - fluorothiazole - 5 - carbonyl chloride (R)

[0692] To a solution of 2 - bromo - 4 - fluorothiazole - 5 - carboxylic acid Q (0.3 g, 1.33 mmol) in THF (6 mL) was added (COCl)2 (0.34 g, 2.65 mmol) and DMF (102.12 uL, 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.

[0693] Step - 2: Synthesis of 2 - bromo - 4 - fluoro - N - (5 - fluoropyridin - 3 - yl)thiazole - 5 - carboxamide (T)

[0694] 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 h. The residue was poured into ice water (100 mL), and the aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (PE:EA = 1:1, Rf = 0.5) to afford Compound T (300 mg, 69% yield) as a white solid.

[0695] 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)

[0696] 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)

[0697] 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), and K3PO4 (397.86 mg, 1.87 mmol) in H2O (0.2 mL) and Tol. (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C under a N2 atmosphere 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 phases were washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative-HPLC column: Phenomenex C18 75 * 30 mm * 3 μm; mobile phase: [water (HCl)-ACN]; B%: 15% - 55%, 8 min) to give Compound 12 (50 mg, 19% yield) as a yellow solid.

[0698] 1H NMR (400 MHz, DMSO-d6) δ = 10.65 (s, 1H), 8.77 (s, 1H), 8.68 - 8.61 (m, 1H), 8.44 - 8.37 (m, 1H), 8.23 - 8.10 (m, 2H), 6.86 (d, J = 9.2 Hz, 1H), 5.63 - 5.41 (m, 1H), 4.11 - 3.68 (m, 3H), 3.65 - 3.52 (m, 1H), 2.43 - 2.12 (m, 2H)

[0699] LCMS: 406.1 [M+H] +

[0700] Example 7 Synthesis of (R)-4-Fluoro-N-(6-fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)Thi Azole-5-Carboxamide Compound 13

[0701]

[0702] Step - 1: Synthesis of tert - butyl (4 - chloro - 5 - formylthiazol - 2 - yl)carbamate (M)

[0703] To a solution of 2 - amino - 4 - chlorothiazole - 5 - carbaldehyde L (10 g, 61.50 mmol) in dioxane (100 mL) was 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 phases were washed with brine (50 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the title compound M (12 g, 74% yield) as a yellow solid.

[0704] 1 1H NMR (400 MHz, DMSO-d6) δ = 9.85 (s, 1H), 1.50 (s, 9H)

[0705] LCMS: 263.0 [M+H] +

[0706] Step - 2: Synthesis of tert - butyl N-(4 - fluoro - 5 - formylthiazol - 2 - yl)carbamate (N)

[0707] 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 phases were washed with brine (300 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative-HPLC (column: Phenomenex C18 75 * 30 mm * 3 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give the title compound N (2.5 g, 27% yield) as a yellow solid.

[0708] 1 1H NMR (400 MHz, CDCl3) δ = 9.96 (s, 1H), 9.23 - 9.17 (m, 1H), 1.60 (s, 9H)

[0709] LCMS: 247.2 [M+H] +

[0710] Step - 3: Synthesis of 2-amino-4-fluorothiazole-5-carbaldehyde (O)

[0711] To a solution of compound N (2.5 g, 10.15 mmol) in DCM (50 mL) was added ZnBr2 (6.86 g, 30.46 mmol). The mixture was heated to 40 °C and stirred for 16 h. The mixture was cooled to 25 °C and the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 10:1 / 1:1) to give the title compound O (1.1 g, 74% yield) as a yellow solid.

[0712] 1H NMR (400 MHz, DMSO-d6) δ = 9.59 (s, 1H), 8.95 (s, 2H)

[0713] LCMS: 147.2 [M+H] +

[0714] Step - 4: Synthesis of 2-bromo-4-fluorothiazole-5-carbaldehyde (P)

[0715] To a solution of compound O (1 g, 6.84 mmol) in ACN (40 mL) was added a solution of CuBr2 (1.53 g, 6.84 mmol) and isoamyl 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 adding 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 to 1 / 1) to give the title compound P (540 mg, 38% yield) as a white solid.

[0716] 1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H)

[0717] Step - 5: Synthesis of 2-bromo-4-fluorothiazole-5-carboxylic acid (Q)

[0718] To a solution of compound P (500 mg, 2.38 mmol) in t-BuOH (4.2 mL) and H2O (2.4 mL) was added 2-methylbut-2-ene (659.50 mg, 9.40 mmol), NaH2PO4 (791.19 mg, 6.59 mmol), and NaClO2 (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). Then the aqueous phase was neutralized to pH = 5 - 6 with citric acid (saturated) and extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine (100 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound Q (400 mg, 74% yield) as a white solid.

[0719] 1H NMR (400 MHz, DMSO-d6) δ = 14.05 (brs, 1H)

[0720] Step - 6: Synthesis of 2-bromo-4-fluorothiazole-5-carbonyl chloride (R)

[0721] To a solution of compound Q (0.3 g, 1.33 mmol) in THF (6 mL) was added (COCl)2 (0.34 g, 2.65 mmol) and DMF (102.12 uL, 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.

[0722] Step - 7: Synthesis of 2 - bromo - 4 - fluoro - N-(6 - fluoropyridin - 3 - yl)thiazole - 5 - carboxamide (S)

[0723] 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 h. The residue was poured into ice - water (100 mL), and the aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo 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.

[0724] 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)

[0725] 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)

[0726] 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)Cl2 (18.29 mg, 24.99 μmol), and K3PO4 (318.29 mg, 1.50 mmol) in H2O (1 mL) and Tol. (5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C under N2 atmosphere 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 phases were washed with brine (30 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative - HPLC (column: Phenomenex luna C18 250 * 50 mm * 10 μm; mobile phase: [water (HCl)-ACN]; B%: 20% - 50%, 10 min) to give Compound 13 (50 mg, 24.31% yield) as a yellow solid.

[0727] 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.27 - 8.19 (m, 1H), 8.13 - 8.06 (m, 1H), 7.23 - 7.15 (m, 1H), 6.73 (d, J = 9.2 Hz, 1H), 5.60 - 5.40 (m, 1H), 3.92 - 3.61 (m, 3H), 3.60 - 3.48 (m, 1H), 2.39 - 2.10 (m, 2H)

[0728] LCMS: 406.1 [M+H] +

[0729] Example Compounds 14 to 15

[0730] According to the coupling method reported in Preparation Example 13 and using the structural units and halogen derivatives shown in Table 3, the following compounds were prepared.

[0731] Table 3

[0732]

[0733]

[0734] 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 precursor of H-compound 12) Synthesis

[0735]

[0736] Step - 1: Synthesis of (R)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxylic acid (V)

[0737] At 25 °C, Pd(dppf)Cl2 (161.86 mg, 221.22 μmol) and Cs2CO3 (1.44 g, 4.42 mmol) were added 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 H2O (1 mL). The reaction mixture was stirred at 110 °C under N2 for 2 h. LCMS showed that 41% of the desired product was detected. The reaction mixture was stirred with a palladium scavenger (100 mg), filtered, and concentrated in vacuo. 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%-45% B over 7 min), and then lyophilized to give the title compound V (200 mg, 29% yield) as a yellow solid.

[0738] 1 H 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)

[0739] LCMS: 312.1 [M+H] +

[0740] Step - 2: Synthesis of (R)-4-fluoro-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carbonyl chloride (W)

[0741] SOCl2 (2 mL) was added to a mixture of compound V (200 mg, 642.46 μmol) in DCM. The mixture was stirred at 70 °C for 1 h. LCMS showed that the reaction was 89% of the desired MS (quenched with MeOH). The reaction mixture was concentrated in vacuo to give compound W (200 mg, crude) as a yellow solid.

[0742] LCMS: 326.2 (quenched with MeOH)

[0743] 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)

[0744] At 0 °C, NaH (72.77 mg, 1.82 mmol, 60% purity) was added to a mixture of 2,4-dibromo-5-fluoropyridin-3-amine (163.70 mg, 606.52 μmol) in THF (2 mL). The mixture was stirred at 0 °C for 0.5 h. Then compound W (200 mg, 606.52 μmol) was added and the mixture was stirred at 25 °C for 1.5 h. LCMS showed that the reaction was 32% of the desired MS. The reaction mixture was poured into saturated aqueous NH4Cl (60 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (20 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, PE:EA = 2:1). Compound 20 (30.12 mg, 8.55% yield) was obtained as a yellow solid.

[0745] 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)

[0746] LCMS: 563.9 [M+H] +

[0747] Example 9 Synthesis of tritium-labeled (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-N-(isothiazol-4-yl)thiazole-5-carboxamide 3 H-compound 4 of

[0748]

[0749] T means 3 H.

[0750] Suspend 3.54 mg of dibromo precursor (16), 9.9 mg of Pd / C (10% metal) and 50 μl of DIPEA in 0.3 ml of DMF. Degas the suspension three times in a high-vacuum apparatus and stir it at room temperature for 16 h under a deuterium atmosphere (5.1 Ci). Remove the solvent under vacuum and exchange the labile deuterium by adding 0.3 ml of methanol. Stir the solution and remove the solvent again under vacuum. Repeat this process twice. Extract the dried solid with 10 ml of methanol / DCM (1:1) and filter the suspension through a 0.2-μm nylon membrane to obtain a clear solution. For the purification of the compound, use the following HPLC conditions: Waters Sunfire C18, 10 x 250 mm; solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); B: acetonitrile + 0.1% TFA. Obtain the purified product 3 H-Compound 4 (SA 43.5 Ci / mmol, 99% purity).

[0751] Example 10 Tritium-labeled (S)-2-(2-(3-fluoropyrrolidin-1-yl)pyrimidin-5-yl)-N-(pyridin-4-yl)thiazole-5-carboxamide 3 H-compound 8 Synthesis

[0752]

[0753] T means 3 H.

[0754] Suspend 2.56 mg of dibromo precursor (17), 11.2 mg of Pd / C (10% metal) and 20 μl of DIPEA in 0.3 ml of DMF. Degas the suspension three times in a high-vacuum apparatus and stir it at room temperature for 50 min under a deuterium atmosphere (5.7 Ci). Remove the solvent under vacuum and exchange the labile deuterium by adding 0.3 ml of methanol. Stir the solution and remove the solvent again under vacuum. Repeat this process twice. Extract the dried solid with 10 ml of methanol / DCM (1:1) and filter the suspension through a 0.2-μm nylon membrane to obtain a clear solution. For the purification of the compound, use the following HPLC conditions: Waters Sunfire C18, 10 x 250 mm; solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); B: acetonitrile + 0.1% TFA. Obtain the purified product 3 H-Compound 8 (SA 42.5 Ci / mmol, 99% purity).

[0755] Example 11(R)-N-(5-Fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide labeled with tritium 3 H-compound 11 Synthesis

[0756]

[0757] T means 3 H.

[0758] Suspend 2.95 mg of the dibromo precursor (18), 17 mg of Pd / C (10% metal), and 20 μl of DIPEA in 0.3 ml of DMF. Degas the suspension three times in a high-vacuum apparatus and at room temperature. Stir for 15 minutes under a deuterium gas atmosphere (9.1 Ci). Remove the solvent under vacuum and exchange the labile deuterium by adding 0.3 ml of methanol. Stir the solution and remove the solvent again under vacuum. Repeat this process twice. Extract the dry solid with 10 ml of methanol / DCM (1:1) and filter the suspension through a 0.2-μm nylon membrane to obtain a clear solution. For the purification of the compound, use the following HPLC conditions: Waters Sunfire C18, 10 x 250 mm; Solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); B: acetonitrile + 0.1% TFA. The purified product is obtained 3 H-Compound 11 (SA 44.3 Ci / mmol, 99% purity).

[0759] Example 12 (R)-N-(5-Fluoropyridin-3-yl)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)thiazole-5-carboxamide labeled with tritium 3 H-Compound 12 Synthesis

[0760]

[0761] T means 3 H.

[0762] Suspend 2.48 mg of dibromo precursor (19), 34 mg of Lindlar catalyst and 50 μl of DIPEA in 0.3 ml of DMF. Degas the suspension three times in a high-vacuum apparatus and stir it for 12 h at room temperature under a deuterium atmosphere (5.7 Ci). Remove the solvent under vacuum and exchange the labile deuterium by adding 0.3 ml of methanol. Stir the solution and remove the solvent again under vacuum. Repeat this process twice. Extract the dry solid with 10 ml of methanol / DCM (1:1) and filter the suspension through a 0.2-μm nylon membrane to obtain a clear solution. For the purification of the compound, use the following HPLC conditions: Waters Sunfire C18, 10 x 250 mm; solvent A: water (+0.1% TFA (Sigma-Aldrich T6508)); B: acetonitrile + 0.1% TFA. Obtain the purified product 3 H-compound 12 (SA 49.23 Ci / mmol, 99% purity).

[0763] Biological assay description

[0764] 1. General method

[0765] Human brain materials used in these studies were obtained from Professor William Seeley of the Neurodegenerative Disease Brain Bank at UCSF (funded by NIH grants P01AG019724 and P50AG023501, the Frontotemporal Dementia Research Consortium and the Tau Consortium), and Professor Tammaryn Lashley of the Queen Square Brain Bank for Neurological Disorders at UCL. All materials were collected from donors, and the brain banks had obtained written informed consent from the donors for brain autopsy and the use of the materials and clinical information for research purposes.

[0766] 1.1 Radioligand

[0767] Use the above 3 H]-compound 1 with a specific activity of 49.1 Ci / mmol (1.0 mCi / mL) in all competitive assays described below, except when using the 3 H]-reference ligand (specific activity 80 Ci / mmol, 1.0 mCi / ml) against TDP-43 aggregates from the brains of FTD patients. 3 The specific activity of 3 H]-compound 4 is 44 Ci / mmol (1.0 mCi / mL). 3 The specific activity of 3The specific activity of [H]-Compound 12 was 29 Ci / mmol (1.0 mCi / mL).

[0768] 1.2. Preparation of Sodium Dodecyl Sarcosine (Sarkosyl)-Insoluble Brain Extracts from Human Frontotemporal Dementia (FTD)

[0769] Human brain extracts were prepared as described by Laferriere et al., 2019, Nature Neurosc. At 4 °C, brain tissue (frontal or temporal cortex) samples were homogenized in homogenization-solubilization (HS) buffer at a 1:4 (w / v) ratio using a tissue homogenizer (Precellys) with a CKmix homogenization tube. The following sequence was used for homogenization: 3 cycles of 30 seconds at 5000 rpm with a 15-second pause between each cycle. The homogenized samples were aliquoted and stored at -80 °C in 1.5 mL low-protein-binding tubes.

[0770] The brain homogenate was thawed on ice and resuspended in HS buffer to obtain a final concentration of 2% sodium dodecyl sarcosine, 1 unit / μL Benzonase, and 1 mM MgCl2. Then, the samples were incubated at 37 °C on a thermal mixer with continuous shaking at 600 rpm for 45 minutes. The supernatant was collected in a new tube (sodium dodecyl sarcosine-soluble fraction, S1). The pellet was resuspended in 1000 μL of myelin float buffer and centrifuged at 20,000 g for 60 minutes at 4 °C. The supernatant was carefully removed to remove all floating lipids. If not all lipids could be removed in a single step, this step was repeated. Subsequently, the pellet was 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 (sodium dodecyl sarcosine-insoluble fraction). Samples were analyzed by immunoblotting under denaturing conditions.

[0771] 2. Bioassay Description and Corresponding Results

[0772] 2.1 Kd Determination of Human FTD Sodium Dodecyl Sarcosine-Insoluble Brain Extracts by Micro-Radioligand Binding Assay with [H]-Compounds 1, 4, 8, 11, 12 3 Human FTD sodium dodecyl sarcosine-insoluble brain extracts were spotted onto microarray slides. The slides were incubated separately with [H]-Compound 1, [H]-Compound 4, [H]-Compound 8, [H]-Compound 11, or [H]-Compound 12 at concentrations ranging from 1.93 to 300 nM

[0773] 3 3 3 3 3 ​​​​​Incubate with [³H]-Compound 12. After incubation, wash the slides and scan them using a real-time autoradiography system (BeaQuant, ai4R). Quantify the signals by using Beamage image analysis software (AI4R). Determine the non-specific signals by using an excess of unlabeled Compound 1, 4, 8, 11, or 12 (2 μM) respectively, and calculate the specific binding by subtracting the non-specific signals from the total signals.

[0774] In GraphPad Prism 8, use the one-site specific binding model to fit the specific binding data by non-linear regression analysis to obtain the Kd (dissociation constant) and R² (a parameter quantifying the goodness of fit, ranging from 0.0 to 1.0, and the best curve fitting value obtained is 1.0).

[0775] Results:

[0776] Determine in a micro-radioligand binding assay 3 the dissociation constants (Kd) of [³H]-Compound 1, 4, 8, 11, and 12 for human FTD sodium dodecyl sarcosinate-insoluble brain extracts. 3 [³H]-Compound 1 has high specific binding, resulting in a high dynamic range, and shows a Kd value of 52 nM for human FTD sodium dodecyl sarcosinate-insoluble brain extracts ( Figure 1 ). Data from two independent experiments gave an average Kd of 53 ± 10 nM. 3 [³H]-Compound 11 shows a Kd value of 80 nM ( Figure 2 ), and 3 [³H]-Compound 12 shows a Kd value of 67 nM ( Figure 3 ). Determine the dissociation constants of Compounds 4 and 8 for different batches of FTD sodium dodecyl sarcosinate-insoluble brain extracts. 3 [³H]-Compound 4 shows a Kd value of 51 nM ( Figure 4 ). 3 [³H]-Compound 8 shows a Kd value of 75 nM ( Figure 5 ). These data indicate that the compounds of the present invention bind to TDP-43 aggregates in human FTD sodium dodecyl sarcosinate-insoluble brain extracts with very good affinities.

[0777] 2.2. Microradioligand Binding Competition Assay for Determining Binding Affinity

[0778] Spot human FTD sodium dodecyl sarcosinate-insoluble brain extracts on microarray slides. Use three batches of extracts. Depending on the batch used, incubate the slides with 25 nM of a tritium-labeled reference ligand or with 40 nM or 50 nM of tritium-labeled Compound 1 ( 3Incubate with [[H]-Compound 1). Use the exemplified compounds at 1 μM and 125 nM (or for Compound 15, 1 μM and 100 nM). In some cases, a series of different concentrations (from 0.24 nM to 2 μM) of non-radiolabeled exemplified compounds were further evaluated for determination of the inhibition constant (Ki). After incubation, the slides were washed and scanned using a real-time autoradiography system (BeaQuant, ai4R). Quantification of the signal was performed using Beamage image analysis software (AI4R). Non-specific signal was determined using an excess of non-radiolabeled reference compound (2 μM), and specific binding was calculated by subtracting the non-specific signal from the total signal. Competition 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. The Ki i value was calculated in GraphPad Prism 8 using a one-site specific binding model by applying non-linear regression curve fitting. Measurements were performed with at least two technical replicates in the dual-concentration competition experiment and with one technical replicate in the experiment including a series concentration range. For compounds tested in more than one experiment, the mean of each replicate in each independent experiment or the Ki i value was reported.

[0779] Results: Evaluate the ability of Exemplified Compounds 1 to 10 to compete with the binding phase of 3 H]-reference ligand and TDP-43 aggregates from brains of FTD patients. The results of the micro-radioligand binding competition assay of the exemplified compounds are shown in Table 2 below: % competition, 1 μM and 125 nM. The Ki i values are also shown in Table 2.

[0780] Evaluate the ability of Exemplified Compounds 11 to 15 to compete with the binding phase of 3 H]-Compound 1 to two different batches of brain extracts. The results of the micro-radioligand binding competition assay of the exemplified compounds are shown in Table 3 below: respectively, % competition, at 1 μM and 125 nM for Compounds 11 to 14 (Compound 1 at 50 nM), or % competition, at 1 μM and 100 nM for Compound 15 (Compound 1 at 40 nM). The Ki i values are also shown in Table 3.

[0781] These data indicate that the compounds of the present invention bind to TDP-43 aggregates with excellent affinity.

[0782] Table 2

[0783]

[0784]

[0785] Table 3

[0786]

[0787] * Average % competition, 100 nM.

Claims

1. A compound having the structure of formula (I) or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof; wherein 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; and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted with F, NH2, CN and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

2. The compound according to claim 1, which has the structure of formula (Ia) or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof; wherein n is 1 or 2; R 1 is H or F; X, Y and Z are independently CH or N; and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein said heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

3. The compound according to claim 1, which has the structure of formula (Ib) or a detectably labeled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof; wherein n is 1 or 2; R 1 is H or F; X, Y and Z are independently CH or N; and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and / or S.

4. The compound according to any one of claims 1 to 3, wherein n is 1, and wherein 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; Z is CH.

5. The compound according to any one of claims 1 to 4, wherein R 2 is (i) wherein R 3 is F, R 4 is -NH2, R 7 and R 8 is H; or (ii) where W 1 is N, S or O, and W 2 is N; or (iii) or (iv) or (v) or (vi) where "----F" indicates that "F" may or may not be present; or (vii) 6. The compound according to claim 1, which is selected from 。 7. The compound according to any one of claims 1 to 6, which comprises a detectably labeled moiety.

8. A compound according to claim 7, wherein the detectable label is 3 H or 18 F.

9. The compound according to claim 8, which has the structure of formula (I-T) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof; wherein n is 1 or 2; R 1 is H or F; X and Z are independently CH or N; Y is CR 6 R 6 is T or H; T is 3 H; R A is H or F; and wherein R 2 is (i') wherein R 3 is F, R 4 is -NH2, and R 7 and R 8 at least one of them is T, and, if applicable, the other is H; preferably R 7 and R 8 are T; or wherein R 2 is (ii’) where W 1 is N, S or O (preferably S); W 2 is N, and R 9 is T, or where R 2 is (iii’) where R 10 is T, and R 6 is T; or where R 2 is (iv’) wherein R 10 is T, and R 6 is T; or wherein R 2 is (v') wherein R 10 is T, and R 6 is T; or wherein R 2 is (vi’) wherein R 10 is T, and R 6 is T; or wherein R 2 is (vii’) wherein R 10 is T, and R 6 is T; or wherein R 2 is (viii‘) wherein R 10 is T, and R 6 is H; or wherein; R 2 is (ix’) wherein R 10 is T, and R 6 is H; wherein "----F" indicates that "F" may be present or absent.

10. The compound according to claim 9, wherein the compound is selected from where T is 3 H.

11. The compound according to claim 8, which has the structure of formula (I-F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or a mixture thereof; wherein R 1’ is 18 F; and n, X, Y, Z, R A and R 2 are as defined in claim 1.

12. The compound according to claim 11, which is 13. A diagnostic composition comprising a compound according to any one of claims 7 to 12 and optionally comprising 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, which is used for diagnosis.

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

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

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

18. The method according to claim 17, the method further comprising the steps of: (d) generating an image representative of the location and / or amount of the compound bound to the TDP-43 aggregates, (e) optionally comparing the generated image with a control image of a healthy control individual, wherein an increase in the binding signal indicates that the individual is suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy or is at risk of developing the disease, disorder or abnormality or TDP-43 proteinopathy.

19. A method for positron emission tomography (PET) imaging of TDP-43 aggregates in an individual's tissue, the method comprising the steps of: (a) administering to the individual a compound according to any one of claims 7 to 12; or a diagnostic composition comprising a compound according to any one of claims 7 to 12 according to claim 13; (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 a positron emission tomography (PET) image of the individual's tissue.

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

21. A method for detecting and optionally quantifying TDP-43 aggregates in an individual's tissue, the method comprising the steps of: (a) contacting a sample or a specific body part or body region suspected of containing TDP-43 aggregates with a compound according to any one of claims 7 to 12 or a diagnostic composition comprising a compound according to any one of claims 7 to 12 according to claim 13; (b) allowing the compound to bind to the TDP-43 aggregates; (c) detecting the compound bound to the TDP-43 aggregates using positron emission tomography; and (d) optionally quantifying the amount of the compound bound to the TDP-43 aggregates.

22. 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, the method comprising the steps of: (a) Contacting a sample suspected of containing TDP-43 aggregates or a specific body part or body region with 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 bind to the TDP-43 aggregates; (c) Detecting the compound bound to the TDP-43 aggregates; and (d) Optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body region.

23. A method of collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates in a patient or for monitoring the progression of a TDP-43 proteinopathy, the method comprising the steps of: (a) Contacting a sample suspected of containing TDP-43 aggregates or a specific body part or body region with 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 bind to the TDP-43 aggregates; (c) Detecting the compound bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body region; and (e) Optionally repeating at least once: steps (a) to (c) and optionally step (d) if present.

24. A method of collecting data for predicting the response of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or suffering from a TDP-43 proteinopathy to treatment with a medicament for the disease, disorder or abnormality associated with TDP-43 aggregates or for treatment with a medicament for a TDP-43 proteinopathy, the method comprising the steps of: (a) Contacting a sample suspected of containing TDP-43 aggregates or a specific body part or body region with 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 bind to the TDP-43 aggregates; (c) Detecting the compound bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body region; and (e) Optionally repeating at least once: steps (a) to (c) and optionally step (d) if present.

25. The method according to any one of claims 22 to 24, wherein the step of optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body region comprises - Determining the amount of the compound bound to the TDP-43 aggregates; - correlating the amount of the compound that binds to TDP-43 aggregates with the amount of TDP-43 aggregates in a sample or a specific body part or body region; and - optionally comparing the amount of the compound that binds to TDP-43 aggregates in the sample or the specific body part or body region with a normal control value in a healthy control individual.

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

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

28. A compound according to any one of claims 7 to 12, which is used as an in vitro analysis reference or an in vitro screening tool.

29. A compound or diagnostic composition used according to claim 16, or a 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, such as sporadic or familial, with or without motor neuron disease (MND), with progranulin (GRN) mutation, with C9orf72 mutation, with TARDBP mutation, with valosin-containing protein (VCP) mutation, associated with chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) including frontotemporal dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), argyrophilic grain disease, Pick's disease, semantic variant primary progressive aphasia (svPPA), behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (e.g., nfvPPA), amyotrophic lateral sclerosis (ALS, such as sporadic ALS, with TARDBP mutation, with angiogenin (ANG) mutation), Alexander disease (AxD), limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Alzheimer's disease (AD, including sporadic and familial forms of AD), Down 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 valosin-containing protein (VCP) mutation; also known as Paget's bone disease and frontotemporal dementia), oculopharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathy with myotilin (MYOT) gene mutation or gene mutation encoding desmin (DES), traumatic brain injury (TBI), Lewy body dementia (DLB) and Parkinson's disease (PD), preferably, 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 age-related TDP-43 encephalopathy (LATE).

30. A compound or diagnostic composition or method used 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. A compound or diagnostic composition or method used 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. A compound, diagnostic composition or method for use 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 dementia with TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).

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

34. A compound having the structure of formula (II) or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof, wherein n is 1 or 2; X, Y and Z are independently CH or N; and R 1 is H or F.

35. A compound of formula (II') wherein R 2 as defined in claim 1 36. A compound having the structure of formula (III) or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof, wherein n is 1 or 2; R 1 is H or F; Z is CH or N; Y 1 Selected from C-Br, C-I, and C-H; R A is H or F; R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may optionally be substituted by Br, I, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S; and Y 1 and / or R 11 at least one of which contains Br or I.

37. A compound having the structure of formula (IV), or its stereoisomers, polymorphs, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates or solvates or mixtures thereof, wherein n is 1 or 2; X, Y and Z are independently CH or N; R A is H or F; R 2 is and R 12 is a leaving group (LG), preferably a mesylate group.

38. A kit for preparing a radiopharmaceutical formulation, which comprises a precursor of a detectable labeled compound according to any one of claims 7 to 12, wherein the precursor 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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