Novel compounds for the diagnosis of TDP-43 proteinopathies

Abstract

The present invention relates to compounds which are suitable for imaging TDP-43 (Transactive response (TAR) DNA binding protein 43 kDa) aggregates. The compounds can be used, for example, for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE).

Description

[0001] New PCT application AC Immune SA Ref.: 24M432 PCT Vossius Ref.: AJ1705 PCT NOVEL COMPOUNDS FOR THE DIAGNOSIS OF TDP-43 PROTEINOPATHIES FIELD OF THE INVENTION The present invention relates to compounds which are suitable for imaging TDP-43 (Transactive response (TAR) DNA binding protein 43 kDa) aggregates. Said compounds can be used, for example, for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, 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 processes for the preparation of said compounds, diagnostic compositions comprising said compounds, methods of using said compounds, kits comprising said compounds and the uses thereof. BACKGROUND OF THE INVENTION Age-associated brain disorders characterized by pathological aggregation of proteins in the CNS (proteinopathies) and peripheral organs represent one of the leading causes of disability and mortality in the world. The best characterized protein that forms extracellular aggregates is amyloid beta (Abeta) in Alzheimer´s disease (AD) and Abeta-related disorders. Other disease-associated, aggregation-prone proteins leading to neurodegeneration include but are not limited to Tau, alpha- synuclein (a-syn), huntingtin, fused in sarcoma (FUS), dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansion, 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 lobar dementia with TDP-43 pathology (FTLD-TDP, frontotemporal lobar degeneration with TDP-43 inclusions) and limbic-predominant age-related TDP- 43 encephalopathy (LATE). TDP-43 introduction Transactive response (TAR) DNA binding protein 43 kDa (TDP-43) is a 414-amino acid proteinencoded by the TARDBP gene on chromosome 1p36.2 (ALS10). TARDBP is comprised of six exons(exon 1 is non-coding; exons 2-6 are protein-coding). TDP-43 belongs to the family of heterogeneousribonucleoprotein (hnRNP) RNA binding proteins (Wang et al., Trends in Molecular Medicine, Vol. 14,No. 11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, ReviewIssue 1 R46-R64). TDP-43 contains five functional domains (Figure 1 in Warraich et al., TheInternational Journal of Biochemistry & Cell Biology, 42 (2010) 1606–1609): two RNA recognition motifs (RRM1 and RRM2), which have two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleioprotein 1 (RNP1) regions, a nuclear export signal (NES) and a nuclear localization signal (NLS) enabling it to shuttle between the nucleus and the cytoplasm transporting bound mRNA, and a glycine rich domain at the C-terminal, which 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 isa highly conserved, ubiquitously expressed protein with a tightly autoregulated expression level that shuttles continuously between the nucleus and cytoplasm but is normally localized predominantly to the nucleus. In 2006, TDP-43 was identified as the protein that accumulates in the vast majority of cases of frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions(then referred to as FTLD-TDP), and in most cases of amyotrophic lateral sclerosis (ALS) (Arai et al.,Biochemical and Biophysical Research Communications, 351 (2006) 602–611; Neumann et al.,Science, 314, (2006), 130-133). Thirty-eight negative-dominant mutations in TDP-43 have been identified in sporadic and familial ALS patients as well as in patients with inherited FTD (K263E, N267S), mainly located in the glycine-richdomain (Figure 1; Lagier-Tourenne and Cleveland, Cell, 136, 2009, 1001-1004). TDP-43 is inherentlyaggregation-prone, as shown by sedimentation assays, and this propensity is increased by someALS-associated TARDBP mutations (Ticozzi et al., CNS Neurol. Disord. Drug Targets, 2010, 9(3),285-296.). TDP-43 in neurodegeneration TDP-43 aggregates have been identified in a growing list 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) mutation, with TARDBP mutation, with valosine-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration with ubiquitin-positive inclusions, argyrophilic grain disease, Pick's disease and the like), amyotrophic lateral sclerosis (sporadic ALS, with TARDBP mutation, with ANG mutation), Alzheimer’s disease (sporadic and familial), Down syndrome, familial British dementia, polyglutamine diseases (Huntington’s disease and SCA3), hippocampal sclerosis dementia and myophaties (sporadic inclusion body myositis, inclusion body myopathy with VCP mutation, oculo-pharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathies with MYOT or DES mutation). Aggregated TDP-43 from patient brains shows a number of abnormal modifications, including hyperphosphorylation, ubiquitination, acetylation and C-terminal fragments through proteolyticcleavage (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 characteristic feature of TDP-43 pathology is redistribution and accumulation of TDP-43 from nucleus to 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) that are immunoreactive for TDP-43, as well as ubiquitin and p62, but negative for other neurodegenerative disease-related proteins. Differences in inclusion morphology and tissue distribution thereof are associated with specific mutations and / or clinical representations. Four types of TDP-43 pathology are described so far by histological methods(Mackenzie and Neumann, J. Neurochem., (2016), 138 (Suppl. 1), 54-70). FTLD-TDP type A casesare characterized by abundant short DN and compact oval or crescentic NCI, predominantly in layerII of the neocortex (Fig.2f in Mackenzie et al., J. Neurochem., 2016, 138 (Suppl.1), 54–70). Lentiformneuronal intranuclear inclusions (NII) are also usually present, but much less abundant. Cases with this pathology usually present clinically with either behavioral-variant frontotemporal dementia (bvFTD) or nonfluent / agrammatic variants of Primary Progressive Aphasia (nfvPPA) and are associated with progranulin (GRN) mutations. Neuropsychiatric manifestations are particularly common in those with an underlying GRN or C9orf72 mutation. Type A is the most common type inthe majority of AD cases (Josephs et al., Acta Neuropathol. 2014, 127(3), 441-50, Arai et al., Actaneuropathologica. 2009, 117, 125–136). TDP-43 neuropathology in most cases of LATE is also similar to that of Type A, which is consistently found in FTD-GRN (Nelson et al., Brain, 2019, 142, 1503–1527). Type B cases show moderate numbers of compact or granular NCI in both superficialand deep cortical layers with relatively few DN and NII (Fig. 2g in Mackenzie et al., J. Neurochem.,2016, 138 (Suppl. 1), 54–70). Most of the NCI have a diffuse granular morphology, sometimes referred to as “pre-inclusions”. Importantly, some cases also have a background of delicate, small TDP-43 threads and dots. Most cases with coappearence of FTD and ALS symptoms are found to have FTLD-TDP type B pathology. Type C cases have an abundance of long tortuous neurites,predominantly in the superficial cortical laminae, with few or no NCI (Fig. 2j in Mackenzie et al.,J. Neurochem., 2016, 138 (Suppl.1), 54–70). This pathology is particularly found in cases presenting with svPPA (semantic variant of primary progressive aphasia). FTLD-TDP type D displays with abundant lentiform neuronal intranuclear inclusions (NII) and short DN in the neocortex with only rareNCI (Fig. 2k in Mackenzie et al., J. Neurochem., 2016, 138 (Suppl. 1), 54–70). This pattern ofpathology is only found in cases with VCP in association with inclusion body myositis. TDP-43 in FTD Frontotemporal dementia (FTD) is a clinical term that covers a wide spectrum of disorders based on the degeneration of frontal and temporal lobes – a pathological feature termed frontotemporal lobar degeneration (FTLD). FTD is the second most abundant cause of early degenerative dementias inthe age group below 65 years (Le Ber, Revue Neurologique, 169 (2013), 811-819). FTD is presentedby several syndromes including bvFTD which is characterized by changes in personality and behavior; semantic dementia (SD) and progressive nonfluent aphasia (PNFA) characterized by changes in the language function; corticobasal syndrome (CBS), progressive supranuclear palsy syndrome and motor neuron disease (FTD-MND) characterized by movement disfunction. Diagnosis of these syndromes is complicated and final conclusion can only be achieved through postmortem tissue analysis based on immunohistochemistry to detect aggregated protein and description of the affected brain regions. In terms of pathological, proteinaceaous inclusions, about 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 pathology term describing FTD cases with TDP-43 pathology found predominantly as cytoplasmic or neuritic protein aggregates in neurons and glia containing misfolded, insoluble, phosphorylated and truncated TDP-43. TDP-43 in ALS 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 marked 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 accumulations of TDP-43 in neurons and glia of the primary motor cortex, brainstem motor nuclei, spinal cord and the associated white matter tracts. ALS with dementia involves accumulation of TDP- 43 in extramotor neocortex and hippocampus. The role of phosphorylation of TDP-43 in ALS patients 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 beenidentified as the major sites of phosphorylation of TDP-43 (Hasegawa et al., Ann Neurol., 2008; 64:60–70; Neumann et al., Acta Neuropathol., 2009, 117: 137-149).TDP-43 in LATE Limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological change (LATE- NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. There is no molecule-specific biomarker for LATE. A discovery of a TDP-43 PET tracer may enable accurate, potentially earlier diagnosis as well as monitoring of disease progression to facilitate longitudinal drug efficacy measurements in patients during clinical trials (including as a potential exclusion criterion for Alzheimer’s disease clinical trials) andlongitudinal studies of the clinical and pathological progression of LATE (Nelson et al., Brain, 2019,Vol.142; issue 6, 1503 - 1527). TDP-43 in AD and other diseasesTDP-43 pathology occurs in up to 57% of brains of patients with Alzheimer’s disease (Josephs KA etal., Acta Neuropathol., 2014; 127(6): 811-824; Josephs KA et al., Acta Neuropathol., 2014; 127(3):441–450; McAleese et al., Brain Pathol., 2017 Jul; 27(4): 472-479). TDP-43 aggregation isassociated with cognitive decline, memory loss and medial temporal atrophy in AD. TDP-43 positive patients are 10-fold more likely to be cognitively impaired at death compared to TDP-43 negative subjects. It appears that TDP-43 represents a secondary or independent pathology that shares overlapping features with AD by targeting the medial temporal lobe. Pathologic TDP-43 follows a stereotypical pattern of deposition that was captured by the TDP-43 in AD (TAD) staging scheme: TDP-43 first deposits in the amygdala (stage I) followed by hippocampus, limbic, temporal, and finallyfrontostriatum (stage V) (Josephs KA et al., Acta Neuropathol., 2014;127(6): 811-824; Josephs KAet al., Acta Neuropathol., 2014; 127(3): 441–450). Diagnostics in FTD and ALS The diagnosis of FTD based on clinical manifestations is insufficient since the clinical representation can overlap with other diseases, in particular, in the earlier stages. Therefore, the development of sensitive and specific biomarkers allowing the differentiation between types of pathology within the FTD spectrum is an urgent task. Such tools will allow better detecting and understanding the specific type of pathology causing neurodegeneration. Eventually this will lead to the development of diagnostic biomarkers enabling more efficient and precise patient selection for longitudinal monitoring in clinical studies, supporting the development of novel therapeutics for ALS and FTD. A number of approaches aim at development of biochemical biomarkers to distinguish different types of FTD pathology. Some studies showed that TDP-43 concentration is increased in cerebrospinal fluid (CSF) of clinically defined FTD or FTD-MND populations, although there is a significant overlap with control or AD subjects and it remains unclear if such an approach will prove clinically useful(Foulds et al., Acta Neuropathol., 2008, 116: 141-146; Steinacker et al., Arch. Neurol., 2008; 65(11):1481–1487). Levels of total Tau or Thr181–phosphorylated Tau do not discriminate FTLD-Tau from control. A possible diagnostic tool for the differentiation of FTLD-Tau and FTLD-TDP is the reducedCSF p-Tau181 to Tau ratio below a value of 0.37 (Hu et al., Neurology., 2013; 81(22): 1945-1952).Another study showed that CSF phosphorylated Tau levels are positively associated with cerebralTau burden in FTD and might help to distinguish TDP-43 proteinopathy from tauopathy (Irwin et al.,Ann. Neurol., 2017 Aug; 82(2):247-258). In parallel to biochemical biomarkers the development of imaging biomarkers will enable early and specific detection of the pathology in FTD and ALS. The ability to image TDP-43 deposition in the brain will be a substantial achievement for diagnosis and drug development for FTD, ALS and other neurodegenerative disorders. Progressive TDP-43 accumulation in the CNS is associated with disease progression and represents an obvious target for development of novel therapeutics and diagnostic tools to study pharmacodynamics and disease progression. Given the relative novelty of TDP-43 as a target, the development of a PET-tracer targeting this protein is at its beginning. However, most of the compound’s reported so far are not specific for TDP-43 and no direct binding to the target was demonstrated for any of these compounds. A number of challenges are associated with the development of a TDP-43-specific PET-tracer including low abundance and heterogenic distribution of the target in the patient's brain as well as the lack of reference compounds. In order to reduce background signal interference resulting from non-specific, off-target binding and to reduce dosing requirements, TDP-43 imaging compounds should bind with high affinity and selectivity to the target. For imaging of TDP-43 aggregates associated with neurological disorders such as FTD and ALS, imaging compounds need to penetrate the blood brain barrier and pass into the relevant regions of the brain. For targeting intracellular amyloid-like inclusions such as TDP-43 aggregates, cell permeability is a further requirement of imaging compounds. A further prerequisite in order to avoid accumulation of the compound in the tissue, which may result in increased risk of unwanted side effects, is a fast compound wash-out from the brain (or other target organ). It was an object of the present invention to provide compounds which are able to bind to TDP-43 aggregates. In particular, the compounds of the present invention should be useful for identification and differentiation of patients and patient groups with TDP-43 proteinopathies (such as FTD, FTLD- TDP, LATE and ALS) and for differentiating TDP-43 proteinopathies from other proteinopathies. The present inventors have surprisingly found that compounds having the formula (I) can recognize and bind to TDP-43 aggregates. Moreover, it was found that compounds of the invention display high selectivity to TDP-43 aggregates over co-pathologies such as Abeta and Tau in AD brain homogenates, as well as over a-syn in PD brain homogenates. Furthermore, it was shown that compounds of the invention have a robust brain uptake and fast washout in non-human primates, satisfying the criteria for PET tracer further development for use in human subjects. SUMMARY OF THE INVENTION The present invention is summarized in the appended claims. In particular, the present invention refers to a compound having the formula (I) or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; whereinn is 1 or 2;R1is H, OH, F, -(C1-C3alkyl)OH (preferably hydroxyethyl or hydroxymethyl, more preferablyhydroxymethyl), or -COORA (wherein RA is (C1-C4)alkyl);R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with – (C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S. In another aspect, the present invention provides a diagnostic composition comprising a compound according to the definition of a compound of formula (I), or subformulae thereof, as defined herein, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient. Said compounds can be used for imaging of TDP-43 aggregates, particularly wherein the imaging is conducted by positron emission tomography or for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates, particularly wherein the diagnosis is conducted by positron emission tomography. In another aspect, the invention provides a compound according to the definition of a compound of formula (I), or subformulae thereof, which can be used in the following methods:^ A method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates,in a subject;^ A method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue ofa subject;^ A method for the detection and optionally quantification of TDP-43 aggregates in a tissue of asubject;^ A method of the diagnostic imaging of the brain of a subject;^ A method of collecting data for the diagnosis of a disease, disorder or abnormality associatedwith TDP-43 aggregates or for the diagnosis of a TDP-43 proteinopathy;^ A method of collecting data for determining a predisposition to a disease, disorder orabnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;^ A method of collecting data for monitoring the progression of a disease, disorder or abnormalityassociated with TDP-43 aggregates or for monitoring the progression of a TDP-43 proteinopathy in a patient; and^ A method of collecting data for predicting responsiveness of a patient suffering from a disease,disorder or abnormality associated with TDP-43 aggregates to a treatment with a medicament.The methods of the present invention can be in vitro or in vivo.In another aspect, the invention provides a compound according to the definition of a compound of formula (I), or subformulae thereof, that can also be used as a TDP-43 aggregates’ biomarker or a TDP-43 proteinopathy biomarker, as a TDP-43 proteinopathy diagnostic agent or diagnostic tool oras an in vitro analytical reference or an in vitro screening tool.Another aspect of the present invention provides a method of preparing a compound according to the definition of a compound of formula (I), or subformulae thereof. In yet another aspect, the present invention relates to kit for preparing a radiopharmaceutical preparation, said kit comprising a precursor of a compound of formula (I), or subformulae thereof. DEFINITIONS Unless defined otherwise, within the meaning of the present application the following definitions apply, and, when appropriate, a term used in the singular will also include the plural and vice versa: Compounds of the invention may have one or more optically active carbons that can exist as racemates and racemic mixtures, stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropoisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described in this specification containing olefinic double bonds include E and Z geometric isomers. Also included in this invention are all salt forms, such as pharmaceutically acceptable salts, polymorphs, hydrates, solvates, and mixtures thereof. Unless specified otherwise, the terms “compound of formula (I)" or "compound of the (present) invention" refer to a “compound of formula (I), or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof”. Unless specified otherwise, the terms “compound of formula (I)" or "compound of the (present) invention" refers to compounds of formula (I), and subformulae thereof, and isotopically labelled compounds (including, but not limitedto 18F and 3H substitutions). The terms “compound of formula (I)" or "compound of the (present)invention" refers to a compound as defined in any one of embodiments mentioned herein below. The term "polymorphs" refers to the various crystalline structures of the compounds of the invention. This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Salts can also be crystalline and may exist as more than one polymorph. Solvates, hydrates as well as anhydrous forms of salt are also encompassed by the invention. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include C1–4alcohols (such as methanol or ethanol). "Pharmaceutically acceptable salts" are defined as derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the compound of formula (I) can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms 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 the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18thed., Mack Publishing Company, Easton, PA, 1990, p.1445, the disclosure of which is hereby incorporated by reference. Typically, the pharmaceutically acceptable salts are salts of amine residues in the compounds of the present invention. The “patients” or “subjects” in the present invention are typically animals, particularly mammals, more particularly humans and mice. Even more particularly humans. A "diagnostic composition" is defined in the present invention as a composition comprising the compound of the invention in a form suitable for administration to a patient, wherein the patient is e.g. a mammal such as a human. "TDP-43 aggregates" are TDP-43-positive multimeric rich assemblies of TDP-43. They can be found in intracellular deposits in a range of diseases termed TDP-43 proteinopathies, in particular 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: compact oval or crescentic neuronal cytoplasmic inclusions (NCI), lentiform neuronal intranuclear inclusions (NII), glial cytoplasmic inclusions (GCI), dystrophic neurites (DN) and long tortous neurites. In pathological aggregates TDP-43 often displays a substantial increase in post-translational modifications such as phosphorylation, ubiquitination, acetylation, sumoylation and proteolytic cleavage to generate C-terminal fragments. The "preclinical state" of disease is defined as the phase of disease where disease-associated changes on the molecular level are not leading to overt clinical representation in the patient. The "clinical state" of a disease is defined as the phase of a disease where disease-associated changes on the molecular level led to overt clinical representation in the patient. The terms "diagnosing" or "diagnosis" generally refer to the process or act of recognizing, deciding on or concluding on a disease or condition in a patient on the basis of symptoms and signs and / or from results of a diagnostic procedure. A "normal control value" is determined by conducting the respective method with a plurality of healthy subjects, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each healthy subject and calculating an average thereof. A “healthy control subject” or “healthy subject” is a person showing no clinical evidence of neurodegenerative disease. Said person needs to meet the following criteria:^ Male and female subjects which are healthy with no clinically relevant findings upon physicalexamination.^ No family history of TDP-43 proteinopathy, TDP-43 aggregates formation, or other early-onsetneurological diseases associated with dementia.^ No personal history of clinically significant neurologic and / or psychiatric disorders.^ No clinical signs or symptoms of a current neurological deficit such as cognitive impairment ormotor deficit. A "preclinical control value" is determined by conducting the respective method with a plurality of subjects who are in a preclinical state, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each subject and calculating an average thereof. A "clinical control value" is determined by conducting the respective method with a plurality of subjects who are in a clinical state, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each subject and calculating an average thereof. The terms "predicting” or "prediction" generally refer to an advance declaration, indication or foretelling of a disease or condition in a patient not having a disease, disorder or abnormality. For example, a prediction of a disease, disorder or abnormality in a patient may indicate a probability, chance or risk that the patient will contract the disease, disorder or abnormality, for example within a certain time period or by a certain age. Detectable labels include suitable isotopes such as radioisotopes, in particular positron emitters orgamma emitters, and include 2H, 3H, 18F, 123I, 124I, 125I, 131I, 11C, 13N, 15O, 99mTc and 77Br, preferably2H, 3H, 11C, 13N, 15O, and 18F, more preferably 2H, 3H and 18F, even more preferably 3H and 18F, mostpreferably 18F.The term "Hal", “halogen” or “halo” means F, Cl, Br or I, particularly Br or I, more particularly Br. The term “carbocyclic” refers to a 5- or 6-membered carbocyclic ring which is not particularly limited and includes any 5- or 6-membered, saturated or unsaturated carbocyclic ring. Unsaturated carbocyclic rings include, but are not limited to, aromatic rings. Examples of 5- or 6-membered carbocyclic rings include, for instance, phenyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. Phenyl being preferred. The term “heterocyclic ring” refers to a stable 5- or 6-membered heterocyclic ring, is not particularly limited and includes any 5- or 6-membered, saturated or unsaturated heterocyclic ring. Unsaturated heterocyclic rings include, but are not limited to, aromatic rings. The heterocyclic ring contains one or more heteroatoms (for instance, one or two heteroatoms) selected from N, O and S. The heteroatom is / are preferably N or O, more preferably N. Examples of 5- or 6-membered heterocyclic rings include, for instance, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, oxathiolidinyl, isoxthiolidinyl, oxathiolyl, isoxathiolyl, thiazolidinyl, iosthiazolidinyl, thiazolyl, and isothiazolyl, preferably pyrazolyl, pyridinyl, and pyrimidinyl. The term “leaving group” (LG) as employed herein is any leaving group and means an atom or group of atoms that can be replaced by another atom or group of atoms. Examples are given, e.g., in Synthesis (1982), p.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, scheme 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, pp.15-50, explicitly: scheme 4 pp.25, scheme 5 pp 28, table 4 pp 30, Figure 7 pp 33). In an embodiment, the "leaving group" (LG) is selected from C1–4 alkyl sulfonate, C6–10aryl sulfonate, trimethyl ammonium or nitro, preferably, mesylate, tosylate, nosylate, trimethyl ammonium or nitro. Even more preferably, the Leaving Group (LG) is mesylate, trimethyl ammonium or nitro. The term “detecting” as used herein encompasses quantitative and / or qualitative detection.The compounds of the present invention can be used as an analytical reference or an in vitroscreening tool. For example, the non-labelled compounds of formula (I) according to of the present invention can be used as an analytical reference for the quality control and release of a corresponding labelledcompound of the present invention, for example a corresponding 18F labelled compound of Formula(I-F) or (I-F’). This quality control is conducted in an in vitro method.The compounds of the present invention can be used as an in vitro screening tool for characterizationof tissue with Tau pathology and for testing of compounds targeting Tau pathology on such tissue. The preferred definitions given in the "Definition"-section apply to all of the embodiments described below unless stated otherwise. Various embodiments of the invention are described herein, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. DETAILED DESCRIPTION OF THE INVENTION Various embodiments of the invention are described herein, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. It is understood that all of the definitions which are given with respect to the formula (I) apply to all of the subgenera thereof, including the formulae (I-H), (I-F), (II), (III), and (IV).In a first aspect, the present invention relates to a compound having the formula (I) or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; whereinn is 1 or 2; R1is H, OH, –(C1-C3alkyl)OH (preferably hydroxyethyl or hydroxymethyl, more preferablyhydroxymethyl), -COORA, wherein RA is (C1-C4)alkyl, or F;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with halo(C1-C3)alkyl, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S. In one preferred embodiment, at least n is 1. In another preferred embodiment, n is 2.The present invention relates to a compound of formula (I), wherein R1 is –(C1-C3alkyl)OH, preferablyhydroxyethyl or hydroxymethyl, more preferably hydroxymethyl, -COORA, wherein RA is (C1-C4)alkyl,or F.In one embodiment, R1 is H or F.In a preferred embodiment R1 is –(C1-C3alkyl)OH. Preferred examples of –(C1-C3alkyl)OH arehydroxymethyl or hydroxyethyl, more preferably hydroxymethyl.In another preferred embodiment R1 is OH.In another embodiment R1 is -COORA, wherein RA is (C1-C4)alkyl, preferably ethyl or methyl, morepreferably methyl.In a more preferred embodiment R1 is selected from the group consisting of -OH, and-CH2-OH.The present invention refers to a compound of formula (I), wherein R2 is a 5- or 6-memberedcarbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo-, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.In one embodiment, R2 is a 5- or 6-membered carbocyclic ring, preferably an aryl ring.In one preferred embodiment, R2 is a 5-membered heteroaryl ring, wherein the 5-memberedheteroaryl ring contains one or more heteroatoms selected from N, O and S, more preferably one or two N, or a 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one or two heteroatoms selected from O, N and S, more preferably one or two N.Preferred examples of the ring of R2 are given in the Definitions section above. Preferably, R2 isphenyl, pyridyl, pyrimidinyl, pyrazolyl, pyridazinyl, thiazolyl or isothiazolyl, preferably pyrazolyl, pyridinyl, and pyrimidinyl.The ring of R2 can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3 at anyavailable position. In one embodiment, the optional substituent is F and / or CH3. In another embodiment, the optional substituent is preferably –(C1-C3alkyl)halo and / or CH3, preferably –(C1-C3alkyl)halo. In another preferred embodiment the 5- or 6-membered carbocyclic or heterocyclic ring is not substituted. In one embodiment, the phenyl can be optionally substituted by –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, for example with CN and NH2or with F and NH2.In another embodiment, the pyridyl can be optionally substituted with F or CH3, preferably pyridyl is unsubstituted. In another embodiment, the isothiazolyl or thiazolyl is unsubstituted. In another embodiment, the pyrazinyl is unsubstituted. In a preferred embodiment, the pyrimidinyl is unsubstituted. In another preferred embodiment, the pyrazolyl can be optionally substituted by –(C1-C3alkyl)halo, preferably by –CH2-CH2-F. In a preferred embodiment, the present invention relates to a compound of formula (I), whereinR2 is (ii) , wherein R5 is H, halo(C -C ) 52 3 alkyl, or CH3; more preferably R is –CH2-CH2-F. In another preferred embodiment, the present invention relates to a compound of formula (I), wherein wherein R9 is selected from H, –(C1-C3alkyl)halo, F, CN, CH3 and NH2; In another preferred embodiment, the present invention relates to a compound of formula (I), wherein wherein R9 is selected from H, –(C1-C3alkyl)halo, F, CH3 and NH2; preferably , wherein R9 is selected from H, –(C1-C3alkyl)halo, F, CH3 and NH2;wherein R9 is selected from H, –(C1-C3alkyl)halo, F, CH3 and NH2; In a more preferred embodiment, R2 is selected from the group consisting of , In another embodiment, the present invention relates to a compound of formula (I), wherein ,whereinNH2, R7 is H, and R8 is H,F, R7 is H, and R8 is H,NH2, R7 is H, and R8 is H, NH2, R7 is H, and R8 is CN,R3 is H, R4 is NH2, R7 is H, and R8 is F, orR3 is H, R4 is NH2, R7 is H, and R8 is CN.In one preferred embodiment, the compound of formula (I) is defined as n is 2, R1 is -CH2OH; and R2is , wherein R9 is selected from H, F, and CH3, preferably H.In another preferred embodiment, the compound of formula (I) is defined as n is 2, R1 is -CH2OH;and R2 is , wherein R9 is selected from H, F, or CH 93. In a preferred embodiment Ris H.In another preferred embodiment, the compound of formula (I) is defined as n is 2, R1 is OH; and R2 In another preferred embodiment, the compound of formula (I) is defined as n is 1, R1 is OH; and In another preferred embodiment, the compound of formula (I) is defined as n is 2, R1 is OH; andthe compound of formula (I) is defined as n is 2, R1 is -CH2OH; In another preferred embodiment, the compound of formula (I) is defined as n is 2, R1 is -C(OOCH3); In another preferred embodiment, the compound of formula (I) is defined as n is 1, R1 is -CH2OH; In a preferred embodiment, the present invention relates to a compound having the formula (Ia), (Ib) or (Ic) or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein R1is H, -OH, –(C1-C3alkyl)OH, (preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl), -COORA, wherein RA is (C1-C4)alkyl, or F; andR2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2,CN and / or CH3, preferably CH2CH2F and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.In a preferred embodiment, R1 is selected from the group consisting of H, OH, -CH2-OH, -COORA,wherein RA is (C1-C2)alkyl.In a more preferred embodiment, R1 is selected from the group consisting of OH, -CH2-OH or-COOCH3.In an even more preferred embodiment, R1 is selected from the group consisting of -OH and-CH2-OH. In another preferred embodiment R2is a 5- or 6-membered aryl or heteroaryl ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, preferably CH2CH2F and / or CH3, wherein the heteroaryl ring contains one or two heteroatoms selected from N and S, preferably N; or a 5- or 6-membered heteroaryl ring, which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2,CN and / or CH3, wherein the heteroaryl ring contains one or two heteroatoms and said heteroatom(s) is / are N.In a preferred embodiment, R2 is selected from the group consisting of , wherein R5 is H, –(C1-C3alkyl)halo, or CH3; , wherein R9 is selected from H,–(C1-C3alkyl)halo, F, CH3and NH2; Preferred compounds of formula (I) include: 1 2 3 4 and 5 6 7 8 9 In one embodiment preferred compounds of formula (I) can be selected from the following stereoisomers: 4 5 9 In one embodiment, the present invention relates to a compound of formula (I), which comprises a detectable label. Preferably, the compound of formula (I) comprises one or more detectable labels. The type of the detectable label is not specifically limited and will depend on the detection method chosen. Examples of possible detectable labels include isotopes such as radioisotopes (namely radionuclides), in particular, positron emitters or gamma emitters. The detectable label such as the radioisotope, in particular, the positron emitter or gamma emitter, should be present in an amount, which is not identical to the natural amount of the respective isotope. Furthermore, the employed amount should allow detection thereof by the chosen detection method.In a preferred embodiment, the detectable label is selected from 3H and 18F, most preferably 18F. Thedetectable label can be present at any available position. Typically, the detectable label is a radioactive isotope of one of the atoms which are present in the compound of formula (I). Forinstance, any reference to "F" in the present invention covers 19F (stable) or 18F (detectable label).Any reference to "H" covers 1H (stable) or 3H (detectable label, so called tritium and representedherein as “T”). Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparative Examples hereinafter using appropriate isotopic variations of suitable reagents, commercially available or prepared by known synthetic techniques. Radioisotopes, in particular positron emitters or gamma emitters, can be included into the compounds of the invention by methods which are usual in the field of organic synthesis. Typically, they will be introduced by using a correspondingly labeled starting material. Illustrative methods of introducing detectable labels are described, for instance, in US 8,932,557 which is incorporated herein by reference.18F can be attached at any position which is suitable for attaching a fluorine. 18F-labeled compoundsare particularly suitable for imaging applications such as positron emission tomography (PET). Thecorresponding compounds which include natural fluorine isotope 19F are also of particular interest asthey can be used as analytical standards and references during manufacturing, quality control,release, and clinical use of their 18F-analogs.In the compounds having the formula (I), 18F can be present, for instance, as the F substituent of R2or as R1. Preferably it is present as R1.If 3H is employed as a detectable label it is preferably attached as -T or -CT3 at any suitable position(T means 3H). 3H may be in the form of –CT3 at any position at which a CH3 group can be attached.Substitution with radioisotopes such as 3H may afford certain diagnostic advantages resulting fromgreater metabolic stability by reducing, for example, defluorination, increasing in vivo half-life orreducing dosage requirements, while keeping or improving the original compound efficacy. In one embodiment, the present invention relates to Tritium (3H) detectably labeled compounds having the formula (I), as described above, wherein at least one Hydrogen (H) is replaced by a detectable label selected from Tritium (3H). Tritium (3H) detectably labeled compounds having the formula (I) are preferably defined wherein 1 to 3 Hydrogens (H) are replaced by Tritium (3H). In an embodiment, the present invention relates to a compound of formula (I-T) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2;R1 is H, OH, –(C -C alkyl)OH, A A1 3 F or -COOR , wherein R is (C1-C4)alkyl;T is 3H; and wherein whereinH a 6 nd R is T or H;or whereinR2 is , wherein R12 is T or H 6 and R is T or H;or whereinR2 is (v) , wherein R5 is –(C1-C4alkyl)halo R12 is T or H, p is 1 or 2 andR6is T or H; or whereinR2 is , where 12 6 in R is T or H and R is T or H;and wherein (I-T) has at least one T, preferably 2 T.In another embodiment, R6 is T or H, wherein R2 is substituted at least one of the hydrogen atoms inR2 is replaced by T, and / or wherein at least one of the hydrogen atoms in R1 is replaced by T. In oneembodiment, R6 is T or H, and / or wherein R2 is substituted by at least one CT3 or at least one of thehydrogen atoms in R2 is replaced by T. T is 3H.In another embodiment, R6 is T. In another embodiment, at least one of the hydrogen atoms in R2 isreplaced by T. In a preferred embodiment, R6 is T and at least one of the hydrogen atoms in R2 isreplaced by T. In yet another embodiment, at least one of the hydrogen atoms in R1 is replaced byT. In an embodiment, the present invention relates to a compound of formula (I-T), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2;R1 is H, OH, –(C1-C3alkyl)OH, F or -COORA, wherein RA is (C1-C4)alkyl;T is 3H; andwhereinR2 iswherein r whereinR2 iswherein whereinR2 is , wherein 12 6 R is T and R is H; or whereinR2 is , wherein R12 is T and R6 is H; or whereinR2 is , wherein R12 is T a 6 nd R is H; or whereinR2 is whe 12 6 rein R is T and R is H; or whereinR2 is (vii) , wherein R5 is –(C1-C3alkyl)halo, R12 is T, p is 1 or 2,preferably 1 or 2, and R6 is H; or whereinR2 is (viii) , wherein R5 is CT3; orR2 is wherein R3 4 7 8 is F, R is NH2, and at least one of R and R is T and, ifapplicable, the other is H; preferably R7 is T and R8 is T; and R6 is T;or wherein, wherein R4 is NH2, R8 is CN, and at least one of R3 or R7 is T and, ifapplicable, the other is H; preferably R7 is T and R3 is T; or R7 is T and R3 is H; and R6 is T.In another embodiment, the present invention relates to a compound of formula (I-T) wherein n is 1 or 2;R1 is H, OH, –(C -C alk A A1 3 yl)OH, F or -COOR , wherein R is (C1-C4)alkyl;R6 is T or H; preferably T;T is 3H; andwherein R8 is T and, ifapplicable, the other is H;preferably R7 is T; and R8 is T; or wherein R8 is CN, R4 is -NH2, and at least one of R7 and R3 is T and, ifapplicable, the other is H; in one embodiment R7 is T; and R3 is T; in another embodiment R7 is T;and R3 is H.In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably n is 2; R1is H or F (preferably H);R6 is T; and wherein R3 is F; R4 is NH2; and at least one of R7 and R8 is T and, if applicable,the other is H.Preferably R7 is T; R8 is T;wherein R8 is CN, R4 is NH2, and at least one of R7 and R3 is T and, ifapplicable, the other is H.In one embodiment R7 is T; and R3 is T; or in another embodiment R7 is T; and R3 is H; orR2 is , wherein R5 is – 12 (C1-C4alkyl)halo R is T, p is 1 or 2 orR2 is (iii) selected from , wherein R9 is selected from H, F, NH2 or CH3; In one embodiment, the present invention relates to a compound of formula (I-T) wherein n is 1 or 2; preferably n is 2; R1is F; R6is H; and , wherein R5 is –(C1-C4alkyl)halo R12 is T, p is 1 or 2.In one embodiment, the present invention relates to a compound of formula (I-T) wherein n is 1 or 2; R1is F; R6is H; and , wherein R5 is CT3 In one embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably n is 2; R1is H or F;R6 is T; and In one embodiment, the present invention relates to a compound of formula (I-T), wherein n is 2; R1is hydroxy(C1-C4)alkyl, preferably -CH2OH;R6 is T; and In one embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; R1is H or F, preferably H;R6 is T; andR2 is (iii) .In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R1is H or F, preferably H;R6 is T; and In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R1is H or F, preferably H; In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R1is H or F, preferably H;R6 is T; and R2 is In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R1is H or F, preferably H;R6 is T; and R2 is (vii) R6is H In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; R1is H or F, preferably H;R6 is T; and , wherein R5 is CT3.In another preferred embodiment, the present invention relates to a compound of formula (I-T’), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2;R6 is T or H;R1 is –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl substituted by one or two, preferablytwo, T,wherein T is 3H; andR2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.In one embodiment, the present invention provides a 18F detectably labeled compound of formula(I-F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; whereinF is 19F;n is 1 or 2;R1 is 18F;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.In a preferred embodiment, the present invention provides a 18F detectably labeled compound offormula (I-F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2;R1 is H, OH, –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl, andR2 is , wherein R9 is H; wherein R5 is–(C1-C4alkyl)halo, preferably –(C1-C2alkyl)F.In a preferred embodiment,n is 1 or 2; andR9 is selected from H, and F, NH2 or CH3; orR5 is H, –(C1-C3alkyl)halo, or CH3 preferably -CH2CH2-F; or R7 is H, and R8 is H; orR3 is H, R4 is NH2, R7 is H, and R8 is CN.In a preferred embodiment, the present invention relates to a compound of formula (I-F), wherein n is 1 or 2;R1 is 18F (detectable label); and , wherein R9 is H; or R2 is , wherein R5 is–(C1-C4alkyl)halo, preferably –(C1-C2alkyl)F.In a preferred embodiment n is 1. In another preferred embodiment n is 2. In another preferred embodiment, (I-F) is the following compound or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1is –(C1-C3alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; orR1 is -COORA, wherein RA is (C1-C4)alkyl; andR2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with -(C1-C3alkyl)halo, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S. In another more preferred embodiment, (I-F) is the following compound or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2;R1 is –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl, and , wherein R9 is H.In another embodiment, In another preferred embodimentR2 is , wherein R5 is -CH2-CH2-halo, CH3 or H, preferably -CH2-CH2F; orR2 is , wherein R9 is selected from H, and F, NH2 or CH3; or R2 is .In one preferred embodiment n is 1 or 2, preferably 2; R1is –(C1-C3alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; orOH, and R2 is , wherein R9 is selected from H, and F, NH2 or CH3, preferably H.In another preferred embodiment, the present invention relates to a compound of formula (I-F), whereinn is 1 or 2, preferably 2;and R1is –(C1-C3alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; and , wherein R9 is H.Diagnostic compositionsIn a second aspect, the present invention relates to a diagnostic composition comprising acompound of formula (I), as described above, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient. The compounds of the present invention are particularly suitable for imaging TDP-43 aggregates.The imaging can be conducted in mammals, preferably in humans. The imaging is preferably in vitroimaging, ex vivo imaging, or in vivo imaging. More preferably the imaging is in vivo imaging. Evenmore preferably, the imaging is brain imaging. The imaging can also be eye / retinal imaging or imaging of tissue of the central nervous system. The compounds of the present invention are particularly suitable for use in diagnostics. The diagnostics can be conducted for mammals, preferably for humans. The tissue of interest on which the diagnostics is conducted can be brain tissue, tissue of the central nervous system, tissue of the eye (such as retinal tissue) or other tissues, or body fluids such as cerebrospinal fluid (CSF). The tissue is preferably brain tissue. A "diagnostic composition" is defined in the present invention as a composition comprising one or more compounds of the present invention, in a form suitable for administration to a patient, (e.g., a mammal such as a human), and which is suitable for use in the diagnosis of the specific disease, disorder or abnormality at issue. In one embodiment, the diagnostic composition comprises a detectably labeled compound of the invention as described above and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient. Preferred detectably labeled compounds of the invention are of formula (I-T) or (I-F). The diagnostic composition is suitable for use in the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, as defined herein below. Preferably a diagnostic composition further comprises, optionally, a physiologically acceptable excipient, carrier, diluent, or adjuvant. Administration is preferably carried out as defined below. More preferably by injection of the composition as an aqueous solution. The diagnostic composition may optionally contain further ingredients such as buffers; pharmaceutically acceptable solubilizers (e.g., cyclodextrins or surfactants such as Pluronic, Tween or phospholipids); and pharmaceutically acceptable stabilizers or antioxidants (such as ascorbic acid, gentisic acid or para-aminobenzoic acid). The dose of the compound of the invention will vary depending on the exact compound to be administered, the weight of the patient, and other variables as would be apparent to a physician skilled in the art. While it is possible for the compounds of the invention to be administered alone, it is preferable to formulate them into a diagnostic composition in accordance with standard pharmaceutical practice. Thus, a diagnostic composition which comprises a diagnostically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, diluent, adjuvant and / or excipient is part of the invention. The preferred pharmaceutically acceptable carrier, diluent, adjuvant and / or excipient is one that is physiologically compatible with the diagnostic composition according to the present invention. Pharmaceutically acceptable excipients are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18thEd. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990). The pharmaceutically acceptable excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. Pharmaceutically useful excipients, carriers, adjuvants and diluents that may be used in the formulation of the diagnostic composition of the present invention may comprise, for example, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, 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 carboxymethyl cellulose, dextrose, hydroxypropyl-ß-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. The routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of: intravenous, gastrointestinal, intraspinal, intraperitoneal, intramuscular, oral (e. g. as a tablet, capsule, 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, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual. Preferably, the route for administration (delivery) of the compounds of the invention is parenteral. If the compounds of the present invention (for instance, detectably labeled compounds such as thosewith a 3H or 18F detectable label) are administered parenterally, then examples of such routes ofadministration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously and / or using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other excipients. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient. The dose of the compounds of the present invention (for instance, detectably labeledcompounds such as those with a 3H or 18F detectable label) will vary depending on the exactcompound to be administered, the weight of the patient, size and type of the sample, and other variables as would be apparent to a physician skilled in the art. Generally, the dose could preferably lie in the range 0.001 µg / kg to 10 µg / kg, preferably 0.01 µg / kg to 1.0 µg / kg. The radioactive dose can be, e.g., 100 to 600 MBq, more preferably 150 to 450 MBq. Due to their design and their binding characteristics, the compounds of the present invention, as defined herein, can be use in 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. The compounds of the present invention, as disclosed herein, are particularly suitable for use in the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy, such as disease, disorder or abnormality selected from, but not limited to, frontotemporal dementia (FTD, such as sporadic or familial with or without motor-neuron disease (MND), with progranulin (GRN) mutation, with C9orf72 mutations, with TARDBP mutation, with valosine-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) including frontotemporal lobar 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), behavioural variant FTD (bvFTD), Nonfluent Variant Primary Progressive Aphasia (such as 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 under Machado Joseph Disease)), hippocampal sclerosis dementia and myopathies (sporadic inclusion body myositis, Inclusion body myopathy with a mutation in the valosin-containing protein (VCP); also Paget disease of bone and frontotemporal dementia), oculo-pharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathies with mutations in the myotilin (MYOT) gene or mutations in the gene coding for desmin (DES), Traumatic Brain Injury (TBI), Dementia with Lewy Bodies (DLB) and Parkinson’s disease (PD), preferably, the disease, the disorder or the abnormality associated with TDP-43 aggregates or the 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). In one embodiment, the diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS). In one embodiment, the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is Alzheimer’s disease (AD). In one embodiment, the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is frontotemporal dementia (FTD) including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In one embodiment, the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is limbic-predominant age-related TDP-43 encephalopathy (LATE). Methods and usesIn a third aspect, the present invention relates to the methods and uses as listed below^ A method of imaging a disease, disorder or abnormality associated with TDP-43 aggregates ina subject;^ A method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue ofa subject;^ A method for the detection and optionally quantification of TDP-43 aggregates in a tissue of asubject;^ A method of the diagnostic imaging of the brain of a subject;^ A method of determining an amount of TDP-43 aggregates in a sample or a specific body partor body area;^ A method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregatesor of diagnosing a TDP-43 proteinopathy;^ A method of collecting data for the diagnosis of a disease, disorder or abnormality associatedwith TDP-43 aggregates or for the diagnosis of a TDP-43 proteinopathy;^ A method of collecting data for determining a predisposition to a disease, disorder orabnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy;^ A method of collecting data for monitoring the progression of a disease, disorder or abnormalityassociated with TDP-43 aggregates or for monitoring the progression of a TDP-43 proteinopathy in a patient,^ A method of collecting data for predicting responsiveness of a patient suffering from a disease,disorder or abnormality associated with TDP-43 aggregates to a treatment with a medicament;^ Use of a compound of the invention as a TDP-43 aggregates’ biomarker or a TDP-43proteinopathy biomarker,^ Use of a compound of the invention as a TDP-43 proteinopathy diagnostic agent or diagnostictool,^ Use of a compound of the invention as an in vitro analytical reference or an in vitro screeningtool. Any of the compounds of the present invention (e.g. compound of formula (I), (I-T) or (I-F)) can be used in the above summarized methods. Preferably, said compounds are detectably labeledcompounds (e.g. such as those with a 3H or 18F detectable label).The methods of the invention can include the step of bringing a sample, a specific body part or a body area suspected to contain TDP-43 aggregates into contact with a compound of the invention. The body is preferably of a mammal, more preferably of a human, including the full body or partial body area / part of the patient suspected to contain TDP-43 aggregates. The sample can be selected from tissue or body fluids suspected to contain TDP-43 aggregates, the sample being obtained from the patient. Preferably, the tissue is selected from tissue of the central nervous system (CNS), eye tissue or brain tissue, more preferably brain tissue. Examples of body fluids include cerebrospinal fluid (CSF) or blood. The sample can be obtained from a mammal, morepreferably a human. Preferably, the sample is an in vitro sample from a patient.An in vitro sample or a specific body part or body area obtained from a patient can be brought intocontact with a compound of the invention by direct incubation.In an in vivo method, the specific body part or body area can be brought into contact with a compoundof the invention by administering an effective amount of a compound of the invention to the patient. The effective amount of a compound of the invention is an amount which is suitable for allowing the presence or absence of TDP-43 aggregates in the specific body part or body area to be determined using the chosen analytical technique. The step of allowing the compound of the invention to bind to the TDP-43 aggregates includes allowing sufficient time for said binding to happen. The amount of time required for binding will dependon the type of test (e.g., in vitro or in vivo) and can be determined by a person skilled in the field byroutine experiments. In an in vitro method the amount of time will depend on the sample or specificbody part or body area and can range, for instance, from about 30 min to about 120 min. In an in vivomethod, the amount of time will depend on the time which is required for the compound of the invention to reach the specific body part or body area suspected to contain TDP-43 aggregates. The amount of time should not be too long to avoid washout and / or metabolism of the compound of the invention. The duration can range, for instance, from about 0 min to about 240 min (which is the duration of a PET scan during initial compound characterization (NHP PET and later FiH-study)). The method of detecting the compound of the invention bound to the TDP-43 aggregates is not particularly limited and depends, among others, on the detectable label, the type of sample, specificbody part or body area and whether the method is an in vitro or in vivo method. Possible detectionmethods include, but are not limited to, a fluorescence imaging technique or a nuclear imaging technique such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). The fluorescence imaging technique and / or nuclear imaging technique can be employed for monitoring and / or visualizing the distribution of the compound of the invention within the sample or the body. The imaging system is such to provide an image of bound detectably label such as radioisotopes, in particular positron emitters or gamma emitters, as present in the tested sample, the tested specific body part or the tested body area. Preferably, the compound of the invention bound to the TDP-43 aggregates is detected by an imaging apparatus such as PET or a SPECT scanner. The amount of the compound bound to the TDP-43 can be determined by visual or quantitative analysis, for example, using PET scan images. In one embodiment, the presence or absence of a compound of the invention bound with the TDP- 43 aggregates can be correlated with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area. The correlation can be qualitative or quantitative. In a preferred embodiment, this step comprises:- Determining the amount of the compound of the invention bound to the TDP-43 aggregates;- Correlating the amount of the compound of the invention bound to the TDP-43 aggregates withthe amount of TDP-43 aggregates in the sample or specific body part or body area; and- Optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. The amount of the compound bound with the TDP-43 aggregates can be determined by any appropriate method. A preferred method is positron emission tomography (PET). In another embodiment, the presence or absence of the compound of the invention bound to TDP- 43 aggregates can be correlated with the disease, disorder or abnormality associated with TDP-43 aggregates or with the TDP-43 proteinopathy or a predisposition thereto. The correlation can be qualitative or quantitative. In a preferred embodiment, this step comprises:- Determining the amount of the compound of the invention bound to the TDP-43 aggregates;- Correlating the amount of the compound of the invention bound to the TDP-43 aggregates withthe amount of TDP-43 aggregates in the sample or specific body part or body area; and- Optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. In any of the methods disclosed herein, steps (a) to (c) and, if present, optional step (d) can be repeated at least one time. The repetition of the steps is particularly useful in the method of collecting data for monitoring the progression and the method of collecting data for predicting responsiveness. In these methods, it may be expedient to monitor the patient over time and repeat the above steps after a certain period of time has elapsed. The time interval before the above-mentioned steps are repeated can be determined by a physician depending on the severity of the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy. In one embodiment, the present invention relates to a method of detecting a neurological disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound which is bound to the TDP-43 aggregates.In one embodiment, the present invention relates to a method (e.g. in vivo or in vitro method) for thedetection and optionally quantification of TDP-43 aggregates in a tissue of a subject, the method comprising the steps: (a) Administering a compound of the invention as disclosed herein; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting and optionally quantifying the compound bound to the TDP-43 aggregates using positron emission tomography. In one embodiment, the present invention relates to a method of the diagnostic imaging of the brain of a subject, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to 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 brain of the subject. Imaging: The present invention relates to a method of imaging TDP-43 aggregates using the compounds of the invention. Imaging can be conducted, for example, using any of the above-mentioned methods, particularly by PET. In one embodiment, the present invention relates to a method of imaging TDP-43 aggregates in a sample or a patient, in particular in a brain or a sample taken from the patient's brain, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates. In one embodiment, the present invention relates to a method of imaging or diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps:(a) Administering a compound of the invention; or a diagnostic composition comprising acompound of the invention as disclosed herein, to the subject;(b) Allowing the compound to bind to the TDP-43 aggregates; and(c) Detecting the compound bound to the TDP-43 aggregates in the brain of the subject.In one embodiment, the present invention relates to a method of imaging or diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates. In one embodiment, the present invention relates to a method of imaging or diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; (c) Detecting the compound bound to the TDP-43 aggregates; and (d) Generating an image representative of the location and / or amount of the compound bound to the TDP-43 aggregates. In one embodiment, the present invention relates to a method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to 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 tissue of the subject. Preferably, the tissue is a tissue of the central nervous system (CNS), an eye tissue or a brain tissue. More preferably, the tissue is brain tissue. In one embodiment, the present invention relates to a method of imaging TDP-43 aggregates in a sample or a patient, the method comprises the steps: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates by imaging the sample, the specific body part or the body area with an imaging system. 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:(a) Bringing the in vitro sample suspected to contain TDP-43 aggregated into contact with acompound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein;(b) Allowing the compound to bind to the TDP-43 aggregates; and(c) Detecting the compound bound to the TDP-43 aggregates by imaging the in vitro sample withan imaging system. In one embodiment, the present invention relates to a method of imaging TDP-43 aggregates in a patient or a specific body part or a body area of a patient, the method comprising the steps:(a) Bringing a sample or a specific body part or body area suspected to contain TDP-43aggregates into contact with a compound of the invention,; or with diagnostic composition comprising a compound of the invention as disclosed herein;(b) Allowing the compound to bind to the TDP-43 aggregates; and(c) Detecting the compound bound to the TDP-43 aggregates by imaging the sample or thespecific body part or the body area of the patient with an imaging system. The step of imaging the sample, the patient, the specific body part or the body area of the patient with an imaging system includes detecting the compound of the invention bound to the TDP-43 aggregates using an imaging system as disclosed herein. Detecting the compound of the invention bound to the TDP-43 aggregates allows to identify by imaging the distribution of TDP-43 aggregates in the tested sample, the patient, the specific body part or body area. The PET imaging should be conducted when the compound has penetrated the tissue and the compound has bound to the TDP- 43 aggregates. Determining the amount of TDP-43 aggregates: In one embodiment, the present invention relates to a method of determining the amount of TDP-43 aggregates in a sample, a specific body part or body area suspected to contain TDP-43 aggregates using a compound of the invention. In one embodiment the present invention provides a method for determining the amount of TDP-43 aggregates in the sample, the specific body part or the body area suspected to contain TDP-43 aggregates, wherein the method comprises the steps of: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Determining the amount of compound of the invention bound to the TDP-43 aggregates; and (e) Optionally calculating the amount of TDP-43 aggregates in the sample, the specific body part or body area. A radioactive signal is observed when a detectably labelled compound of the invention, whichcomprises at least one radiolabeled atom (e.g. 3H, 2H, or 18F), is bound to the TDP-43 aggregates.Diagnosing: In one embodiment, the present invention relates to a method of 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: (a) Detecting the compound of the invention bound to the TDP-43 aggregates; and (b) Correlating the presence or absence of the compound of the invention bound to TDP-43 aggregates with the disease, disorder or abnormality associated with TDP-43 aggregates or with the TDP-43 proteinopathy. Preferably, the method of diagnosing the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy or a predisposition thereto comprises the steps of: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; and (d) Correlating the presence or absence of the compound of the invention bound to TDP-43 aggregates with the disease, disorder or abnormality associated with TDP-43 aggregates or with the TDP-43 proteinopathy. In one embodiment, the present invention relates to a method of collecting data for the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy or a predisposition thereto, the method comprising the following steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; and (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area. After the sample or a specific body part or body area has been brought into contact with the compound of the present invention, the compound is allowed to bind to the TDP-43 aggregates. Theamount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and canbe determined by a person skilled in the field by routine experiments. The compound which has bound to the TDP-43 aggregates can be subsequently detected by any appropriate method. The specific method chosen will depend on the detectable label which has been chosen. Examples of possible methods include, but are not limited to, a fluorescence imaging technique or a nuclear imaging technique such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). The fluorescence imaging technique and / or nuclear imaging technique can be employed for monitoring and / or visualizing the distribution of the detectably labelled compound within the sample or a specific body part or body area. 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 area; as mentioned herein above, comprises the steps of- determining the amount of the compound bound to the TDP-43 aggregates;- correlating the amount of the compound bound to the TDP-43 aggregates with the amount ofTDP-43 aggregates in the sample or specific body part or body area; and- optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. The amount of compound bound with the TDP-43 aggregates can be compared to a normal control value which has been determined in a sample or a specific body part or body area of a healthy subject, wherein an increase in the amount of the compound bound with the TDP-43 aggregates compared to a normal control value may indicate that the patient is suffering from or is at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates. If the amount of the compound bound with the TDP-43 aggregates is higher than the normal control value, as defined herein, then it can be expected that the patient is suffering from or is likely to suffer from a disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy. Determining a predisposition: A further aspect of the present invention relates to a method of collecting data for determining a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP- 43 proteinopathy. The method comprises the steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; and (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area. 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 area; as mentioned herein above, comprises the steps of- determining the amount of the compound bound to the TDP-43 aggregates;- correlating the amount of the compound bound to the TDP-43 aggregates with the amount ofTDP-43 aggregates in the sample or specific body part or body area; and- optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. If the amount of the compound bound to the TDP-43 aggregates is higher than a normal control value of a healthy / reference subject this indicates that the patient / subject is suffering from or is at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates. In particular, if the amount of the compound bound to the TDP-43 aggregates is higher than what expected in a person showing no clinical evidence of neurodegenerative disease, it can be assumed that the patient has a disposition to a disease, disorder or abnormality associated with TDP-43 aggregates or with a TDP-43 proteinopathy. Monitoring disease progression: In one embodiment, the present invention relates to a method of monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy in a patient. Typically, the patient is or has been undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or is or with TDP-43 proteinopathy. In particular, the treatment can involve administration of an anti-TDP-43 medicament. The method of collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or for monitoring the progression of a TDP-43 proteinopathy in a patient comprises the steps: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with the compound of the invention; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area; and (e) Optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time. In order to monitor the progression over time of the disease, disorder or abnormality associated with TDP-43 aggregates or the 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. 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 area; as mentioned herein above, comprises the steps of- Determining the amount of the compound bound to the TDP-43 aggregates;- Correlating the amount of the compound bound to the TDP-43 aggregates with the amount ofTDP-43 aggregates in the sample or specific body part or body area; and- Optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. In the method of monitoring progression over time the amount of the compound of the invention bound to the TDP-43 aggregates can be optionally compared at various points of time during the treatment, for instance, before and after onset of the treatment and / or at various points of time after the onset of the treatment. A change, especially a decrease, in the amount of the compound of the invention bound to the TDP-43 aggregates may indicate that the disease is not progressing. Predicting responsiveness: In one embodiment, the present invention relates to a method of predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates, or suffering from a TDP-43 proteinopathy to a treatment of said disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy. The method can be used to predict the treatment which is most suitable for the patient. In particular, the treatment can involve administration of an anti-TDP-43 medicament. The method for predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or suffering from a TDP-43 proteinopathy to a treatment of said disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy can comprise the steps of: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area; and (e) Optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time. Typically, the patient is / has been undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy. In particular, the treatment can involve administration of a medicament which is suitable for treating the disease, disorder or abnormality associated with TDP-43 aggregates. The present method allows to predict the responsiveness of a patient to a certain treatment. In one embodiment, the responsiveness can be estimated, e.g., by repeating steps (a) to (c) and, if present, optional step (d) and monitoring the amount of the compound of the invention bound with the TDP- 43 aggregates over a period of time during which the patient is undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or with TDP-43 proteinopathy. If the amount changes over time, the skilled practioner can deduce whether the patient is responsive to the treatment. Typically, if the amount of the compound of the invention bound with the TDP-43 aggregates decreases over time, it can be assumed that the patient is responsive to the treatment. Typically, if the amount of the compound bound with the TDP-43 aggregates is essentially constant or increases over time, it can be assumed that the patient is non-responsive to the treatment. Alternatively, the responsiveness can be estimated by determining the amount of the compound of the invention bound to the TDP-43 aggregates. The amount of the compound bound to the TDP-43 aggregates can be compared to a control value such as a normal control value, a preclinical control value or a clinical control value. The control value may refer to the control value of healthy control subjects. Alternatively, the control value may refer to the control value of subjects known to be responsive to a certain therapy, or to the control value may refer to the control value of subjects known to be non-responsive to a certain therapy. The outcome with respect to responsiveness can either be "responsive" to a certain therapy, "non-responsive" to a certain therapy or “response undetermined” to a certain therapy. Response to the therapy may be different for the respective patients. 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 area; as mentioned herein above, comprises the steps of- Determining the amount of the compound bound to the TDP-43 aggregates;- Correlating the amount of the compound bound to the TDP-43 aggregates with the amount ofTDP-43 aggregates in the sample or specific body part or body area; and- Optionally comparing the amount of the compound bound with the TDP-43 aggregates in thesample or specific body part or body area to a normal control value in a healthy control subject. The control value can be, e.g., a normal control value, a preclinical control value and / or a clinical control value. A “healthy control subject” or “healthy subject” is a person showing no clinical evidence of neurodegenerative disease. If in any of the above summarized methods the amount of the compound bound with the TDP-43 aggregates is higher than the normal control value, then it can be expected that the patient is suffering from or is likely to suffer from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. Any of the compounds of the present invention can be used in the above summarized methods. Preferably detectably labeled compounds of the present invention, as disclosed herein, are employed in the above summarized methods.In a fourth aspect, the present invention relates to the use of the compounds of the invention as aTDP-43 aggregates’ diagnostic agent or diagnostic tool. In one embodiment, the present inventionrelates to the use of the compounds of the invention as an in vitro analytical reference or an in vitroscreening tool. Said compounds of the invention are also useful in in vivo diagnostic methods. Insuch instances, the compounds of the invention may be detectably labeled compounds or contain cold isotopes. In another embodiment, the present invention further relates to the use of the compounds of the present invention, more specifically detectably labelled compounds of the invention as defined herein, as diagnostic biomarkers enabling more efficient and precise patient selection, e.g., for longitudinal monitoring in clinical studies, or for supporting the development of novel therapeutics for treating TDP-43 proteinopathies. In another embodiment, the present invention further relates to the use of the compounds of the present invention, more specifically detectably labelled compounds of the invention as defined herein, as a TDP-43 aggregates’ biomarker or a TDP-43 proteinopathy biomarker. In another embodiment, the compounds of the invention may be employed for research use, in particular, as an analytical tool or reference molecule. Said compounds may also be used in detectingTDP-43 aggregates in vitro or in vivo. The compounds of the invention may be used to stain TDP-43aggregates. For example, compounds of the invention may be used for histochemical detection in postmortem tissue such as brain tissue. The compounds of the invention are preferably detectably labelled compounds and may be directly or indirectly labelled as discussed herein. Kit of partsIn a fifth aspect, the present invention relates further to a kit for use in one or more of the methodsof the invention, wherein the kit comprises a compound of the invention as described herein. The kit typically comprises a container 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 detectably labelled compound (e.g. compound of formula (I-T), (I-T'), (I-F) or (I-F')). The term "kit" refers in general to any diagnostic kit known in the art. More specifically, the latter termrefers to a diagnostic kit as described in Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.The dose of the detectably labelled compounds of the present invention will vary depending on the exact compound to be administered, the weight of the patient, size and type of the sample, and other variables as would be apparent to a physician skilled in the art. Generally, the dose could preferably lie in the range 0.001 µg / kg to 10 µg / kg, preferably 0.01 µg / kg to 1.0 µg / kg. The radioactive dose can be, e.g., 100 to 600 MBq, more preferably 150 to 450 MBq. In particular, such kits may be useful for performing the methods of the invention (which include, for example, but not limited to, imaging, diagnosing, and monitoring methods), e.g., for diagnosing of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy. Such kits may comprise all necessary components for performing the herein provided methods. Typically, each component is stored separately in a single overall packaging. Suitable additional components for inclusion in the kits are, for example, buffers, detectable dyes, laboratory equipment, reaction containers, instructions and the like. Instructions for use may be tailored to the specific method for which the kit is to be employed. The present invention relates further to a kit for the preparation of a detectably labeled compound of the invention, wherein in particular the detectable label is a radioisotope. Thus, the kit comprises a precursor of the detectably labeled compound of the formula (I) and a labeling agent which reacts with the precursor to introduce a detectable (e.g., radioactive) label. Preferred precursors are compounds of the formulae (II), (III) and (IV). The labeling agent which reacts with the precursor canbe an agent which introduces a detectable (e.g., radioactive) label such as 18F or 3H. The labelingagent can be a 18F-fluorination agent.Method for preparing a compound of the invention In a sixth aspect, the present invention relates further to a method for preparing a compound of formula (I). Cold isotope compounds: In one embodiment, the present invention relates to a method for preparing a compound of formula (I), as described above, the method comprising the step of:Reacting a compound of formula (II) with R10 to provide a compound of formula (I) whereinn, R1, and R2 are as defined above; R10is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with – -(C1-C3alkyl)halo, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, wherein the 5- or 6-membered carbocyclic or heterocyclic ring is substituted with Br or I.In one embodiment, R10 is selected from the following groups: , wherein R5 is -CH2-CH2-halo, CH3 or H, preferably -CH2-CH2F; and wherein Hal is Bror I; preferably Br, or R3 is F, R4 is NH2, R7 is H, and R8 is H;R3 is NH2, R4 is F, R7 is H, and R8 is H,R3 is CN, R4 is NH2, R7 is H, and R8 is H,R3 is H, R4 is NH , R7 is H 82 , and R is CN,R3 is H, R4 is NH2, R7 is H, and R8 is F, orR3 is H, R4 is NH 7 82, R is H, and R is CN; or , orpreferably ,wherein Hal is Br or I; preferably Br; and wherein R9 is selected from H, F, NH2 or CH3.The method of reacting the compound having the formula (II) with R10 can be conducted by anysuitable method. In one option, the reaction can be conducted in the presence of a diamine chelator 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 conducted under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph)3]4or Pd sources such as Pd(OAc)2and XantPhos. Tritium (3H) detectably labeled compounds In one embodiment, the present invention provides a method for preparing the Tritium (3H) detectably labeled compounds of the invention having the formula (I-T) or (I-T'), said method comprises the step of radiolabeling a precursor of the compound having the formula (I-T) or (I-T') with a radioisotope, wherein at least one leaving group of the precursor of the compound having the formula (I-T) or (I-T') is replaced by Tritium (3H). Tritium (3H) detectably labeled compounds having the formula (I-T) or (I-T') preferably have at least 1 to 3 Hydrogen (H) which are each replaced by Tritium (3H). In another embodiment, the present invention provides a method for preparing a compound of formula (I-T) or (I-T'), said method comprises the step of:Radiolabeling a precursor compound having the formula (III) with T (i.e., 3H) by either exchange ofBr or I with T utilizing T2 and a suitable catalyst or introduction of a CT3-group or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, whereinZ and Z’ are independently selected from C-Br, C-I, and C-H, whereinn is 1 or 2;R1 is H, OH, –(C1-C3alkyl)OH, F or -COORA, wherein RA is (C1-C4)alkyl;R11is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with Br, I, F, NH2,CN –(C1-C3alkyl)halo and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S;and at least one of Z, Z’ and / or R11 comprises Br or I, preferably Br.In one embodiment, in formula (III), the at least one Br or I is replaced by T; orR11comprises a NH moiety; wherein the NH-moiety is replaced by N-CT3,and wherein T is 3H.In a preferred embodiment, Z’ is H and Z is C-Br or C-I, more preferably C-Br, and the Br or I isreplaced by T.In another embodiment Z is H and Z’ is C-Br or C-I, more preferably C-Br, and the Br or I is replacedby T.In another preferred embodiment, R11 comprises Br or I and the Br or I is replaced by T.In one preferred embodiment Z’ is H, Z is C-Br or C-I and the Br or I is replaced by T; and R11comprises Br or I and the Br or I is replaced by T.In another embodiment, the present invention provides a method for preparing a compound offormula (I-T) comprising radiolabeling a precursor compound having the formula (III) with T (i.e., 3H) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, wherein n is 1 or 2; R11is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with F, NH2,CN, –(C1-C3alkyl)halo and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, preferably N;R1 is -COORA, wherein RA is (C 11-C4)alkyl, wherein at least one of the hydrogen atoms in R isreplaced by T; preferably two of the hydrogen atoms in R1 are replaced by T;Z and Z’ are independently selected from C-Br, C-I, and C-H;T is 3H; and- at least one of Z, Z’ comprises Br or I, wherein the at least one Br or I is replaced by T; and / or- at least one of the hydrogen atoms in R1 is replaced by T; preferably two of the hydrogenatoms in R1 are replaced by T.The methods used for introducing a radioisotope such as 3H are well known in the art and includethe methods described below. In this scheme, the substituents Br, NH2, F and CN are just shown as an example. The definitions of formula (1-T) apply in this respect. A further example is shown in the following scheme: A further example is shown in the following scheme: means that the nitrogen atom can be present at any available position in the ring. A further preferred example is shown in the following scheme: A further example is shown in the following scheme: For the introduction of T (tritium), the 3H radiolabeling agent can be tritium gas. The method can beconducted in the presence of a catalyst such as palladium on carbon (Pd / C) or Lindlar’s catalyst, asolvent such as N,N-dimethylformamide (DMF) and a base such as N,N-diisopropylethylamine(DIEA). Alternatively, the 3H radiolabeling agent can be LiT, prepared from n-BuLi and tritium gas inthe presence of TMEDA, in the presence of AlCl3 and a solvent such as THF. For example a method for preparing a precursor compound of formula (III), as described above, may comprise the step of:Reacting a compound of formula (II) as defined above with R10 to provide a compound of formula (Ia)followed by either NBS bromination or acid cleavage of a trimethylsilylethoxymethyl (SEM)-protecting group. The following examples are given as an illustration:

[0002] whereinn and R1 are as defined above;R10is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –-(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, wherein the 5- or 6-membered carbocyclic or heterocyclic ring is substituted with Br or I and may be optionally substituted with SEM.In one embodiment, R10 is selected from the following groups: , wherein Hal is Br or I; andR3 is F, R4 is NH2, R7 is H, and R8 is H;R3 is NH2, R4 is F, R7 is H, and R8 is H,R3 is CN, R4 is NH 7 82, R is H, and R is H,R3 is H, R4 is NH , R7 is H, 82 and R is CN,R3 is H, R4 is NH 7 82, R is H, and R is F;R3 is H, R4 is NH 7 82, R is H, and R is CN; , wherein R9 is selected from H, F, NH2 or CH3, wherein Hal is Br if Cl is present orHal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; and , wherein Hal is Br if Cl is present or Hal is I if Br is present.The method of reacting the compound having the formula (II) with R10 can be conducted by anysuitable method. In one option, the reaction can be conducted in the presence of a diamine chelator 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 conducted under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph)3]4 or Pd(OAc)2, XantPhos. Fluorine (18F) detectably labeled compounds: In one embodiment, the present invention provides a method for preparing the Fluorine (18F) detectably labeled compounds of the invention, said method comprises radiolabeling a precursor having the formula (IV) with a radioisotope [18F]: whereinn is 1 or 2;R2is as defined for formula (I); and R14is a leaving group (LG), preferably MsO.In one embodiment R14 is replaced by 18F in the radiolabeling step.In one preferred embodiment, the present invention provides a method for preparing the fluorine (18F) detectably labeled compounds of the invention, said method comprises radiolabeling a precursor having the formula (IV) with a radioisotope [18F]: whereinn is 1 or 2;R1 is H, OH, –(C1-C3alkyl)OH, COORA, wherein RA is (C1-C4)alkyl, preferably R1 is OH or -CH2OH or-C(OOCH3); R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or moreheteroatoms selected from N, O and S, preferably R2 is , wherein R5 is –(C1-C3alkyl)halo, preferably -CH2CH2-F; wherein R9 is H; andR14is a leaving group (LG), preferably trimethyl ammonium or NO2.In one embodiment, R14 is replaced by 18F in the radiolabeling step.The fluorination can be conducted in the presence of a 18F-fluorination agent which can be selectedfrom K[18F], Cs18F, Na18F, Rb18F, Kryptofix

[0222] K18F, tetra(C1-6alkyl) ammonium salt of 18F, andtetrabutylammonium [18F]fluoride. Preferably, the Leaving Group (LG) is C1–4 alkyl sulfonate or C6–10 aryl sulfonate or nitro, preferably mesylate, tosylate, nosylate, trimethyl ammonium or nitro. Even more preferably, the Leaving Group (LG) is mesylate, trimethyl ammonium or nitro.Suitable solvents for the 18F-fluorination step are known to a skilled person. The solvent can be, forexample, selected from the group consisting of DMF, DMSO, acetonitrile, DMA, or mixtures thereof. Preferably, the solvent is acetonitrile or DMSO.For example, a method for preparing the Fluorine (18F) detectably labeled Compound 18 maycomprise a radiolabeling step in which the Leaving Group (LG), which in this case is mesylate, of theprecursor L1 is replaced with a Fluorine (18F) in the presence of the 18F-fluorinating agent, such asK[18F] or [18F]TBAF, as shown below: As a further example, a method for preparing the fluorine (18F) detectably labeled Compound 19 maycomprise a radiolabeling step in which the Leaving Group (LG), which in this case is nitro, of theprecursor 20 is replaced with a fluorine (18F) in the presence of the 18F-fluorinating agent, such asK[18F] or [18F]TBAF, as shown below: The compounds of the invention can be prepared by one of the general methods shown in the following schemes. These methods are only given for illustrative purposes and should not be construed as limiting. The precursor compounds having the formulae (II), (III), (IV), or (V) as defined above or the stereoisomer, the polymorph, the racemic mixture, the tautomer, the pharmaceutically acceptable salt, the hydrate, or the solvate thereof are part of the invention. Abbreviations Boc2O Di-tert.-butyldicarbonateCH3CN Acetonitrile CCl4Carbon tetrachloride Cs2CO3 Cesium carbonate CsF Cesium fluoride CuBr2Copper bromide CuCl Copper(I)-chloride CuI Copper iodideDCM DichloromethaneDIEA N,N-Diisopropyethyllamine DMA N,N-Dimethylacetamide DMAP DimethylaminopyridineDMEDA 1,2-Dimethylethylenediamine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide EtOH Ethanol dppf 1,1′-Ferrocenediyl-bis(diphenylphosphine)EtOAc Ethyl acetateh Hour HCl Hydrochloric acid K2CO3 Potassium carbonate LCMS Liquid chromatography–mass spectrometry n-BuOH n-BuOH NMR Nuclear magnetic resonance NBS N-Bromosuccinimide Pd(PPh3)4 Palladium tetrakistriphenylphosphine Pd(dppf)Cl2x CH2Cl21,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex Pd(OAc)2Palladium(II) acetateRCP Radiochemical purityRT, rt Room temperature (approx.25 °C) TBDMSCl Tert-butyldimethylsilylchlorideSEM TrimethylsilylethoxymethyltBuONO Tert-butyl nitriteTEA TriethylamineTFA Trifluoroacetic acidXantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0003] GENERAL SYNTHETIC SCHEMES: Synthetic scheme for the preparation of 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (Compound 1) Synthetic scheme for the preparation of 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-5-(pyrimidin-2-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (Compound 2) Synthetic scheme for the preparation of 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl) pyridin-3-yl)- 5-(pyridin-3-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (Compound 3) Synthetic scheme for the preparation of (R)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl) pyridin-3- yl)-5-(pyridin-3-yl)-4,5-dihydro -6H-pyrrolo[3,4-d]thiazol-6-one (Compound 4) Synthetic scheme for the preparation of (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl) pyridin-3- yl)-5-(pyridin-3-yl)-4,5-dihydro -6H-pyrrolo[3,4-d]thiazol-6-one (Compound 5) Synthetic scheme for the preparation of 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl) pyridin-3-yl)-5- (pyrimidin-2-yl)-4,5-dihydro -6H-pyrrolo[3,4-d]thiazol-6-one (Compound 6) Synthetic scheme for the preparation of 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-5-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one

[0004] Synthetic scheme for the preparation of 1-(6-fluoro-5-(6-oxo-5-(pyrimidin-2-yl)-5,6-dihydro-4H- pyrrolo[3,4-d] thiazol-2-yl)pyridin-2-yl)piperidine-4-carboxylate (Compound 8) Synthetic scheme for the preparation of (S)-2-(2-fluoro-6-(3-(hydroxymethyl)pyrrolidin-1- yl)pyridin-3-yl)-5-(pyrimidin-2-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (Compound 9) Although the reaction is shown above with respect to 18F as a radioactive label, other radioactivelabels can be introduced following similar procedures. The invention is illustrated by the following examples which, however, should not be construed as limiting. EXAMPLES All reagents and solvents were obtained from commercial sources and were used without further purification. Proton (1H) NMR spectra were recorded on a JEOL-400 MHz or JEOL 500 MHz NMR spectrometer. Mass spectra (MS) were recorded on an UPLC H-Class Plus with Photodiode Array detector and a QDa Mass spectrometer. Chromatography was performed using silica gel (Fluka: Silica gel 60, 0.063-0.2 mm) and suitable solvents as indicated in the specific examples. Flash purification was conducted with a Biotage Isolera One flash purification system using HP-Sil or KP- NH SNAP cartridges (Biotage) and the solvent gradient indicated in the specific examples. Thin layer chromatography (TLC) was carried out on silica gel plates with UV detection. Although some of the present examples do not indicate that the respective compounds were detectably labeled, it is understood that corresponding detectably labeled compounds are intended and can be easily prepared, e.g., by using detectably labeled starting materials, such as startingmaterials containing 3H, C(3H)3, (11C)H3 or 18F.Example 1 Synthesis (Example Compound 1) Step-1: methyl 2-amino-4-(hydroxymethyl) thiazole-5-carboxylate (B)To a stirred solution of (A) (5.0 g, 37.2 mmol) in dry methanol (50 mL, 10 vol) was added thiourea(3.1 g, 40.8 mmol). The mixture was allowed to heat to 70oC and was kept for 6 h until the reactants were consumed as monitored by TLC. After completion of the reaction, solvent was removed under vacuum and the mixture was cooled to 0oC. The mixture was treated with an aqueous saturated NaHCO3 (50 mL) solution to maintain a pH of 8 to 9. The crude reaction mass was filtered through a Büchner funnel. The obtained mass was washed with hexane (50 mL), and dried under vacuum toafford (B) as a white solid (3.4 g, 48%). MS (ESI): 189.05 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ7.78 (s, 2H), 4.88 (t, 1H), 4.56 (d, 2H), 3.69 (s, 3H). Step-2: methyl 2-amino-4-(((tert-butyldimethylsilyl) oxy) methyl) thiazole-5-carboxylate (C)Imidazole (2.4 g, 36.1 mmol) was added to a solution of (B) (3.4 g, 18.1 mmol) in DMF (34 mL, 10vol). The reaction mixture was cooled to 0oC and to this solution was added TBDMS chloride (3.26 g, 21.7 mmol). The mixture was allowed to come to rt and was stirred for 9 h until the reactants were consumed as monitored by TLC. After that the reaction mixture was quenched with ice cool water (50 mL). The crude reaction mass was filtered through a Büchner funnel. The obtained mass waswashed with hexane (40 mL), and dried under vacuum to get (C) as a white solid (4.4 g, 81%). MS(ESI): 303.40 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 7.80 (s, 2H), 4.78 (s, 2H), 3.69 (s, 3H), 0.86(s, 9H), 0.044 (s, 6H). Step-3: methyl 2-bromo-4-(((tert-butyldimethylsilyl) oxy) methyl) thiazole-5-carboxylate (D)To a stirred mixture of (C) (4.4 g, 14.6 mmol) and CuBr2 (4.8 g, 21.8 mmol) in acetonitrile (53 mL, 12vol.) was added tert-butyl nitrite (2.6 mL, 21.8 mmol) dropwise at 0oC under N2 atmosphere and the mixture was stirred at rt for 4 h. The reaction was monitored by TLC. After completion of the reaction, solvent was removed under vacuum and the mixture was cooled to 0oC. Mixture was treated with an aqueous saturated NaHCO3(50 mL) solution until the pH reached up to 8-9. The aqueous layer was extracted with EtOAc (60 mL X 3). Combined organic layers were dried over Na2SO4 and concentrated under vacuum. The obtained crude mass was purified by column chromatography overneutral alumina eluted in 5% EtOAc in hexane to furnish (D) as a colourless liquid (4.5 g, 84%). MS(ESI): 368.22 (M+2)+; 1H NMR (500 MHz, CDCl3) δ 5.06 (s, 2H), 3.88 (s, 3H), 0.92 (s, 9H), 0.12 (s,6H). Step-4: methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2,6-difluoropyridin-3-yl)thiazole- 5-carboxylate (E)In an oven-dried screw capped vial was added (D) (1.0 g, 2.7 mmol), boronic acid (863 mg, 5.5mmol), K3PO4 (1.1 g, 5.5 mmol), and 1,4-dioxane (50 mL, 50 vol) under an argon atmosphere. The reaction mixture was degassed with argon for 15 min. Pd(dppf)Cl2.DCM (222 mg, 0.27 mmol) was added and the mixture was heated to 100oC for 16 h. The reactants were consumed as monitored by TLC. The reaction mixture was quenched with ice-water and extracted in EtOAc (50 mL X 3). The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (230-400 mesh) and eluted in 5% EtOAc in hexane to get (E) as an off-white solid (900 mg, 85%). MS(ESI): 401.52 (M+H)+; 1H NMR (500 MHz, CDCl3) δ 8.92 (q, 1H), 7.01 (dd, 1H), 5.19 (s, 2H), 3.92(s, 3H), 0.95 (s, 9H), 0.15 (s, 6H). Step-5: methyl 2-(2,6-difluoropyridin-3-yl)-4-(hydroxymethyl)thiazole-5-carboxylate (F)To a stirred solution of (E) (900 mg, 2.2 mmol) in DCM (18 mL, 20 vol.) was added 4M HCl in 1,4-dioxane (9.0 mL, 10 vol) at 0oC under N2atmosphere and the mixture was stirred at rt for 4 h. The reaction time was monitored by TLC. After completion of the reaction, solvent was removed under vacuum and the mixture was cooled to 0oC. The mixture was treated with an aqueous saturated NaHCO3 (25 mL) solution until the pH reached up to 8-9. The obtained mass was filtered through aBüchner funnel, was washed with hexane (15 mL X 3), and was dried under vacuum to afford (F) asa white solid (600 mg, 93%). MS (ESI): 287.04 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 8.93 (dd,1H), 7.44 (dd, 1H), 5.36 (t, 1H), 4.88 (d, 2H), 3.87 (s, 3H). Step-6: methyl 2-(2,6-difluoropyridin-3-yl)-4-formylthiazole-5-carboxylate (G)To an ice cool solution of (F) (600 mg, 2.1 mmol) in DCM (12 mL, 20 vol.) was added DMP (1.7 g,4.2 mmol) portionwise at 0oC under N2atmosphere and the mixture was stirred at rt for 20 h. The reaction time was monitored by TLC. After completion, the reaction mixture was cooled to 0°C and sat. NaHCO3(20 mL) was added. The solvent was extracted with DCM (30 mL X 3). Combined organic layers were washed with cold brine solution (30 mL), dried over Na2SO4 and concentrated under vacuum. The obtained crude mass was purified by column chromatography over silica gel(230-400 mesh) and eluted in 20% EtOAc in hexane to afford (G) as a white solid (450 mg, 67%).MS (ESI): 285.06 (M+H)+, 1H NMR (500 MHz, CDCl3) δ 10.68 (s, 1H), 9.03 (q, 1H), 7.05 (dd, 1H),4.04 (s, 3H). Step-7: methyl 2-(2,6-difluoropyridin-3-yl)-4-((pyridin-3-ylamino)methyl)thiazole-5-carboxylate (H)To a solution of (G) (200 mg, 0.7 mmol) and pyridin-3-amine (133 mg, 1.4 mmol) in methanol (10 mL,50 vol) was added glacial AcOH (0.08 mL, 1.4 mmol) at rt under N2. The mixture was stirred for 4 hat 900 C on a preheated oil bath. 2-picoline-borane complex (Pic borane) (150 mg, 23.1 mmol) wasadded at 0°C and the mixture was allowed to stir at rt for another 18 h. Progress of the reaction was monitored by TLC. After completion, the solvent was evaporated under vacuum and water (25 mL) was added to the residue. The aqueous layer was extracted with EtOAc (30 mL x 3) and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The obtained crude mass was purified by column chromatography over silica gel (230-400 mesh) and eluted in 3% MeOH inDCM to afford (H) as a brownish solid (150 mg, 58%). MS (ESI): 363.41 [M+H]+; 1H NMR (400 MHz,DMSO-d6) δ 8.84 (dd, 1H), 8.10 (d, 1H), 7.78 (dd, 1H), 7.44 (dd, 1H), 7.09-7.04 (m, 2H), 6.44 (t, 1H), 4.74 (d, 2H), 3.92 (s, 3H). Step-8: methyl 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (I)In an oven-dried round bottom flask was added (H) (70 mg, 0.2 mmol), piperidin-4-ylmethanol (12)(23 mg, 0.2 mmol), DIPEA (0.07 mL, 0.38 mmol), and DMSO (7 mL, 100 vol) under an argonatmosphere. The mixture was allowed to stir at rt for 2 h. After completion, the reaction mixture was quenched with ice cold water (15 mL) and filtered through a Büchner funnel. The obtained mass was purified by column chromatography over silica gel (230-400 mesh) and eluted in 8% MeOH in DCMto afford (I) as a brownish solid (60 mg, 68%). MS (ESI) 458.65 [M+H]+; 1H NMR (400 MHz, DMSO- d6) δ 8.29 (dd, 1H), 8.09 (d, 1H), 7.77 (q, 1H), 7.08-7.03 (m, 2H), 6.91 (dd, 1H), 6.37 (t, 1H), 4.68 (d, 2H), 4.50 (d, 1H), 4.36 (d, 2H), 3.87 (s, 3H), 3.27 (q, 2H), 2.96 (t, 2H), 1.76-1.64 (m, 3H), 1.14-1.09 (m, 2H). Step-9: 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyridin-3-ylamino) methyl) thiazole-5-carboxylic acid (J)To a solution of (I) (55 mg, 0.12 mmol) in (THF: water) (4:2, 5 mL, 90 vol.) was added lithiumhydroxide (11 mg, 0.48 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with a saturated aqueous citric acid solution until the pH reached 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (5 mL X 3), and dried under highvacuum to afford (J) as a yellow solid (50 mg, 92%), LC-MS (ESI) 442.18 [M-H]+;Step-10: 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-4,5- dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (1)To a solution of (J) (50 mg, 0.11 mmol) in DMF (1.0 mL, 20 vol.) was added HATU (85 mg, 0.23mmol), followed by DIPEA (0.06 mL, 0.34 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 16 h. The reaction mixture was quenched with ice-cool water (15 mL) and the product was extracted with 5% MeOH in DCM (20 mL x 3). The organic layer was dried over Na2SO4and concentrated under vacuum. The residue was purified by chromatography over silica gel (230-400 mesh) and eluted in 5% MeOH in DCM to afford the title product (1) as a yellow solid (17 mg,35%). LC-MS (ESI) 426.47 (M+H)+ ; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.40-8.35 (m, 2H),8.26 (dq, 1H), 7.47 (dd, 1H), 6.96 (dd, 1H), 5.20 (d, 2H), 4.53 (t, 1H), 4.39 (d, 2H), 3.28 (t, 2H), 3.00 (t, 2H), 1.77 (d, 3H), 1.15-1.11 (m, 2H). Example 2 Synthesis (Example Compound 2) Step-1: methyl 2-(2,6-difluoropyridin-3-yl)-4-((pyrimidin-2-ylamino)methyl)thiazole-5- carboxylate (K)To a solution of (G) (400 mg, 0.7 mmol) and pyrimidin-2-amine (267 mg, 2.8 mmol) in methanol (20mL, 50 vol) was added glacial AcOH (0.16 mL, 2.8 mmol) at rt under N2. The mixture was stirred for 4 h at 80°C. Pic borane (300 mg, 2.8 mmol) was added at 0°C and the mixture was allowed to stir at rt for another 18 h. Progress of the reaction was monitored by TLC. After completion, the solvent was evaporated under vacuum and water (35 mL) was added to the residue. The aqueous layer was extracted with EtOAc (35 mL x 3) and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The obtained crude mass was purified by column chromatography oversilica gel (230-400 mesh) and eluted in 30% EtOAc in hexane to afford (K) as a brownish solid (350mg, 68%). MS (ESI): 364.45 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.74-8.68 (m, 1H), 8.25 (d,2H), 7.49 (t, 1H), 7.37 (dd, 1H), 6.56 (t, 1H), 4.90 (d, 2H), 3.85 (s, 3H). Step-2: methyl 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyrimidin- 2-yl amino) methyl)thiazole-5-carboxylate (L)In an oven-dried round bottom flask was added (K) (350 mg, 0.96 mmol), piperidin-4-ylmethanol (12)(110 mg, 0.96 mmol), DIPEA (0.58 mL, 3.3 mmol), and DMSO (35 mL, 100 vol) under an argonatmosphere. The mixture was allowed to stir at rt for 3 h. After completion, the reaction mixture was quenched with ice cold water (40 mL). The crude reaction mass was filtered through a Büchnerfunnel, washed with hexane (10 mL X 3), and dried under vacuum to afford (L) as a white solid (390mg, 88%). MS (ESI) 459.66 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, 2H), 8.19 (dd, 1H), 7.41(t, 1H), 6.88 (dd, 1H), 6.60 (t, 1H), 4.93-4.87 (m, 2H), 4.51 (t, 1H), 4.35 (d, 2H), 3.89-3.82 (m, 3H), 3.26 (t, 2H), 2.98-2.92 (m, 2H), 1.76-1.65 (m, 3H), 1.14-1.04 (m, 2H). Step-3: 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-4-((pyrimidin-2-yl amino) methyl) thiazole-5-carboxylic acid (M)To a solution of (L) (200 mg, 4.4 mmol) in (THF: water) (4:2, 6 mL, 30 vol.) was added lithiumhydroxide (40 mg, 1.7 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), and driedunder vacuum to afford (M) as a yellow solid (175 mg, 90%), MS (ESI) 445.47 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ 13.41 (s, 1H), 8.29 (d, 2H), 8.20 (t, 1H), 7.40 (s, 1H), 6.87 (dd, 1H), 6.60 (t, 1H), 4.86 (d, 2H), 4.50 (t, 1H), 4.34 (d, 2H), 3.26 (t, 2H), 2.94 (t, 2H), 1.75-1.67 (m, 3H), 1.10 (qd, 2H). Step-4: 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-5-(pyrimidin-2-yl)-4,5- dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (2)To a solution of (M) (100 mg, 0.22 mmol) in DMF (2 mL, 20 vol.) was added HATU (170 mg, 0.45mmol) followed by DIPEA (0.12 mL, 0.68 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 16 h. The reaction mixture was quenched with ice-cool water (20 mL) and the product was extracted with 5% MeOH in DCM (25 mL x 3). The organic layer was dried over Na2SO4and concentrated under vacuum. The residue was purified by chromatography over silica gel (230-400 mesh) and eluted in 2% MeOH in DCM to afford the title product (2) as a yellow solid (30 mg,31%). LC-MS (ESI) 427.42 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, 2H), 8.38 (dd, 1H), 7.26 (t, 1H), 6.95 (dd, 1H), 5.15 (s, 2H), 4.52 (t, 1H), 4.39 (d, 2H), 3.28 (t, 2H), 3.01-2.96 (m, 2H), 1.77 (d, 2H), 1.78-1.67 (m, 1H), 1.16-1.11 (m, 2H). Example 3 Synthesis (Example Compound 3) Step-1: methyl 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (N)In an oven-dried round bottom flask was added (H) (110 mg, 0.30 mmol), piperidin-4-ol (12) (30 mg,0.30 mmol), DIPEA (0.1 mL, 0.61 mmol), and DMSO (11 mL, 100 vol) under an argon atmosphere.The mixture was allowed to stir at rt for 3 h. After completion, the reaction mixture was quenched with ice cold water (25 mL). The crude reaction mass was filtered through Büchner funnel, washed withhexane (5 mL X 3), and dried under vacuum to afford (N) as a yellow solid (120 mg, 89%). MS (ESI)444.70 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.29 (dd, 1H), 8.09 (d, 1H), 7.77 (dd, 1H), 7.09-7.03(m, 2H), 6.93 (dd, 1H), 6.38 (t, 1H), 4.80 (d, 1H), 4.68 (d, 2H), 4.03-3.99 (m, 2H), 3.87 (s, 3H), 3.77 (td, 1H), 3.29 (t, 2H), 1.81-1.77 (m, 2H) 1.40-1.35 (m, 2H). Step-2: 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-4-((pyridin-3-ylamino)methyl) thiazole-5-carboxylic acid (O)To a solution of (N) (110 mg, 0.24 mmol) in (THF: water) (4:2, 10 mL, 90 vol.) was added lithiumhydroxide (22 mg, 0.99 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with a saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), and driedunder vacuum to afford (O) as a yellow solid (100 mg, 94%), MS (ESI) 430.35 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ 8.29 (dd, 1H), 8.09 (s, 1H), 7.76-7.75(m, 1H), 7.07-7.06 (m, 2H), 6.91 (dd, 1H), 6.40 (s, 1H), 4.78 (d, 1H), 4.67 (s, 2H), 4.01-3.98 (m, 2H), 3.76 (q, 1H), 3.47-3.42 (m, 2H), 1.80 (q, 2H), 1.40-1.35 (m, 2H). Step-3: 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro- 6H-pyrrolo[3,4-d]thiazol-6-one (3)To a solution of (O) (100 mg, 0.23 mmol) in DMF (2.0 mL, 20 vol) was added HATU (177 mg, 0.46mmol), followed by DIPEA (0.12 mL, 0.7 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 20 h. The reaction mixture was quenched with ice-cool water (20 mL). The crude reaction mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), and driedunder vacuum to afford (3) as a brown solid (50 mg, 57%), LC-MS (ESI) 412.2 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ 9.04 (d, 1H), 8.41-8.37 (m, 2H), 8.26 (d, 1H), 7.47 (q, 1H), 6.98 (d, 1H), 5.19 (s, 2H), 4.82 (d, 1H), 4.04 (d, 2H), 3.80-3.77 (m, 1H), 3.38-3.36 (m, 2H), 1.82 (dd, 2H), 1.43-1.23 (m, 2H). Example 4 Synthesis (Example Compound 4) Step-1: methyl (R)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (P)In an oven-dried round bottom flask was added (H) (110 mg, 0.30 mmol), (R)-pyrrolidin-3-ol (12) (26mg, 0.30 mmol), DIPEA (0.1 mL, 0.61 mmol), and DMSO (11 mL, 100 vol) under an argonatmosphere. The mixture was allowed to stir at rt for 2 h. After completion, the reaction mixture was quenched with ice cold water (25 mL). The crude reaction mass was filtered through a Büchner funneland washed with hexane (5 mL X 3), dried under vacuum to afford (P) as a yellow solid (118 mg,90%). MS (ESI) 430.98 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.32-8.27 (m, 1H), 8.10 (s, 1H), 7.79(s, 1H), 7.12-7.07 (m, 2H), 6.56 (d, 1H), 6.44 (t, 1H), 5.08 (s, 1H), 4.68 (d, 2H), 4.41 (s, 1H), 3.87 (s, 3H), 3.55-3.51 (m, 4H), 1.99 (d, 2H). Step-2: (R)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl) pyridin-3-yl)-4-((pyridin-3-ylamino) methyl) thiazole-5-carboxylic acid (Q)To a solution of (P) (118 mg, 0.27 mmol) in THF (10.6 mL, 90 vol) and water (3.5 mL, 30 vol) wasadded lithium hydroxide (26 mg, 1.1 mmol) at rt. The resulting mixture was stirred at rt for 6 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), anddried under vacuum to afford (Q) as a yellow solid (90 mg, 94%). MS (ESI) 416.27 [M+H]+; 1H NMR(400 MHz, DMSO-d6) δ 8.30 (t, 1H), 8.10 (s, 1H), 7.76 (t, 1H), 7.07 (d, 2H), 6.55 (d, 1H), 6.38 (s, 1H), 5.07 (s, 1H), 4.67 (s, 2H), 4.41 (s, 1H), 3.54-3.45 (m, 4H), 1.98 (d, 2H). Step-3: (R)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro- 6H-pyrrolo[3,4-d]thiazol-6-one (4)To a solution of (Q) (90 mg, 0.22 mmol) in DMF (1.8 mL, 20 vol) was added HATU (165 mg, 0.43mmol) followed by DIPEA (0.1 mL, 0.65 mmol) at 0oC. The resulting mixture was stirred at rt under N2atmosphere for 24 h. The reaction mixture was quenched with ice-cool water (20 mL). The crude reaction mass was filtered through a Büchner funnel. The obtained mass purified by columnchromatography over silica gel (230-400 mesh) eluted in 5% MeOH in DCM to afford (4) as abrownish solid (50 mg, 58%). LC-MS (ESI) 398.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.41-8.36 (m, 2H), 8.26 (dq, 1H), 7.47 (q, 1H), 6.61 (d, 1H), 5.18 (s, 2H), 5.09 (d, 1H), 4.42 (s, 1H), 3.57-3.54 (m, 4H), 2.05-1.94 (m, 2H). Example 5 Synthesis (Example Compound 5) Step-1: methyl (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (R)In an oven-dried round bottom flask was added (H) (110 mg, 0.30 mmol), (S)-pyrrolidin-3-ol (12) (26mg, 0.30 mmol), DIPEA (0.1 mL, 0.61 mmol), and DMSO (11 mL, 100 vol) under an argonatmosphere. The mixture was allowed to stir at rt for 2 h. After completion, the reaction mixture was quenched with ice cold water (25 mL). The crude reaction mass was filtered through a Büchnerfunnel,washed with hexane (5 mL X 3),and dried under vacuum to afford (R) as a yellow solid (120mg, 92%). MS (ESI) 430.77 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.30 (t, 1H), 8.10 (d, 1H), 7.77(q, 1H), 7.07 (m, 2H), 6.55 (d, 1H), 6.38 (t, 1H), 5.07 (d, 1H), 4.67 (d, 2H), 4.41 (s, 1H), 3.89 (m, 3H), 3.53 (dd, 4H), 1.98 (d, 2H). Step-2: (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylic acid (S)To a solution of (R) (120 mg, 0.27 mmol) in THF (10.8 mL, 90 vol) and water (3.6 mL, 30 vol) wasadded lithium hydroxide (26 mg, 1.2 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), anddried under vacuum to afford (S) as a yellow solid (80 mg, 68%). MS (ESI) 416.27 [M+H]+; 1H NMR(400 MHz, DMSO-d6) δ 8.30 (t, 1H), 8.09 (s, 1H), 7.76 (t, 1H), 7.07 (t, 2H), 6.55 (d, 1H), 5.06 (s, 1H), 4.67 (s, 2H), 4.40 (s, 1H), 3.52 (dd, 4H), 1.98 (d, 2H). Step-3: (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl) pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro- 6H-pyrrolo[3,4-d]thiazol-6-one (5)To a solution of (S) (80 mg, 0.19 mmol) in DMF (1.6 mL, 20 vol) was added HATU (146 mg, 0.38mmol) followed by DIPEA (0.10 mL, 0.58 mmol) at 0oC. The resulting mixture was stirred at rt under N2atmosphere for 20 h. Then the reaction mixture was quenched with ice-cool water (20 mL). The crude reaction mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), anddried under vacuum to afford (5) as a brown solid (55 mg, 72%). LC-MS (ESI) 398.3 [M+H]+; 1H NMR(400 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.41-8.36 (m, 2H), 8.26 (d, 1H), 7.47 (q, 1H), 6.61 (d, 1H), 5.18 (s, 2H), 5.09 (s, 1H), 4.43 (s, 1H), 3.55-3.50 (m, 3H), 3.39-3.36 (m, 1H), 2.00 (d, 2H). Example 6 Synthesis (Example Compound 6) Step-1: methyl 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl pyridin-3-yl)-4-((pyrimidin-2- ylamino)methyl)thiazole-5-carboxylate (T)In an oven-dried round bottom flask was added (K) (110 mg, 0.3 mmol), piperidin-4-ol (12) (30 mg,0.3 mmol), DIPEA (0.1 mL, 0.6 mmol), and DMSO (11 mL, 100 vol) under an argon atmosphere. Themixture was allowed to stir at rt for 4 h. After completion, the reaction mixture was quenched with ice cold water (25 mL). The crude reaction mass was filtered through a Büchner funnel, washed withhexane (10 mL X 3), and dried under vacuum to afford (T) as a yellow solid (120 mg, 89%). MS (ESI)445.66 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, 2H), 8.19 (dd, 1H), 7.40 (t, 1H), 6.90 (dd,1H), 6.60 (t, 1H), 4.88 (d, 2H), 4.79 (d, 1H), 3.99 (q, 2H), 3.85 (s, 3H), 3.77 (td, 1H), 3.31-3.28 (m, 2H), 1.79 (m, 2H), 1.80-1.77 (qd, 2H). Step-2: 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-4-((pyrimidin-2- ylamino)methyl)thiazole-5-carboxylic acid (U)To a solution of (T) (120 mg, 0.27 mmol) in (THF: water) (4:2, 11 mL, 90 vol.) was added lithiumhydroxide (25 mg, 1.1 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (5 mL X 3), and driedunder vacuum to afford (U) as a yellow solid (100 mg, 86%). MS (ESI) 431.36 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ 13.49 (s, 1H), 8.28 (d, 2H), 8.21 (t, 1H), 7.51 (s, 1H), 6.88 (d, 1H), 6.59 (t, 1H), 4.86 (s, 2H), 4.78 (s, 1H), 3.99 (d, 2H), 3.76 (s, 1H), 3.28 (d, 2H), 1.79 (d, 2H), 1.39-1.34 (m, 2H). Step-3: 2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-5-(pyrimidin-2-yl)-4,5- dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (6)To a solution of (U) (120 mg, 0.28 mmol) in DMF (2.4 mL, 20 vol.) was added HATU (212 mg, 0.56mmol) followed by DIPEA (0.14 mL, 0.84 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 20 h. The reaction mixture was quenched with ice-cool water (25 mL), filteredthrough a Büchner funnel, washed with hexane (5 mL X 3), and dried under vacuum to afford (6) asa yellow solid (58 mg, 60%). LC-MS (ESI) 413.39 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d,2H), 8.39 (t, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 5.16 (s, 2H), 4.81 (d, 1H), 4.03 (dd, 2H), 3.79 (td, 1H), 3.80-3.77 (m, 2H), 1.82 (t, 2H), 1.40 (tt, 2H). Example 7 Synthesis (Example Compound 7) Step-1: methyl 2-(2,6-difluoropyridin-3-yl)-4-(((1-(2-fluoroethyl)-1H-pyrazol-4- yl)amino)methyl) thiazole-5-carboxylate (V)To a solution of (G) (500 mg, 1.7 mmol) and 1-(2-fluoroethyl)-1H-pyrazol-4-amine (454mg, 3.5 mmol)in methanol (25 mL, 50 vol) was added glacial AcOH (0.2 mL, 3.5 mmol) at rt under N2. Then the mixture was stirred for 4 h at 80°C. Pic borane (373 mg, 3.5 mmol) was added at 0°C and the mixture was allowed to stir at rt for another 18 h. Progress of the reaction was monitored by TLC. After completion, the solvent was evaporated under vacuum and water (40 mL) was added to the residue. The aqueous layer was extracted with DCM (40 mL x 3) and the combined organic layers were dried over Na2SO4and concentrated under vacuum. The obtained crude mass was purified by columnchromatography over silica gel (230-400 mesh) and eluted in 2% MeOH in DCM to afford (V) as abrownish solid (350 mg, 50%). MS (ESI): 398.73 [M+H]+; 1H NMR (500 MHz; DMSO-d6) δ 8.96 (dd,1H), 7.45 (dd, 1H), 7.21 (s, 1H), 7.09 (d, 1H), 5.07 (s, 1H), 4.74 (m, 1H), 4.60 (t, 1H), 4.50 (s, 2H), 4.28 (t, 1H), 4.21 (t, 1H), 3.89 (s, 3H). Step-2: methyl 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-4-(((1-(2-fluoro ethyl) -1H-pyrazol-4-yl) amino) methyl) thiazole-5-carboxylate (W)In an oven-dried round bottom flask was added (V) (100 mg, 0.25 mmol), piperidin-4-ylmethanol(12) (29 mg, 0.25 mmol), DIPEA (0.09 mL, 0.5 mmol), and DMSO (10 mL, 100 vol) under an argonatmosphere. The mixture was allowed to stir at rt for 4 h. After completion, the reaction mixture was quenched with ice cold water (25 mL). The crude reaction mass was filtered through a Büchnerfunnel, washed with hexane (5 mL X 3), and dried under vacuum to afford (W) as a white solid (120mg, 95%). LCMS: 491.43 [M-H]+. Step-3: 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-(((1-(2-fluoroethyl)-1H- pyrazol-4-yl)amino)methyl)thiazole-5-carboxylic acid (X)To a solution of (W) (120 mg, 0.24 mmol) in THF (10.8 mL, 90 vol) and water (3.6 mL, 30 vol) wasadded lithium hydroxide (24 mg, 0.97 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), anddried under vacuum to afford (X) as a yellow solid (110 mg, 96%). MS (ESI): 479.4 [M+H]+; 1H NMR(500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.37 (t, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 6.90 (d, 1H), 4.73 (t, 1H), 4.61 (t, 1H), 4.52 (s, 1H), 4.43 (s, 2H), 4.36 (d, 2H), 4.29 (t, 1H), 4.22 (t, 1H), 3.27 (s, 2H), 2.96 (t, 2H), 1.75-1.71 (m, 3H), 1.11 (q, 2H), Step-4: 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-5-(1-(2-fluoroethyl)- 1H-pyrazol-4-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (7)To a solution of (X) (110 mg, 0.23 mmol) in DMF (2.2 mL, 20 vol.) was added HATU (174 mg, 0.46mmol) followed by DIPEA (0.12 mL, 0.69 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 16 h. After completion as monitored by TLC, the reaction mixture was quenched with ice-cool water (20 mL) and the product was extracted with 5% MeOH in DCM (25 mL x 3). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography over silica gel (230-400 mesh) and eluted in 2% MeOH in DCM to afford the titleproduct (7) as a yellow solid (20 mg, 20%). LCMS: 461.25 (M+H)+ ; 1H NMR (500 MHz, DMSO-d6) δ8.38-8.31 (m, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 6.96-6.93 (m, 1H), 4.96 (s, 2H), 4.83 (t, 1H), 4.71 (t, 1H), 4.52-4.49 (m, 2H), 4.42-4.37 (m, 3H), 3.28 (t, 2H), 3.01-2.95 (m, 2H), 1.76 (d, 3H), 1.16-1.07 (m, 2H). Example 8 Synthesis (Example Compound 8) Step-1: 2-(6-(4-carboxypiperidin-1-yl)-2-fluoropyridin-3-yl)-4-((pyrimidin-2- ylamino)methyl)thiazole-5-carboxylic acid (Y)To a solution of (K) (350 mg, 0.72 mmol) in THF (32 mL, 90 vol) and water (10.5 mL, 30 vol) wasadded lithium hydroxide (68 mg, 2.9 mmol) at rt. The resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0oC and treated with saturated aqueous citric acid solution until the pH reached up to 3-4. The obtained mass was filtered through a Büchner funnel, washed with hexane (10 mL X 3), anddried under vacuum to afford (Y) as a yellow solid (300 mg, 90%). MS (ESI) 459.52 (M+H)+ ; 1H NMR(400 MHz, DMSO-d6) δ 13.47 (s, 2H), 12.31 (s, 1H), 8.29 (d, 2H), 8.22 (dd, 1H), 7.45 (s, 1H), 6.90 (dd, 1H), 6.60 (t, 1H), 4.86 (d, 2H), 4.22 (d, 2H), 3.14-.3.08 (m, 2H), 1.92-1.88 (m, 2H), 1.55-1.50 (m, 2H). Step-2: 1-(6-fluoro-5-(6-oxo-5-(pyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2- yl)pyridin-2-yl)piperidine-4-carboxylic acid (Z)To a solution of (Y) (200 mg, 0.44 mmol) in DMF (4 mL, 20 vol.) was added HATU (330 mg, 8.7mmol) followed by DIPEA (0.2 mL, 1.3 mmol) at 0oC. The resulting mixture was stirred at rt under N2 atmosphere for 24 h. After completion as monitored by TLC, the reaction mixture was quenched with ice-cool water (30 mL). The obtained mass was filtered through a Büchner funnel, washed withhexane (10 mL X 3), and dried under vacuum to afford (Z) as a yellow solid (100 mg, 52%). MS (ESI)441.29 (M+H)+. Step-3: methyl 1-(6-fluoro-5-(6-oxo-5-(pyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2- yl)pyridin-2-yl)piperidine-4-carboxylate (8)To a solution of (Z) (80 mg, 0.18 mmol) in MeOH (2 mL, 20 vol.) was added H2SO4 (0.001 mL,0.018mmol) at 0oC. The resulting mixture was stirred at rt under N2atmosphere for 16 h. After completion as monitored by TLC, solvent was removed under vacuum. The reaction mixture was quenched with ice-cool water (10 mL) and the product was extracted with 5% MeOH in DCM (15 mL x 3). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography over silica gel (230-400 mesh) and eluted in 2% MeOH in DCM to affordthe title product (8) as a yellow solid (12 mg, 13%). LCMS: 455.51(M+H)+ ; 1H NMR (500 MHz,DMSO-d6) δ 8.76 (d, 2H), 8.41 (t, 1H), 7.26 (t, 1H), 6.97 (d, 1H), 5.16 (s, 2H), 4.28 (d, 2H), 3.63 (s, 3H), 3.19-3.14 (m, 2H), 2.76-2.70 (m, 1H), 1.95 (d, 2H), 1.60-1.53 (m, 2H), 1.69 (d, 2H). Example 9 Synthesis (Example Compound 9) Step-1: Synthesis of ethyl (S)-2-(2-fluoro-6-(3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-3-yl)-4- ((pyrimidin-2-ylamino)methyl)thiazole-5-carboxylate (AA)Title compound (K) (0.2 g, 5.3 mmol), (S)-pyrrolidin-3-ylmethanol (0.053 g, 5.3 mmol) and N,N-diisopropylethylamine (0.1 mL, 11.6 mmol) were dissolved in DMSO (6 mL) with stirring at RT for 2h. The reaction mixture was quenched with ice-cold water (60 mL) and extracted with 10% methanol in DCM (2 x 30mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product obtained was purified by silica gel (100-200) chromatography using a methanol in DCM gradient (0.5 / 99.5 -> 1 / 99)to afford the title compound (AA) as a pale-yellow solid (0.17 g, 70%). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (dd, 1H), 8.31 (dd, 2H), 6.56-6.53 (m, 1H), 6.29 (dd, 2H),5.03-4.99 (m, 2H), 4.40-4.37 (m, 2H), 3.71-3.61 (m, 4H), 3.59-3.49 (m, 1H), 3.38-3.35 (m, 1H), 3.10 (q, 2H), 2.66-2.54 (m, 1H), 2.22- 2.14 (m, 1H), 1.89 (dd, 1H), 1.41 (td, 2H). LCMS (ESI) 459.5 m / z [M+H]+. Step-2: Synthesis of ethyl (S)-2-(6-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-1-yl)-2- fluoropyridin-3-yl)-4-((pyrimidin-2-ylamino)methyl)thiazole-5-carboxylate (AB)Title compound (AA) (0.05 g, 1.09 mmol), 4-dimethylaminopyridine (0.002 g, 0.02 mmol) andimidazole (0.07 g, 10.09 mmol) were dissolved in DMF (3 mL). The reaction mixture was cooled to 0°C, followed by portionwise addition of TBDMS-Cl (0.08 g, 5.4 mmol) with stirring and continued stirring at RT for 2h. The reaction mixture was quenched with ice-cold water (30 mL), and extracted with 10% methanol in DCM (2 x 30mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product obtained was purified by basic silica gel (100-200) chromatography using a methanol in DCMgradient (0.5 / 99.5 -> 1 / 99-> 2 / 98) to afford (AB) as a yellow solid (0.03 g, 50%).1H NMR (400 MHz,DMSO-d6): δ 8.29 (d, 2H), 8.17-8.21 (m, 1H), 7.39 (t, 1H), 6.60 (t, 1H), 6.52 (dd, 1H), 4.88 (d, 2H), 4.31 (q, 2H), 3.55-3.62 (m, 4H), 3.47-3.43 (m, 1H), 3.25-3.23 (m, 1H), 2.05-2.03 (m, 1H), 1.79-1.78 (m, 1H), 1.31(t, 4H), 0.86(s, 9H), 0.037 (d, 6H). LCMS (ESI) 573.7 m / z [M+H]+. Step-3: Synthesis of (S)-2-(6-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-1-yl)-2- fluoropyridin-3-yl)-4-((pyrimidin-2-ylamino)methyl)thiazole-5-carboxylic acid (AC)A solution of (AB) (0.12 g, 2.0 mmol) in THF:MeOH:H2O (4:4:2, 10mL) was cooled to 0°C with stirring.LiOH (0.017 g, 4.0 mmol) was added with continued stirring at RT for 2h. The reaction mixture was concentrated under reduced pressure. The residue obtained was cooled to 0°C, acidified with saturated citric acid solution, the white solid was filtered and dried under reduced pressure to afford(AC) as a brown solid (0.08 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 13.45 (s, 1H), 9.24 (s, 1H),8.29 (d, 2H), 8.21 (t, 1H), 7.35 (s, 1H), 6.60 (t, 1H), 6.51 (dd, 1H), 4.87 (d, 2H), 3.63-3.54 (m, 4H), 3.07 (t, 2H), 2.05 (s, 1H), 1.78 (s, 1H), 0.86(s, 9H), 0.038 (d, 6H). LCMS (ESI) 545.6 m / z [M+H]+. Step-4: Synthesis of (S)-2-(6-(3-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-1-yl)-2- fluoropyridin-3-yl)-5-(pyrimidin-2-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (AD)Title compound (AC) (0.43 g, 7.9 mmol) was dissolved in DMF (20 mL) and cooled 0°C with stirring.N,N-diisopropylethylamine (0.26 mL, 15.8 mmol) and HATU were added to above reaction mixture and stirring was continued at RT for 16h. After completion, the reaction mixture was quenched with ice-cold water (200 mL), and extracted with 10% methanol in DCM (2 x 100mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product obtained was purified by basic silica gel (100-200)chromatography using a methanol in DCM gradient (0.5 / 99.5 -> 1 / 99-> 2 / 98) to afford (AD) as ayellow solid (0.25 g, 65%). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.76 (d, 2H), 8.40 (t, 1H),7.26 (t, 1H), 6.58 (dd, 1H), 5.15 (s, 2H), 3.63 (qd, 4H), 3.48 (t, 2H), 2.07 (s, 1H), 1.18 (s, 1H), 0.87 (s, 9H), 0.049 (d, 6H). LCMS (ESI) 527.9 m / z [M+H]+. Step-5: Synthesis of (S)-2-(2-fluoro-6-(3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-3-yl)-5- (pyrimidin-2-yl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (9)Title compound (AD) (0.03 g, 5.7 mmol) was dissolved in THF (6 mL) and cooled to 0 °C in an icebath with stirring. TFA (0.9 mL, 30 vol) was added and stirring was continued at 50°C for 24 h. After completion of the reaction, the solvent was removed under reduced pressure. The residue obtained was dissolved in ice cold water (5 mL) and basified with aqueous saturated sodium bicarbonate solution to pH 8-9. Further extraction with 10% methanol in DCM (2 x 30mL) followed. The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude product obtained was purified by silica gel (100-200)chromatography using a methanol in DCM gradient (0.5 / 99.5 -> 1 / 99) to afford (9) as a pale-yellowsolid (0.014 g, 60%). 1H NMR (500 MHz, DMSO-d6): δ 8.76 (d, 2H), 8.40 (t, 1H), 7.26 (t, 1H), 6.59(dd, 1H), 5.16 (s, 2H), 4.77 (s, 1H), 3.49-3.38 (m, 6H), 3.28 (s, 1H), 2.07 (s, 1H), 1.80 (s, 1H). LCMS (ESI) 413.4 m / z [M+H]+. BIOLOGICAL ASSAY DESCRIPTION 1. General methods Human brain material for these studies was obtained from Prof. William Seeley at the Neurodegenerative Disease Brain Bank UCSF (funding support from NIH grants P01AG019724 and P50AG023501, the Consortium for Frontotemporal Dementia Research, and the Tau Consortium), and also from the Netherland Brain Bank. All material has been collected from donors from whom a written informed consent for brain autopsy and the use of the material and clinical information for research purposes has been obtained by the brain bank. 1.1 Radioligands [3H]-Reference Compounds 1 and 2 (which are the compound described as [3H]-Compound 16 in WO2023 / 285661 and [3H]-Compound 21 in WO2024 / 068948) having a specific activity of 72.5 Ci / mmol (1.0 mCi / mL) and 55.4 Ci / mmol (1.0 mCi / mL) respectively, were used in the assays below. 1.2. Preparation of human frontotemporal dementia (FTD) sarkosyl-insoluble brain extractsHuman brain extracts were prepared as described in Laferriere et al., 2019, Nature Neurosc. Asample of brain tissue (frontal or temporal cortex) was homogenized at 1:4 (w / v) ratio in the homogenization-solubilization (HS) buffer at 4°C using tissue homogenizer (Precellys) with CKmix homogenization tubes. The following sequence was used for homogenization: 3 cycles of 30 seconds at 5000 rpm (with 15 seconds pause between each cycle). Homogenized samples were aliquoted and stored at -80°C in 1.5 mL low protein binding tubes. Brain homogenates were thawed on ice and resuspended in HS buffer to obtain a final concentration of 2% sarkosyl, 1 unit / µL Benzonase and 1 mM MgCl2. The samples were then incubated at 37°C under constant shaking at 600 rpm on a thermomixer for 45 minutes (min). The supernatants were collected in a new tube (sarkosyl-soluble fraction, S1). The pellet was resuspended in 1000 µL of myelin floatation buffer and centrifuged at 20,000 g for 60 min at 4°C. The supernatant was carefully removed to remove all the floating lipids. This step was repeated if all the lipids could not be removed in a single step. The pellet was subsequently washed with Phosphate-Buffered Saline (PBS) and centrifuged for 30 min at 20,000g at 4°C. The final pellet was resuspended in 200 µL PBS and stored at -80°C (sarkosyl-insoluble fraction). The samples were analyzed by immunoblotting in denaturing conditions. 2. Biological assays description and corresponding results 2.1. Micro-radiobinding competition assay for the determination of binding affinity to TPD-43 Human FTD sarkosyl-insoluble brain extracts were spotted onto microarray slides. The slides were incubated with [3H]-Reference Compounds 1 and 2 at 40 and 20 nM, respectively and the example compounds (non-radiolabeled) at 1 µM and 100n M. In some cases, the non-radiolabeled example compounds were further assessed for a range of different concentrations, varying from 0.24 nM to 2 µM for determination of the inhibition constant (Ki). After incubation, slides were washed and scanned by a real-time autoradiography system (BeaQuant, ai4R). Quantification of the signal was performed by using the Beamage image analysis software (ai4R). Non-specific signal was determined with an excess of non-radiolabeled reference compound (2µM) and specific binding was calculated by subtracting the non-specific signal from the total signal. Competition was calculated as percent, where 0% was defined as the specific binding in the presence of vehicle and 100% as the values obtained in the presence of excess of the non-radiolabeled reference compound. Ki values were calculated in GraphPad Prism8 by applying a nonlinear regression curve fit using a one site, specific binding model. Measurements were performed with at least two technical replicates in the two- concentration competition experiment and with one technical replicate in the experiments including a range of concentrations. For compounds tested in more than one experiment, the mean of the replicates or Ki values in independent experiments is reported. Results: Example compounds were assessed for their potency to compete with the binding of [3H]- reference ligand to FTD patient brain-derived TDP-43 aggregates. Results of the micro-radiobinding competition assay for the example compounds are shown in Table 5 below as: % competition at 1 µM and 100 nM. Ki values are also shown in Table 5. Table 5 Example Product Human brainHuman Human derived TDP- brain brain 43 aggregates derived derived TDP-43 TDP-43 aggregates aggregates Mean % Mean % Ki [nM] competition competition at 1 μM at 100 nM 1621 641 1512 661 931 1116 852 862 1629 972 572 n.d.aan.d.: not determined;1screening against reference compound 1;2screening against reference compound 2 2.5 Selectivity for TDP-43 2.5.1 Radiobinding assay on Alzheimer’s disease (AD) brain homogenates 2.5.1.1 Preparation of human AD insoluble fraction of brain homogenates The procedure used was adapted from Bagchi et al., 2013, describing extraction of homogenizedinsoluble fraction containing protein aggregates from human brain tissue for in vitro binding andcompetition studies. Approximately 4 g of frozen tissue block from frontal cortex brain region was used from an AD donor with confirmed burden of Tau and Abeta aggregates. The tissue was homogenized in high salt buffer (50 mM Tris-HCl pH 7.5, 750 mM NaCl, 5mM EDTA) supplemented with protease inhibitors (Complete; Roche 11697498001) at 4 °C with a glass Dounce homogenizer. The homogenate was transferred into polycarbonate centrifuge bottles (16 x 76 mm; Beckman 355603) and centrifuged at 100,000 x g (38,000 RPM) in an ultracentrifuge (Beckman, XL100K) for 60 minutes at 4 °C using a pre-cooled 70.1 rotor (Beckman, 342184). Pellets were resuspended in high salt buffer supplemented with 1 % Triton X-100 and homogenized at 4 °C with a syringe. The homogenates were centrifuged again at 100,000 x g (38,000 RPM, 70.1 rotor) for 60 minutes at 4°C. Pellets were resuspended in high salt buffer supplemented with 1% Triton X-100 and 1 M sucrose and homogenized at 4°C with a syringe. The homogenates were centrifuged at 100,000 x g (38,000 RPM, 70.1 rotor) for 60 minutes at 4°C. The resulting pellets containing insoluble fraction were resuspended in PBS, aliquoted and stored at -80°C until use. 2.5.1.2 Radiobinding competition assay using Abeta reference compound for determination of inhibitor constant (Ki) on AD insoluble fraction of brain homogenates Fixed concentration of AD insoluble fraction was incubated with fixed concentration of radiolabeled Abeta reference compound (Kd = 20 nM on AD brain homogenate) and increasing concentrations of a non-radiolabeled compound ranging from 0.41 nM to 2 µM. The reaction was performed in assay buffer (50 mM Tris pH 7.5 in 0.9 % NaCl, 0.1 % BSA) and incubated for two hours at room temperature (RT). Samples in duplicate were then filtered under vacuum in GF / C filter plates (PerkinElmer) to trap the aggregates with the bound radioligand and washed with 100 μL ice-cold 50 mM Tris pH 7.5. The GF / C filters were then dried and scintillation liquid (UltimateGold, PerkinElmer, 6013151) was added in each well. The filters were analyzed on a Microbeta2 scintillation counter (PerkinElmer). Values for the maximal signal were obtained in the absence of non-radiolabeled compound, while 100 % displacement was obtained using 1 μM of non-radiolabeled reference compound. Ki values were calculated by nonlinear regression, using a one site - fit Ki model in Prism V7 (GraphPad). Average Ki for the non-radiolabeled Abeta reference compound is 22 nM. Results: Example compounds were assessed for selectivity to TDP-43 over Abeta. To evaluate selectivity over Abeta, the inhibitor constant (Ki) values were measured on AD brain homogenates against a [3H]Abeta reference compound ([3H]Abeta ref) (Table 7). As seen from the high Ki values in Table 7, compounds of the invention show good selectivity for TDP-43 over Abeta. Table 7 Example Ki (nM) on AD brainhomogenates1 >10002 >10006 472

Claims

New PCT application AC Immune SA Ref.: 24M432 PCT Vossius Ref.: AJ1705 PCT CLAIMS 1. A compound having the formula (I)or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein nis 1 or 2;R1is H, OH, –(C1-C3alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl, -COORA, wherein RA is (C1-C4)alkyl, or F;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2,CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.

2. A compound having the formula (Ia), (Ib) or (Ic)or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein R1 and R2 are asdefined in claim 1.

3. The compound having the formula (I), (Ia), (Ib) or (Ic) according to claim 1 or 2, wherein R1is selected from the group consisting of H, OH, -CH2-OH, F or -COORA, wherein RA is(C1-C2)alkyl.

4. The compound according to any one of claims 1 to 3, wherein R1 is selected from the groupconsisting of OH, -CH2-OH or -COOCH3.

5. The compound according to any one of claims 1 to 4, wherein R2 is a 5- or 6-membered aryl orheteroaryl ring which can be optionally substituted with –(C1-C3alkyl)halo, F and / or CH3, wherein the heteroaryl ring contains one or two heteroatoms selected from N and S, preferably N.

6. The compound according to any one of claims 1 to 5, wherein R2 is a 5- or 6-memberedheteroaryl ring, which can be optionally substituted with –(C1-C3alkyl)halo, F, and / or CH3, wherein the heteroaryl ring contains one or two heteroatoms and said heteroatom(s) is / are N.

7. The compound according to any one of claims 1 to 6, wherein R2 is selected from the groupconsisting of, wherein R5 is H, –(C1-C3alkyl)halo, or CH3;wherein R9 is selected from H, –(C1-C3alkyl)halo, F, CH3 and NH2;preferably R2 is selected from the group consisting.

8. The compound according to any one of claims 1 to 7, which is selected from 9. The compound according to any one of claims 1 to 8, which comprises a detectable label.

10. The compound according to claim 9, wherein the detectable label is 3H or 18F.

11. The compound according to claim 10, having the formula (I-T)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1 is H, OH, –(C1-C3alkyl)OH, F or COORA, wherein RA is (C1-C4)alkyl;T is 3H; andwhereinwherein R12 is T or H and R6 is T or H; or whereinnd R6 is T or H;or wherein R2 is, wherein R12 is T or H and R6 is T or H;or wherein R2 iswherein R5 is –(C1-C4alkyl)halo R12 is T, p is 1 or 2, or wherein:R2 is, wherein R12 is T or H and R6 is T or H; or whereinR2 is (vii) , wherein R5 is CT3;and wherein (I-T) has at least one T, preferably 2 T.

12. The compound according to claim 10, having the formula (I-T’)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R6 is T or H;R1 is –(C1-C3alkyl)OH or -COORA, wherein RA is (C1-C4)alkyl, wherein R1 is substituted by oneor two, preferably two, T;wherein T is 3H; andR2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.

13. The compound according to claim 10, having the formula (I-F)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1 is 18F;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.

14. The compound according to claim 10, having the formula (I-F’)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; Fis 18F;R1 is -OH, –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl, andR2is as defined in claim 1.

15. A diagnostic composition comprising a compound according to any one of claims 1 to 14, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient.

16. A compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15, for use in diagnostics.

17. A compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15, for use in the imaging of TDP-43 aggregates, particularly wherein the imaging is conducted by positron emission tomography.

18. A compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15, for use in the diagnosis of a disease, disorder or abnormality associated with TDP- 43 aggregates, particularly wherein the diagnosis is conducted by positron emission tomography.

19. A method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a predisposition thereto in a subject, the method comprising the steps: (a) Administering a compound according to any one of claims 1 to 14; or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14 to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates.

20. The method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a predisposition thereto according to claim 19, the method further comprising the step 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 the control image of a healthy control subject, wherein an increase in binding signal indicates that the subject is suffering from or at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates.

21. A method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject, the method comprising the steps:(a) Administering a compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14 to the subject; (b) Allowing the compound to 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 tissue of the subject.

22. The method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject according to claim 21, wherein the tissue is a tissue of the central nervous system (CNS), an eye tissue, or a brain tissue, preferably wherein the tissue is brain tissue.

23. A method for the detection and optionally quantification of TDP-43 aggregates in a tissue of a subject, the method comprising the steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14; (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.

24. A method of collecting data for the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or a predisposition thereto, the method comprising the steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14; (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 with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area.

25. A method of collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates in a patient, the method comprising the steps:(a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with the compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14; (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 with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area; and (e) Optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time.

26. A method of collecting data for predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates to a treatment with a medicament, the method comprising the steps: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound according to any one of claims 1 to 14, or a diagnostic composition according to claim 15 which comprises a compound according to any one of claims 1 to 14; (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 with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area; and (e) Optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time.

27. The method of any one of claims 24 to 26, 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 area; comprises -Determining the amount of the compound bound to the TDP-43 aggregates;- Correlating the amount of the compound bound to the TDP-43 aggregates with theamount of TDP-43 aggregates in the sample or specific body part or body area; and -Optionally comparing the amount of the compound bound with the TDP-43 aggregates ina sample or specific body part or body area to a normal control value in a healthy control subject.

28. Use of a compound according to any one of claims 1 to 14 as a TDP-43 aggregates’ biomarker or a TDP-43 proteinopathy biomarker.

29. Use of a compound according to any one of claims 1 to 14 as a TDP-43 proteinopathy diagnostic agent or diagnostic tool.

30. The compound according to any one of claims 1 to 14 for use as an in vitro analytical referenceor an in vitro screening tool.

31. The compound for use or the diagnostic composition for use according to claim 15 or 16, or the method according to any one of claims 19 to 27, wherein the disease, disorder or abnormality associated with TDP-43 aggregates or the 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 mutations, with TARDBP mutation, with valosine-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) including frontotemporal lobar 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), behavioural variant FTD (bvFTD), Nonfluent Variant Primary Progressive Aphasia (such as 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 under Machado Joseph Disease)), hippocampal sclerosis dementia and myopathies (sporadic inclusion body myositis, inclusion body myopathy with a mutation in the valosin-containing protein (VCP); also Paget disease of bone and frontotemporal dementia), oculo-pharyngeal muscular dystrophy with rimmed vacuoles, myofibrillar myopathies with mutations in the myotilin (MYOT) gene or mutations in the gene coding for desmin (DES), Traumatic Brain Injury (TBI), Dementia with Lewy Bodies (DLB) and Parkinson’s disease (PD), preferably the disease, the disorder or the abnormality associated with TDP-43 aggregates or the 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).

32. The compound for use or the diagnostic composition for use, or the method according to claim 31, wherein the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

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

34. The compound for use or the diagnostic composition for use, or the method according to claim 31, wherein the disease, the disorder or the abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy is frontotemporal dementia (FTD) including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).

35. The compound for use or the diagnostic composition for use, or the method according to claim 31, wherein the disease, the disorder or the abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy is limbic-predominant age-related TDP-43 encephalopathy (LATE).

36. The compound for use or the diagnostic composition for use, or the method according to claim 31, wherein the disease, the disorder or the abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy is frontotemporal dementia (FTD) with progranulin (GRN) mutation, or frontotemporal dementia (FTD) with C9orf72 mutations.

37. A compound having the formula (II)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, wherein n is 1 or 2; and R1 is H, OH, –(C1-C3alkyl)OH, F, or -COORA, wherein RA is (C1-C4)alkyl.

38. A compound having the formula (III)or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, wherein Zis selected from C-Br, C-I, and C-H;n is 1 or 2; R1 is H, OH, –(C A A1-C3alkyl)OH, F or -COOR , wherein R is (C1-C4)alkyl;R11is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with Br, I, F, NH2, CN, –(C1-C3alkyl)halo and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S; and at least one of Z and / or R11 comprises Br or I, preferably Br.

39. A compound having the formula (IV)wherein nis 1 or 2;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S; and R14is a leaving group (LG), preferably MsO.

40. A compound having the formula (V)wherein nis 1 or 2;R1 is H, OH, –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl;R2is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and / or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S; and R14is a leaving group (LG), preferably trimethyl ammonium or NO2.

41. A kit for preparing a radiopharmaceutical preparation comprising a precursor of the detectably labeled compound according to any one of claims 9 to 14, wherein the precursor is a compound of formula (II) as defined in claim 37, a compound of formula (III) as defined in claim 38, a compound of formula (IV) as defined in claim 39 or a compound of formula (V) as defined in claim 40.

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