Novel compounds for diagnosis

Abstract

The present invention relates to novel compounds of formula (I) or detectably labeled compounds thereof, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, which are useful for imaging and determining the amount of alpha-synuclein aggregates. Furthermore, the compounds may be used to diagnose a disease, disorder or disorder associated with alpha-synuclein aggregates (e.g., Parkinson's disease or e.g., or multi-system atrophy (MSA)), to determine a susceptibility to the disease, disorder or disorder, to predict a prognosis of the disease, disorder or disorder, and to diagnose a disease, disorder or disorder associated with alpha-synuclein aggregates. In some embodiments, disease evolution in a patient suffering from the disease, disorder or abnormality is monitored, progression of the disease, disorder or abnormality is monitored, and responsiveness of a patient suffering from the disease, disorder or abnormality to its treatment is predicted.

Description

Field of the Invention

[0001] The present invention relates to novel compounds of formula (I) or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, which can be used to image α-synuclein aggregates and determine their amount. In addition, the compounds can be used to diagnose diseases, disorders or abnormalities associated with α-synuclein (α-synuclein, A-synuclein, a-synuclein, A-syn, α-syn, aSyn, α-syn) aggregates, such as Parkinson's disease or multiple system atrophy, determine the susceptibility to such diseases, disorders or abnormalities, predict the prognosis of the diseases, disorders or abnormalities, monitor the disease development of patients suffering from the diseases, disorders or abnormalities, monitor the progression of the diseases, and predict the responsiveness of patients suffering from such diseases, disorders or abnormalities to their treatment. The present invention also relates to methods for preparing the compounds and their precursors, diagnostic compositions comprising the compounds, methods of using the compounds, kits comprising the compounds and their uses. Background of the Invention

[0003] Many age-related diseases are based on or associated with extracellular or intracellular deposits of amyloid or amyloid proteins, which promote the pathogenesis and progression of the diseases. The best characterized amyloid protein that forms extracellular aggregates is β-amyloid (Abeta or Aβ).

[0004] Amyloid-like proteins that mainly form intracellular aggregates include, but are not limited to, Tau, alpha-synuclein, and huntingtin (HTT). Diseases involving alpha-synuclein aggregates are commonly classified as synucleinopathies (or alpha-synucleinopathies), and these include, but are not limited to, Parkinson's disease (PD) or multiple system atrophy (MSA). Synucleinopathies with mainly neuronal aggregates include, but are not limited to, Parkinson's disease (sporadic, familial with SNCA mutations (the gene encoding alpha-synuclein) or SNCA gene duplications or triplications, familial with gene mutations other than SNCA, pure autonomic failure, and Lewy body dysphagia), SNCA duplication carriers, Lewy body dementia (LBD), dementia with Lewy bodies (DLB) ("pure" Lewy body dementia), Parkinson's disease dementia (PDD), diffuse Lewy body disease (DLBD), Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2, or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, and normal aging in Down syndrome. Synucleinopathies with neuronal and glial aggregates of alpha-synuclein include, but are not limited to, multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy). Other diseases that may have alpha-synuclein immunoreactive lesions are, but are not limited to, traumatic brain injury, chronic traumatic encephalopathy, boxer's dementia, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Niemann-Pick disease type C1, frontotemporal dementia with parkinsonism associated with chromosome 17), motor neuron disease, Huntington's disease, amyotrophic lateral sclerosis (sporadic, familial, and the ALS-dementia syndrome in Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), prion diseases, Creutzfeldt-Jakob disease, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gerstmann-Straussler-Scheinker disease, inclusion body myositis, Gaucher's disease, Krabbe's disease, and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder (Jellinger, Mov. Disord. 2003, 18 Suppl 6, S2-12; Galvin et al. JAMA Neurology 2001, 58(2), 186-190; Kovari et al., Acta Neuropathol. 2007, 114(3), 295-8; Saito et al., J. Neuropathol. Exp. Neurol.2004, 63(4), 323 - 328; McKee et al., Brain, 2013, 136(Pt 1), 43 - 64; Puschmann et al., Parkinsonism Relat.Disord. 2012, 18S1, S24 - S27; Usenovic et al., J.Neurosci. 2012, 32(12), 4240 - 4246; Winder - Rhodes et al., Mov.Disord. 2012, 27(2), 312 - 315; Ferman et al., J.Int.Neuropsychol.Soc. 2002, 8(7), 907 - 914; Smith et al., J.Pathol. 2014; 232:509 - 521, Lippa et al., Ann Neurol. 1999 Mar; 45(3):353 - 7; Schmitz et al., Mol.Neurobiol. August 22, 2018; Charles et al., Neurosci.Lett. July 28, 2000; 289(1):29 - 32; Wilhelmsen et al., Arch Neurol. March 2004; 61(3):398 - 406; Yamaguchi et al., J.Neuropathol.Exp.Neurol. 2004, 80th Annual Meeting, Vol. 63; Askanas et al., J.Neuropathol.Exp.Neurol. July 2000; 59(7):592 - 8).

[0005] α-Synuclein is a naturally unfolded protein of 140 amino acids (Iwai et al., Biochemistry 1995, 34(32), 10139-10145). The sequence of α-synuclein can be divided into three main domains: 1) an N-terminal region containing residues 1-60, which contains an 11-mer amphipathic imperfect repeat residue (KTKEGV) with a highly conserved hexamer. This region is involved in regulating the binding of α-synuclein to membranes and its internalization; 2) a hydrophobic non-β-amyloid component (NAC) domain spanning residues 61-95, which is crucial for the protofibrillation of α-synuclein; and 3) a C-terminal region spanning residues 96-140, which is strongly acidic and rich in proline and has no obvious structural preference. α-Synuclein has been shown to undergo multiple post-translational modifications, including truncation, phosphorylation, ubiquitination, oxidation, and / or transglutaminase-catalyzed covalent cross-linking (Fujiwara et al., Nat. Cell Biol. 2002, 4(2); 160-164; Hasegawa et al., J. Biol. Chem. 2002, 277(50), 49071-49076; Li et al., Proc. Natl. Acad. Sci. USA 2005, 102(6), 2162-2167; Oueslati et al., Prog. Brain Res. 2010, 183, 115-145; Schmid et al., J. Biol. Chem. 2009, 284(19), 13128-13142). Interestingly, most of these modifications involve residues within the C-terminal region.

[0006] Multiple phosphorylation sites have been detected in the carboxyl-terminal region at Tyr-125, -133, and -136, as well as Ser-129 (Negro et al., FASEB J 2002, 16(2), 210-212). The Tyr-125 residue can be phosphorylated by two Src family protein tyrosine kinases, c-Src and Fyn (Ellis et al., J. Biol. Chem. 2001, 276(6), 3879-3884; Nakamura et al., Biochem. Biophys. Res. Commun. 2001, 280(4), 1085-1092). Phosphorylation by Src family kinases does not inhibit or enhance the tendency of α-synuclein to polymerize. α-Synuclein has been shown to be a protein tyrosine kinase p72 in vitro syk(Syk)'s outstanding substrate; once extensively Tyr-phosphorylated by Syk or tyrosine kinases with similar specificities, it loses its ability to form oligomers, suggesting a putative anti-neurodegenerative role for these tyrosine kinases (Negro et al., FASEB J. 2002, 16(2), 210-212). Alpha-synuclein can be Ser-phosphorylated by protein kinases CKI and CKII (Okochi et al., J. Biol. Chem. 2000, 275(1), 390-397). Residue Ser-129 can also be phosphorylated by G protein-coupled receptor protein kinases (Pronin et al., J. Biol. Chem. 2000, 275(34), 26515-26522). Extensive and selective phosphorylation of alpha-synuclein at Ser-129 is evident in synucleinopathy lesions including Lewy bodies (Fujiwara et al., Nat. Cell Biol. 2002, 4(2); 160-164). Other post-translational modifications in the carboxyl terminus, including glycosylation on Ser-129 (McLean et al., Neurosci Lett 2002, 323(3), 219-223) and nitration on Tyr-125, -133 and -136 (Takahashi et al., Brain Res 2002, 938(1-2), 73-80), can affect the aggregation of alpha-synuclein. Truncation of the carboxyl-terminal region by proteolysis has been reported to play a role in the formation of alpha-synuclein fibrils in various neurodegenerative diseases (Rochet et al., Biochemistry 2000, 39(35), 10619-10626). Full-length as well as partially truncated and insoluble alpha-synuclein aggregates have been detected in highly purified Lewy bodies (Crowther et al., FEBS Lett 1998, 436(3), 309-312).

[0007] Aberrant protein aggregation is clearly a common feature of the aging brain and various neurodegenerative diseases (Trojanowski et al., 1998, Cell Death Differ. 1998, 5(10), 832-837, Koo et al., Proc Natl Acad Sci. 1999, 96(18), 9989-9990, Hu et al., Chin. Sci. Bull. 2001, 46, 1-3); however, its exact role in the disease process remains to be determined. In in vitro models, α-synuclein (or certain truncated forms thereof) readily assembles into filaments that resemble those isolated from the brains of patients with Lewy body (LB) dementia and familial PD (Crowther et al., FEBS Lett 1998, 436(3), 309-312). α-Synuclein and its mutant forms (A53T and A30P) have a random coil conformation and do not form significant secondary structures in aqueous solutions at low concentrations; however, at higher concentrations, they tend to self-aggregate, generating amyloid fibrils (Wood et al., J Biol Chem 1999, 274(28), 19509-19512). Many differences in the aggregation behavior of PD-linked mutants and wild-type proteins have been documented. Monomeric α-synuclein aggregates in vitro through a metastable oligomeric (i.e., protofibril) state to form stable fibrils (Volles et al., Biochemistry 2002, 41(14), 4595-4602).

[0008] Parkinson's disease (PD) is the most common neurodegenerative movement disorder. PD is mainly an idiopathic disease, although in at least 5% of PD patients, the pathology is associated with mutations in one or several specific genes. Several point mutations (A30P, E46K, H50Q, G51D, A53T) in the α-synuclein gene have been described, which cause familial PD with autosomal dominant inheritance. In addition, diploid and triploid of the α-synuclein gene have been described in patients with PD, highlighting the role of α-synuclein in the pathogenesis of PD (Lesage et al., Hum. Mol. Genet., 2009, 18, R48-59). The pathogenesis of PD remains elusive. However, increasing evidence suggests the role of pathogenic folding of α-synuclein leading to the formation of amyloid fibrils. In fact, the hallmark of PD is the presence of intracellular α-synuclein aggregation structures called Lewy bodies and neurites mainly in the substantia nigra neurons, and the death of dopaminergic neurons in the substantia nigra and other sites. α-Synuclein is a naturally unfolded presynaptic protein that can misfold and aggregate into larger oligomeric and fibrillar forms, which are related to the pathogenesis of PD. Recent studies have shown that the small soluble oligomeric and fibrillar forms of α-synuclein are the most neurotoxic species (Lashuel et al., J. Mol. Biol., 2002, 322, 1089-102). However, the exact role of α-synuclein in neuronal cytotoxicity remains to be elucidated (review: Cookson, Annu. Rev. Biochem., 2005, 74, 29-52).

[0009] In addition to Parkinson's disease, the accumulation of aggregated α-synuclein into Lewy bodies is a characteristic of all Lewy body diseases, including Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) (Capouch et al., Neurol Ther. 2018, 7, 249-263). In DLB, Lewy bodies are diffusely distributed throughout the cerebral cortex, and in addition to Lewy bodies and neurites, more linear and punctate structures (Lewy dots) immunoreactive for phosphorylated α-synuclein at Ser-129 are found (Outeiro et al., Mol Neurodegener. 2019, 14, 5).

[0010] α - synuclein aggregates have also been found in multiple system atrophy (MSA). MSA is a rare sporadic neurodegenerative disease characterized by rapidly progressive autonomic and motor dysfunction, as well as variable cognitive decline. These disorders include Shy - Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy. Depending on the predominant motor phenotype, the disease can be clinically classified into parkinsonian (MSA - P) or cerebellar (MSA - C) variants (Fanciulli et al., N. Engl. J. Med. 2015; 372, 249 - 63). It is characterized by the aggregation of α - synuclein in the cytoplasm of oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). GCIs mainly consist of the fibrillar form of α - synuclein, which are the neuropathological hallmark of MSA and are found throughout the neocortex, hippocampus, brainstem, spinal cord, and dorsal root ganglia (Galvin et al., Arch Neurol. 2001, 58, 186 - 90). GCIs are regarded as core participants in the pathogenesis of MSA. A correlation has been reported between GCI load in the striatum and olivopontocerebellar regions and the degree of neuronal loss (Stefanova et al., Neuropathol. Appl. Neurobiol. 2016, 42, 20 - 32).

[0011] In addition, in transgenic mice overexpressing human α - synuclein in oligodendrocytes under the control of different oligodendrocyte - specific promoters, a causal relationship exists between GCI formation and the induction of neuronal loss. The key event in the pathophysiological cascade is thought to be the permissive templating ('prion - like' propagation) of misfolded α - synuclein.

[0012] The diagnosis of Parkinson's disease is largely clinical and depends on the presence of a specific set of symptoms and signs (the initial core features are bradykinesia, rigidity, resting tremor, and postural instability), the absence of atypical features, a slowly progressive course, and the response to symptomatic drug therapy, which is mainly limited to dopamine replacement therapy. Accurate diagnosis requires complex clinical skills and is to some extent subjective and prone to error because several other degenerative and non - degenerative diseases can mimic PD symptoms (multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), essential tremor, dystonic tremor) (Guideline No.113: Diagnosis and pharmacological management of Parkinson’s disease, January 2010. SIGN). Definitive pathological confirmation can only be made by post - mortem neuropathological analysis.

[0013] Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans in patients with Parkinson's disease (PD) are usually normal. However, these techniques can be used to rule out other diseases that may be secondary causes of parkinsonism, such as basal ganglia tumors, vascular lesions, and hydrocephalus. Specific techniques of MRI (diffusion MRI) have been reported to be useful in differentiating typical from atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane ( 123 I) (trade name DaTSCAN) and iodobenzotropine (Dopascan) for SPECT or fluorodeoxyglucose ( 18 F) ( 18 F-FDG) and dihydrotetrabenazine ( 11 C) ( 11 C-DTBZ) for PET. Patterns of reduced dopaminergic activity in the basal ganglia can help in the diagnosis of PD, especially in the symptomatic stage (Brooks, J. Nucl. Med., 2010, 51, 596 - 609; Redmond, Neuroscientist, 2002, 8, 457 - 88; Wood, Nat. Rev. Neurol., 2014, 10, 305).

[0014] Strategies are being developed to apply recent advances in understanding the underlying causes of Parkinson's disease to the development of biochemical biomarkers (Schapira Curr Opin Neurol 2013; 26(4): 395 - 400). Such biomarkers that have been studied in different body fluids (cerebrospinal fluid (CSF), plasma, saliva) include α-synuclein levels, as well as DJ-1, Tau, and Aβ, and neurofilament proteins, interleukins, osteopontin, and hypocretin (Schapira Curr Opin Neurol 2013; 26(4): 395 - 400), but so far, none of these biomarkers alone or in combination are useful for definitive diagnostic tests. To our knowledge, despite the urgent need in Parkinson's disease research and drug development, there are currently no approved α-synuclein diagnostic reagents on the market (Eberling et al., J Parkinsons Dis. 2013; 3(4): 565 - 7).

[0015] The ability to image α-synuclein deposition in the brain would be a great achievement for the study of α-synucleinopathies, including Parkinson's disease (PD) and MSA research, diagnosis, and drug development. The accumulation of aggregated α-synuclein in the brain is regarded as a key pathological hallmark of PD and MSA and can start many years before symptoms appear. Thus, α-synuclein is a priority target for drug development, not only considering its potential contribution to neurodegeneration but also because it offers the possibility of treating diseases while still in the asymptomatic or prodromal stage. In vivo imaging of α-synuclein pathology can be used as a biomarker to (i) potentially detect the presence of disease at an early stage, (ii) assess disease progression, and (iii) serve as a pharmacodynamic tool for drug development. Currently, starting with the optimal selection of the trial population, considering the development of α-synuclein PET imaging agents is crucial for the accurate diagnosis of synucleinopathies and for supporting the clinical development of therapeutics targeting α-synuclein (Eberling, Dave, and Frasier, J. Parkinson’s Disease, 3, 565-567 (2013)).

[0016] Until recently, the first non-invasive images of pathological α-synuclein (a-syn) in the human brain were reported, providing positive clinical proof-of-concept data for an a-syn positron emission tomography (PET) tracer as an imaging agent for identifying patients with MSA (Capotosti F.; Discovery of a novel and promising PET-tracer for alpha-synuclein; Oral presentation, ADPD 2022 International Conference; Barcelona, Spain; March 18, 2022; Smith R.; Initial scans using a novel PET-tracer for alpha-synuclein; Oral presentation, ADPD 2022 International Conference; Barcelona, Spain; March 18, 2022).

[0017] There is clearly a need to find molecular probes with high α-synuclein selectivity to identify and bind to pathological α-synuclein. To minimize background signal interference caused by non-specific off-target binding and reduce dosing requirements, α-synuclein imaging compounds should bind to their target with high affinity and selectivity.

[0018] For imaging of α-synuclein aggregates associated with neurological diseases such as Parkinson's disease or multiple system atrophy, the imaging compound needs to penetrate the blood-brain barrier and enter the relevant regions of the brain. Cellular permeability is a further requirement for imaging compounds used to target intracellular amyloid inclusions such as α-synuclein. Another prerequisite for avoiding unnecessary accumulation of the compound (which may lead to an increased risk of unwanted side effects) is rapid clearance of the compound from the brain (or other target organs).

[0019] WO 2011 / 128455 relates to specific compounds suitable for treating disorders related to amyloid or amyloid-like proteins. US2012 / 0302755 relates to certain imaging agents for detecting neurological disorders. Other compounds for diagnosing neurodegenerative diseases on the olfactory epithelium are discussed in WO2012 / 037928.

[0020] WO 2010 / 063701 relates to a certain in vivo imaging agent in a method for determining the presence or susceptibility of Parkinson's disease, wherein the in vivo imaging agent comprises an α-synuclein binder labeled with an in vivo imaging moiety, and wherein the in vivo imaging agent binds to α-synuclein with a binding affinity.

[0021] US 2014 / 0142089 relates to a method for preventing or treating degenerative brain diseases, which comprises administering to a subject in need an effective amount of a pharmaceutical composition comprising a specific compound, its pharmaceutically acceptable salts, isomers, solvates, hydrates, and combinations thereof.

[0022] WO 2009 / 155017 describes aryl- or heteroaryl-substituted azabenzoxazole derivatives, which are alleged to be useful as tracers in positron emission tomography (PET) imaging for in vivo studies of amyloid deposits in the brain for diagnosing Alzheimer's disease.

[0023] WO 2016 / 033445 relates to specific compounds for imaging huntingtin.

[0024] WO 2017 / 153601, WO 2019 / 234243, and WO 2021 / 224489 relate to bicyclic compounds for imaging α-synuclein aggregates.

[0025] There is still a need for a new class of imaging compounds that have a reasonably high affinity for α-synuclein. Summary of the Invention

[0027] The present invention provides compounds that can be used to diagnose diseases, disorders or abnormalities associated with α-synuclein aggregates, such as Parkinson's disease or MSA, predict the prognosis of such diseases, disorders or abnormalities, and monitor the progression of such diseases, disorders or abnormalities. In particular, the compounds should be suitable for determining the susceptibility to such diseases, disorders or abnormalities, monitoring the progression of the disease, disorder or abnormality, or predicting the responsiveness of a patient suffering from such a disease, disorder or abnormality to treatment with a certain drug. In addition, these compounds should be suitable for positron emission tomography (PET) imaging of diseases, disorders or abnormalities associated with α-synuclein aggregates and / or detecting and optionally quantifying α-synuclein aggregates.

[0028] Various embodiments of the present invention are described herein.

[0029] In one aspect, the present invention provides compounds of formula (I):

[0030]

[0031] or a detectable-labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0032] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0033] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0034] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen;

[0035] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0036] R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl.

[0037] In another aspect, the present invention provides a compound of formula (I):

[0038]

[0039] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein

[0040] is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl;

[0041] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen; or

[0042] R 1 is a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; or

[0043] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and

[0044] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl.

[0045] In another aspect, the present invention also relates to a compound having the following sub-formula (Ia)

[0046]

[0047] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0048] wherein

[0049] R 1 and R 2 are as defined above,

[0050] R 3 is a halogen or C1-C4 alkyl; and

[0051] q is 0, 1 or 2.

[0052] In one aspect, the present invention provides a diagnostic composition comprising a compound of formula (I) and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and / or adjuvant.

[0053] In one aspect, the present invention provides a compound of formula (I) or a diagnostic composition as defined herein, which can be used for imaging of α-synuclein aggregates.

[0054] In another aspect, the compound of formula (I) or the diagnostic composition can be used for positron emission tomography (PET) imaging of α-synuclein aggregates.

[0055] In another aspect, the compound of formula (I) or the diagnostic composition as defined herein can be used for in vitro imaging, ex vivo imaging or in vivo imaging, preferably for in vivo imaging, more preferably for brain imaging.

[0056] In yet another aspect, the compound of formula (I) or the diagnostic composition as defined herein can be used for diagnosis.

[0057] In another aspect, the present invention relates to a method for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates in a subject, the method comprising the following steps:

[0058] (a) administering to the subject a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein;

[0059] (b) binding the compound to α-synuclein aggregates; and

[0060] (c) detecting the compound bound to α-synuclein aggregates.

[0061] In another aspect, the present invention relates to a method for positron emission tomography (PET) imaging of α-synuclein aggregates in a subject's tissue, the method comprising the following steps:

[0062] (a) administering to the subject a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein;

[0063] (b) binding the compound to α-synuclein aggregates; and

[0064] (c) detecting the compound bound to α-synuclein aggregates by acquiring a positron emission tomography (PET) image of the subject's tissue.

[0065] In another aspect, the present invention relates to a method for detecting and optionally quantifying α-synuclein aggregates in a subject's tissue, the method comprising the steps of:

[0066] (a) contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0067] (b) binding the compound to the α-synuclein aggregates;

[0068] (c) detecting the compound bound to the α-synuclein aggregates; and

[0069] (d) optionally quantifying the amount of the compound bound to the α-synuclein aggregates.

[0070] The present invention relates to a method for collecting data for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the method comprises the steps of:

[0071] (a) contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0072] (b) binding the compound to the α-synuclein aggregates;

[0073] (c) detecting the compound bound to the α-synuclein aggregates; and

[0074] (d) optionally, correlating the presence or absence of the compound bound to the α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample or the specific body part or body region.

[0075] The present invention also relates to a method for collecting data to determine the susceptibility to a disease, disorder or abnormality associated with α-synuclein aggregates, the method comprising the steps of:

[0076] (a) contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0077] (b) binding the compound to the α-synuclein aggregates;

[0078] (c) detecting the compound bound to the α-synuclein aggregates; and

[0079] (d) Optionally, establish a correlation between the presence or absence of a compound that binds to α-synuclein aggregates and the presence or absence of α-synuclein aggregates in a sample or a specific body part or body region.

[0080] In another aspect, the present invention also relates to a method of collecting data to predict the prognosis of a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the method comprises the following steps:

[0081] (a) Contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0082] (b) Binding the compound to α-synuclein aggregates;

[0083] (c) Detecting the compound that binds to α-synuclein aggregates;

[0084] (d) Optionally, establish a correlation between the presence or absence of the compound that binds to α-synuclein aggregates and the presence or absence of α-synuclein aggregates in the sample or a specific body part or body region; and

[0085] (e) Optionally repeat steps (a)-(c), and if present, optionally repeat step (d) at least once.

[0086] In another aspect, the present invention relates to a method of collecting data to monitor the progression of a disease, disorder or abnormality associated with α-synuclein aggregates in a patient, the method comprising the following steps:

[0087] (a) Contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0088] (b) Binding the compound to α-synuclein aggregates;

[0089] (c) Detecting the compound that binds to α-synuclein aggregates;

[0090] (d) Optionally, establish a correlation between the presence or absence of the compound that binds to α-synuclein aggregates and the presence or absence of α-synuclein aggregates in the sample or a specific body part or body region; and

[0091] (e) Optionally repeat steps (a)-(c), and if present, optionally repeat step (d) at least once.

[0092] In another aspect, the present invention relates to a method for collecting data for predicting the responsiveness of a patient suffering from a disease, disorder or abnormality associated with α-synuclein aggregates to a drug, the method comprising the following steps:

[0093] (a) contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0094] (b) binding said compound to α-synuclein aggregates;

[0095] (c) detecting the compound bound to α-synuclein aggregates;

[0096] (d) optionally, correlating the presence or absence of the compound bound to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample or the specific body part or body region; and

[0097] (e) optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0098] In another aspect, the present invention further relates to a compound of formula (III-F):

[0099]

[0100] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0101] is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0102] R 1F is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably wherein R 1F is a 4- to 6-membered heterocyclic group, or

[0103] R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is C1-C4 alkoxy or C1-C4 alkyl; or

[0104] R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl; and

[0105] R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0106] R 4 and R 5 are independently selected from H and C1-C4 alkyl;

[0107] LG is a leaving group; and

[0108] n is at least 1 (e.g., 1 or 2 or 3), preferably 1.

[0109] In a preferred aspect, the present invention relates to a compound of formula (III-F)

[0110]

[0111] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0112] is a 6-membered heteroaryl, optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0113] R 1F is a 4- to 6-membered heterocyclic group, or

[0114] R 1F is C1-C4 alkoxy or C1-C4 alkyl; or

[0115] R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl; and

[0116] R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0117] LG is a leaving group; and

[0118] n is at least 1.

[0119] In another preferred aspect, the present invention relates to a compound of formula (III-F’)

[0120]

[0121] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0122] is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0123] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0124] R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0125] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen;

[0126] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo-C1-C4 alkyl; and

[0127] R 2F is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl; and

[0128] LG is a leaving group.

[0129] Another aspect of the present invention relates to a compound of formula (I-F)

[0130]

[0131] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0132] is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0133] R 1Fis a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one C1-C4 alkoxy group, NR 4 R 5 or C1-C4 alkyl group, preferably R 1F is a 4- to 6-membered heterocyclic group, or

[0134] R 1F is a C1-C4 alkoxy group, NR 4 R 5 or C1-C4 alkyl group, preferably R 1F is a C1-C4 alkoxy group or C1-C4 alkyl group; or

[0135] R 1F is -NH-C3-C6 cycloalkyl group or C3-C6 cycloalkyl group; and

[0136] R 2 is a 5- or 6-membered heteroaryl group, which is optionally substituted by 1 or 2 substituents independently selected from halo C1-C4 alkyl group, halo C1-C4 alkoxy group, C1-C4 alkoxy group and C1-C4 alkyl group;

[0137] R 4 and R 5 are independently selected from H and C1-C4 alkyl groups; and

[0138] n is at least 1 (e.g., 1, 2 or 3), preferably 1.

[0139] In a preferred aspect, the present invention relates to a compound of formula (I-F)

[0140]

[0141] or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, wherein

[0142] is a 6-membered heteroaryl group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl group, halo C1-C4 alkoxy group, C1-C4 alkoxy group or C1-C4 alkyl group;

[0143] R 1F is a 4- to 6-membered heterocyclic group; or

[0144] R 1F is a C1-C4 alkoxy group or C1-C4 alkyl group; or

[0145] R 1F is -NH-C3-C6 cycloalkyl group or C3-C6 cycloalkyl group; and

[0146] R 2is a 5- or 6-membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0147] n is at least 1, preferably 1.

[0148] In another aspect, the present invention relates to a compound of formula (I-F’):

[0149]

[0150] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0151] is a 6-membered heteroaryl, optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0152] R 1 is a 4- to 6-membered heterocyclic group, optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0153] R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0154] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen;

[0155] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl; and

[0156] R 2F is a 5- or 6-membered heteroaryl, optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl.

[0157] In another aspect, the present invention also relates to a compound of formula (III-H)

[0158]

[0159] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0160] is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0161] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen; or

[0162] R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0163] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and

[0164] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0165] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl;

[0166] X is bromine, chlorine or iodine;

[0167] m is 0, 1, 2 or 3;

[0168] p is 0, 1, 2 or 3; and

[0169] provided that the compound of formula (III-H) contains at least one X.

[0170] In a preferred embodiment, the compound of formula (III-H) is defined

[0171]

[0172] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0173] is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0174] R 1 is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one halogen; or

[0175] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0176] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and

[0177] R 2 is a 5- or 6-membered heteroaryl which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0178] X is bromine, chlorine or iodine;

[0179] m is 0, 1, 2 or 3;

[0180] p is 0, 1, 2 or 3; and

[0181] provided that the compound of formula (III-H) contains at least one X.

[0182] In another aspect, the present invention also relates to a compound of formula (I-H)

[0183]

[0184] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0185] R 1is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0186] R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0187] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen; and

[0188] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted by 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0189] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl;

[0190] Y is D, CD3, T or CT3;

[0191] m is 0, 1, 2 or 3;

[0192] p is 0, 1, 2 or 3;

[0193] provided that the compound of formula (I-H) contains at least one D, CD3, T or CT3, wherein D is 2 H (deuterium) and T is 3 H (tritium). In one embodiment, the compound of formula (I-H) contains at least one T or CT3. In one embodiment, the compound of formula (I-H) contains at least one D or CD3.

[0194] In a preferred aspect, the present invention relates to a compound of formula (I-H)

[0195]

[0196] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0197] R 1 is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one halogen; or

[0198] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0199] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and

[0200] R 2 is a 5- or 6-membered heteroaryl which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0201] Y is D, CD3, T or CT3;

[0202] m is 0, 1, 2 or 3;

[0203] p is 0, 1, 2 or 3;

[0204] provided that the compound of formula (I-H) contains at least one D, CD3, T or CT3, wherein D is deuterium and T is 3 H (tritium).

[0205] In another aspect, the present invention also relates to a method for preparing a compound of formula (I-F), by reacting a compound of formula (III-F) with 18 an F-fluorinating agent (such as K 18 F, Rb 18 F, Cs 18 F, Na 18 F, 18 F's tetra(C 1-6 alkyl)ammonium salt, Kryptofix

[222] 18 F, 18 F] tetrabutylammonium fluoride or any other suitable reagent) such that the leaving group (LG) is replaced by 18 F.

[0206] In another aspect, the present invention also relates to a method for preparing a compound of formula (I-H), which is carried out by reacting a compound of formula (III-H) with 3 an H-radiolabeling reagent (such as tritium gas or any other suitable reagent) such that X is replaced by T or CT3.

[0207] In another aspect, the present invention also relates to a method for preparing a compound of formula (I-H), which is carried out by reacting a compound of formula (III-H) with an 2 H-radiolabeling reagent containing D (such as D2O, D4-methanol or any other suitable reagent), preferably in the presence of a catalyst such as Pd / C, such that X is replaced by D or CD3 (where D is deuterium).

[0208] In another aspect, the present invention also relates to the use of a compound of formula (I) as an in vitro analysis reference or an in vitro screening tool.

[0209] In another aspect, the present invention also relates to a test kit for detecting and / or diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the test kit comprises at least one compound of formula (I) as defined herein, preferably at least one detectably labeled compound, more preferably at least one compound of formula (I-F) or (I-H).

[0210] The present invention also relates to a kit for preparing a radiopharmaceutical formulation, wherein the kit comprises a sealed vial containing at least one compound of formula (III-F) or (III-H).

[0211] Definitions

[0212] For the purpose of interpreting this specification, unless otherwise stated, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural and vice versa. It must also be noted that, unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" used herein and in the appended claims include plural referents. Thus, for example, reference to "a compound" includes reference to one or more compounds and the like.

[0213] The term "C1-C4 alkyl" refers to a saturated straight-chain or branched-chain organic moiety consisting only of carbon and hydrogen atoms, having no unsaturation, having 1-4 carbon atoms, and typically being linked to the remainder of the molecule by a single bond. Examples of suitable alkyls having 1 to 4 carbon atoms include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-methylethyl, n-butyl, tert-butyl and isobutyl.

[0214] The term "C1-C4 alkoxy" refers to a group having the formula -ORa, where Ra is a C1-C4 alkyl group as generally defined above. Examples of C1-C4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0215] The term "halo C1-C4 alkyl" refers to a C1-C4 alkyl group as defined above, which is substituted by one or more (e.g., 1, 2, or 3, preferably 1 or 2, more preferably 1) halogen groups as defined below. Examples of "halo C1-C4 alkyl" include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0216] The term "halo C1-C4 alkoxy" refers to a C1-C4 alkoxy group as defined above, which is substituted by one or more (e.g., 1, 2, or 3, preferably 1 or 2, more preferably 1) halogen groups as defined below. Examples of "halo C1-C4 alkoxy" include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 2,2-difluorobutoxy, and 4-bromobutoxy.

[0217] The term "heterocyclic group" refers to a stable 4- to 6-membered non-aromatic monocyclic group containing 1 or 2 heteroatoms selected, for example, from N, O, or S. The heterocyclic group can be unsaturated or saturated. The heterocyclic group can be bonded through a carbon atom or a heteroatom. Examples include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl, preferably azetidinyl, pyrrolidinyl, or piperidinyl, more preferably pyrrolidinyl.

[0218] The term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring that contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heteroaryl can be bonded through a carbon atom or a heteroatom selected from N, O, and S. Examples of heteroaryl include, but are not limited to, thiopyranyl, dioxolanyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, pyrazolyl, thiazolyl, or pyridyl, where pyridyl, isothiazolyl, pyrazolyl, and thiazolyl are preferred.

[0219] The term "Hal" or "halogen" or "halo" refers to F, Cl, Br, and I. In diagnostic and pharmaceutical applications, F is particularly preferred (e.g., 19 F and 18 F).

[0220] As used herein, the term "leaving group" (LG) is any leaving group and refers to an atom or group of atoms that can be replaced by another atom or group of atoms. Examples are given in Synthesis (1982), p. 85 - 125, Table 2, Carey and Sundberg, Organische Synthese, (1995), pp. 279 - 281, Table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71 - 83, Schemes 1, 2, 10 and 15 etc.). (Coenen, Fluorine - 18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006),: Schubiger P.A., Friebe M., Lehmann L., (eds), PET - Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15 - 50, specifically: Scheme 4 on page 25, Scheme 5 on page 28, Table 4 on page 30, Figure 7 on page 33). Preferably, the "leaving group" (LG) is selected from halogen, C 1-4 alkylsulfonates and C 6-10 arylsulfonates, where the C 6-10 aryl may optionally be substituted by -CH3 or -NO2.

[0221] Unless otherwise specified, the term "compound of the invention" refers to a compound of formula (I) or its sub - formulas (such as (Ia), (I - F), (I - H*), (I - H)) or its detectably labeled compounds, stereoisomers (including mixtures of diastereoisomers and individual diastereoisomers, mixtures of enantiomers and single enantiomers, mixtures of conformational isomers and single conformational isomers), racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates. It should be understood that each mention of a compound of formula (I) as defined herein also encompasses its sub - formulas (such as (Ia), (I - F), (I - H*), (I - H)). Compounds of formula (III - F) and (III - H) are referred to as precursors of the compounds of the invention.

[0222] The compounds of the invention and their precursors having one or more optically active carbons can exist in the form of racemates and racemic mixtures, stereoisomers (including mixtures of diastereoisomers and individual diastereoisomers, mixtures of enantiomers and single enantiomers, mixtures of conformational isomers and single conformational isomers), tautomers, atropisomers and rotamers. All isomeric forms are included in the invention.

[0223] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc. Pharmaceutically acceptable salts of the compounds of the present invention and their precursors can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base 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 both. Organic solvents include, but are not limited to, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0224] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0225] "Solvates" can be formed by the compounds of the present invention and any suitable pharmaceutically acceptable solvent. Examples include C 1-4 alcohols (such as methanol or ethanol).

[0226] The patient or subject in the present invention is typically an animal, particularly a mammal, more particularly a human.

[0227] α-Synuclein aggregates are β-sheet-rich polymeric assemblies of α-synuclein monomers that can form soluble oligomers or soluble / insoluble protofibrils or mature fibrils, which coalesce into intracellular deposits that are detected as a range of Lewy pathologies in Parkinson's disease and other synucleinopathies. α-Synuclein aggregates that make up the Lewy pathological conditions can be detected as having the following morphologies: Lewy bodies, Lewy neurites, premature Lewy bodies or pale bodies, perinuclear deposits with a diffuse, granular, punctate or polymorphic pattern. In addition, α-synuclein aggregates are the major component of intracellular fibrillar inclusions detected in oligodendrocytes (also termed glial cytoplasmic inclusions) and neuronal somata, axons and nuclei (termed neuronal cytoplasmic inclusions), which are histological hallmarks of multiple system atrophy. α-Synuclein aggregates in Lewy pathologies typically show a significant increase in post-translational modifications such as phosphorylation, ubiquitination, nitration and truncation.

[0228] Lewy bodies are abnormal aggregates of proteins that develop within nerve cells in Parkinson's disease (PD), dementia with Lewy bodies and other synucleinopathies. Lewy bodies appear as spherical masses that displace other cellular components. Morphologically, Lewy bodies can be classified as brainstem or cortical type. A typical brainstem Lewy body is an eosinophilic cytoplasmic inclusion composed of a dense core surrounded by a halo of 5- to 10-nm-wide radiating protofibrils, with α-synuclein as its major structural component; cortical Lewy bodies differ by the absence of a halo. The presence of Lewy bodies is a hallmark of Parkinson's disease.

[0229] Lewy neurites are abnormal neuronal processes in diseased neurons that contain granular material, abnormal α-synuclein (α-syn) filaments similar to those found in Lewy bodies, punctate, varicose structures and axonal spheroids. Like Lewy bodies, Lewy neurites are characteristic of synucleinopathies such as dementia with Lewy bodies and Parkinson's disease.

[0230] Glial cytoplasmic inclusions (GCI or Papp-Lantos inclusions) are argyrophilic cytoplasmic aggregates in oligodendrocytes composed of filamentous α-synuclein. They are triangular, semilunar or sickle-shaped in morphology. In MSA, in addition to GCIs, inclusions composed of α-synuclein filaments are detected in the cytoplasm or in neurons under the nuclear membrane, termed neuronal cytoplasmic inclusions and intranuclear neuronal inclusions, respectively. GCIs are regarded as a defining morphological feature of MSA; their widespread distribution is a definitive criterion for the neuropathological diagnosis of MSA at autopsy.

[0231] The terms "disease", "disorder" or "abnormality" are used interchangeably herein.

[0232] The compounds of formula (I) can bind to α-synuclein aggregates. The type of binding to the compounds of formula (I) has not been elucidated, and any type of binding is encompassed by the present invention. The terms "compounds that bind to α-synuclein aggregates" and the like are used interchangeably herein and are not considered limited to any specific type of binding.

[0233] Unless otherwise specified, the preferred definitions given in the "Definitions" section apply to all embodiments described below. Different embodiments of the present invention are described herein, and it should be recognized that the features specified in each embodiment can be combined with other specified features to obtain other embodiments of the present invention. Detailed Description of the Invention

[0235] Compounds of the present invention

[0236] The compounds of the present invention and their precursors are described below. It should be understood that all possible combinations of the following definitions are also contemplated. It should also be understood that all embodiments and preferred embodiments given with respect to formula (I) apply similarly to formula (Ia), (III-F), (I-F), (III-H), (I-H), and (I-H*), etc., and vice versa. It should also be understood that the preferred embodiments given with respect to formula (III-F) apply similarly to formula (I-F), and vice versa. It should also be understood that the preferred embodiments given with respect to formula (III-H) apply similarly to formula (I-H) and (I-H*), respectively, and vice versa.

[0237] The present invention relates to compounds of formula (I):

[0238]

[0239] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0240] is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl, provided that if is substituted, then is substituted with 1, 2 or 3, preferably 1 or 2, more preferably 1 halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl;

[0241] R 1 is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5or substituted with a C1-C4 alkyl group, preferably R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen; or

[0242] R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0243] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and

[0244] R 2 is a 5- or 6-membered heteroaryl group, which is optionally substituted with 1 or 2 substituents independently selected from halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0245] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo-C1-C4 alkyl.

[0246] Throughout this application, R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo-C1-C4 alkyl, preferably at least one of R 4 and R 5 is not H.

[0247] In one embodiment, is preferably selected from:

[0248]

[0249] It can be attached to the triazole heterocycle at any available position;

[0250] and wherein can be optionally substituted with one or more substituents selected from halogen;

[0251] halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl.

[0252] In a preferred embodiment, is preferably selected from

[0253]

[0254] It can be attached to the triazole-fused heterocycle at any available position;

[0255] and wherein may optionally be substituted with one or more substituents selected from halogen;

[0256] halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl.

[0257] Any optional substituent of is preferably halogen or C1-C4 alkyl.

[0258] In a preferred embodiment, is a 6-membered heteroaryl containing at least one N, preferably is pyridyl, which can be substituted by R at any available position 1 substituted, more preferably R 1 - is R 1 as defined above.

[0259] In one embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl (e.g., 1-3, preferably 1 or 2, preferably 1). In a preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen (e.g., 1-3, preferably 1 or 2, more preferably 1). In a preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is substituted with at least one halogen. Preferably, the heterocyclic group is substituted with at least one halogen, more preferably with one or two halogens, even more preferably with one halogen. In another preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is unsubstituted.

[0260] In one embodiment, R 1 is selected from the following:

[0261]

[0262] wherein R 1’ is independently halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; and s = 0, 1, 2 or 3.

[0263] In one embodiment, R 1 is a 4- to 6-membered heterocyclic group selected from the following:

[0264]

[0265] wherein R 1a is F or H, preferably F. In another preferred embodiment, R 1a is H.

[0266] Preferably, R 1 is a 4- or 5-membered heterocyclic group selected from the following:

[0267]

[0268] wherein R 1a is F or H, preferably F. In another preferred embodiment, R 1a is H.

[0269] In yet another embodiment, R 1 is a 5-membered heterocyclic group which is:

[0270]

[0271] In yet another embodiment, R 1 is a 5-membered heterocyclic group which is:

[0272]

[0273] In another embodiment, R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 , or C1-C4 alkyl. In one embodiment, R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl. Preferably, R 1 is halo-C1-C4 alkyl or halogen, more preferably R 1 is -O-(CH2) x -Hal (x = 1-4, preferably 1-3, more preferably 1 or 2, even more preferably 2), even more preferably -O-CH2-CH2-F. In another preferred embodiment, R 1 is NR 4 R 5 , preferably wherein R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo-C1-C4 alkyl.

[0274] In yet another embodiment, R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen.

[0275] In each of the embodiments, F is preferably 19 F or 18 F.

[0276] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl, preferably halo C1-C4 alkyl or C1-C4 alkyl.

[0277] In a preferred embodiment, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0278]

[0279] Preferably

[0280] wherein

[0281] R 2a is independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0282] R 2b is selected from H, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0283] s is 0, 1 or 2 (preferably 0 or 1, more preferably 0). In another preferred embodiment, s is 1.

[0284] More preferably R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0285]

[0286] Preferably

[0287] wherein

[0288] R 2b is selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, alkoxy, H or C1-C4 alkyl, preferably H, halo C1-C4 alkyl (preferably wherein the halogen is F) or C1-C4 alkyl, preferably H or C1-C4 alkyl.

[0289] In another preferred embodiment, the present invention provides a compound having the formula (Ia):

[0290]

[0291] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof,

[0292] wherein R 1 and R 2 are as defined above, and R 3 is halogen or C1-C4 alkyl; and

[0293] q is 0, 1 or 2.

[0294] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is selected from

[0295]

[0296]

[0297]

[0298]

[0299] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0300] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is selected from

[0301]

[0302]

[0303]

[0304]

[0305] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0306] In one embodiment, the present invention provides a compound of formula (I) which is a detectably labeled compound. The detectable label can be a radioisotope. In one embodiment, the compound of formula (I) comprises at least one radioisotope. Preferably the detectable label is a radioisotope selected from 18 F,2 H and 3 H. The most preferred radioisotopes are preferably 18 F and 3 H.

[0307] In one embodiment, the present invention provides a compound of formula (I), wherein R 1 is

[0308] In another embodiment, the present invention provides a compound of formula (I), wherein R 1 is -O-CH2-CH2- 18 F.

[0309] In another embodiment, the present invention provides a compound of formula (I), wherein R 2 is wherein R 2b is -CH2-CH2- 18 F or -CH2-CH2-CH2- 18 F.

[0310] In another embodiment, the present invention provides a compound of formula (I), wherein R 2 is

[0311] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is a detectable labeled compound of formula (I-F):

[0312]

[0313] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0314] is a 6-membered heteroaryl; which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0315] R 1F is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably a 4- to 6-membered heterocyclic group; or

[0316] R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably C1-C4 alkoxy or C1-C4 alkyl; or

[0317] R1F is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, and

[0318] R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl;

[0319] R 4 and R 5 are independently selected from H and C1-C4 alkyl; and

[0320] n is at least 1 (e.g., 1, 2, or 3), preferably 1.

[0321] In one embodiment, R 1F is -NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkyl, or a heterocyclic group. Preferably -R 1F -( 18 F) n is selected from the following:

[0322]

[0323] wherein R 1’ is 18 F; and s = 1, 2, or 3, preferably s = 1.

[0324] In a preferred embodiment, -R 1F -( 18 F) n is selected from the following:

[0325]

[0326] More preferably -R 1F -( 18 F) n is selected from the following:

[0327]

[0328] Even more preferably -R 1F -( 18 F) n is:

[0329]

[0330] In another embodiment, -R 1F -( 18 F) n is -O-(CH2) x - 18F (x = 1 - 4, preferably 1 - 3, more preferably 1 or 2, even more preferably 2), even more preferably -O-CH2-CH2- 18 F.

[0331] In another embodiment, the present invention provides a compound of formula (I), wherein the compound is a detectable-labeled compound of formula (I-F'):

[0332]

[0333] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0334] is a 6-membered heteroaryl, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0335] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0336] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0337] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen;

[0338] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl; and

[0339] R 2F is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy.

[0340] In a preferred embodiment, -R 2F -( 18 F) n is selected from the following: wherein R 2b is -CH2-CH2- 19F or -CH2-CH2-CH2- 18 F; or

[0341] The detectable labeled compound of formula (I-F) or (I-F’) comprises at least one 18 F. Preferably, the detectable labeled compound of formula (I-F) or (I-F’) comprises one 18 F.

[0342] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is a detectable labeled compound of formula (I-H*)

[0343]

[0344] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is a 6-membered heteroaryl, which is optionally substituted with at least one halogen; halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0345] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen; or

[0346] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0347] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen;

[0348] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0349] R 4 and R 5independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl;

[0350] provided that the compound of formula (I-H*) contains at least one 2 H (deuterium "D") or 3 H (tritium "T"), preferably 1, 2, or 3 D or T, even more preferably 2 or 3 D or T. Preferably, the compound of formula (I-H*) contains at least one 3 H (tritium "T"), preferably 1, 2, or 3 T, even more preferably 2 or 3 T. 3 H can exist as T or as -CT3. 2 H can exist as D or as -CD3.

[0351] In a preferred embodiment, the compound is a detectable-labeled compound of formula (I-H)

[0352]

[0353] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, is a 6-membered heteroaryl, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl;

[0354] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0355] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; or

[0356] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen; and

[0357] R 2is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0358] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl;

[0359] Y is D, CD3, T or CT3;

[0360] m is 0, 1, 2 or 3;

[0361] p is 0, 1, 2 or 3;

[0362] provided that the compound of formula (I-H) contains at least one D, CD3, T or CT3, where D is 2 H (deuterium), and T is 3 H (tritium). In one embodiment, the compound of formula (I-H) contains at least one D or CD3. In another embodiment, the compound of formula (I-H) contains at least one T or CT3.

[0363] It should be understood that deuterium or tritium can be present at any available position where hydrogen is present. For example, in the group R 2 deuterium or tritium can be directly bonded to the 5- or 6-membered heteroaryl (e.g., in the form of D or T), or can be present in the halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl (e.g., in the form of CD3 or CT3). In the 4- to 6-membered heterocyclic group of R 1 deuterium or tritium can be, for example, directly bonded to the 4- to 6-membered heterocyclic group.

[0364] In a preferred embodiment, is a 6-membered heteroaryl, which is optionally substituted with one halogen or C1-C4 alkyl, and m is 1, 2 or 3, preferably 1.

[0365] In one embodiment, R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl, and p is 1, 2 or 3, preferably 1.

[0366] Preferably R 2 is a 5- or 6-membered heteroaryl selected from:

[0367]

[0368] Preferably

[0369] wherein

[0370] R 2a is independently selected from T, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0371] R 2b is selected from H, T, halo C1-C4 alkyl and C1-C4 alkyl, wherein the halo C1-C4 alkyl and C1-C4 alkyl optionally contain one or more T (preferably R 2b preferably T or CT3); and

[0372] s is 0, 1 or 2 (preferably 0 or 1, more preferably 0).

[0373] Preferably R 2a is -T, -OCH3, -CH3 or -H; and R 2b is preferably -H, -T or -CT3.

[0374] Preferably R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0375]

[0376] Preferably

[0377] wherein

[0378] R 2b is selected from T, H or C1-C4 alkyl (such as CT3), preferably T, H or C1-C4 alkyl (such as CT3).

[0379] In a preferred embodiment, the detectable labeled compound of formula (I-H*) or (I-H) contains one, two or three T. Preferably, the detectable labeled compound of formula (I-H*) or (I-H) contains one T. In another embodiment, the detectable labeled compound of formula (I-H*) or (I-H) contains two T. In another embodiment, the detectable labeled compound of formula (I-H*) or (I-H) contains three T, such as -CT3.

[0380] In another embodiment, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0381]

[0382] Preferably

[0383] wherein

[0384] R 2a independently selected from D, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl;

[0385] R 2b selected from H, D, halo C1-C4 alkyl, and C1-C4 alkyl, wherein the halo C1-C4 alkyl and C1-C4 alkyl optionally contain one or more D (preferably R 2b is selected from D or CD3); and s is 0, 1, or 2 (preferably 0).

[0386] Preferably R 2a is -D, -OCH3, -CH3, or -H; and R 2b is selected from -H, -D, or -CD3.

[0387] Preferably R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0388]

[0389] wherein

[0390] R 2b is selected from D, H, or C1-C4 alkyl (such as CD3).

[0391] In one embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) contains one, two, or three D. Preferably, the detectable-labeled compound of formula (I-H*) or (I-H) contains one D. In another embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) contains two D. In another embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) contains three D, such as -CD3.

[0392] In another embodiment, the present invention provides a detectable-labeled compound of formula (I-H*) or (I-H), wherein 3 hydrogen tritium (“T”) can be 2 replaced by 2 hydrogen deuterium (“D”). The deuterated compound can be prepared by reacting a compound of formula (III-H) with

[0393] The compounds of the present invention and their precursors can be detectably labeled. There is no particular limitation on the type of label, and it will depend on the detection method selected. Examples of possible labels include isotopes such as radionuclides, positron emitters, and gamma emitters, and preferably the detectable label is a radioisotope. With respect to the detectably labeled compounds and precursors of the present invention, including radioisotopes, positron emitters, or gamma emitters, it should be understood that the radioisotope, positron emitter, or gamma emitter is present in an amount that is different from the natural amount of the corresponding radioisotope, positron emitter, or gamma emitter. In addition, the amount used should permit detection by the selected detection method. Examples of suitable isotopes such as radionuclides, positron emitters, and gamma emitters include 2 H, 3 H, 11 C, 13 N, 15 O and 18 F, preferably 2 H, 3 H and 18 F.

[0394] 18 F-labeled compounds are particularly suitable for imaging applications such as PET. Also of particular interest are the corresponding compounds that include the natural 19 F isotope, as they can be used as analytical standards and reference materials during the manufacture, quality control, release, and clinical use of their 18 F-analogues.

[0395] In addition, substitution with isotopes such as deuterium (i.e., 2 H or D) can provide certain diagnostic and therapeutic advantages due to greater metabolic stability obtained by, for example, reducing defluorination, increasing the in vivo half-life, or reducing the dose requirement, while maintaining or improving the efficacy of the original compound.

[0396] Isotopically variant forms of the compounds of the present invention can generally be prepared by conventional methods, such as by the exemplary methods or by the preparation methods described in the Examples and Preparation Examples below, using appropriate isotopically variant forms of suitable reagents, which are commercially available or prepared by known synthetic techniques.

[0397] Radioactive nuclides, positron emitters, and gamma emitters can be included in the compounds of the present invention and their precursors by methods commonly used in the field of organic synthesis. Typically, when preparing the desired compounds and precursors of the present invention, they can be introduced by using the corresponding labeled starting materials. Exemplary methods for introducing detectable labels are described, for example, in US 2012 / 0302755.

[0398] There is no particular limitation on the position where the detectable label binds to the compounds and their precursors of the present invention. For example, radionuclides, positron emitters, and gamma emitters can be attached at any position where the corresponding non-emitting atoms can also be attached. For example, 18 F can be attached at any position suitable for attaching F. The same applies to other radionuclides, positron emitters, and gamma emitters. Due to ease of synthesis, preferably R 1 is 18 substituted by 3 F. 2 H can be attached at any available position where H is present. If

[0399] In another embodiment, the present invention also relates to a compound of formula (III-F), which is a precursor of a compound of formula (I-F)

[0400]

[0401] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein

[0402] is a 6-membered heteroaryl, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl;

[0403] R 1F is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is a 4- to 6-membered heterocyclic group, or

[0404] R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is C1-C4 alkoxy or C1-C4 alkyl; or

[0405] R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl, and

[0406] R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted by 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl;

[0407] R 4 and R5 Independently selected from H and C1-C4 alkyl;

[0408] LG is a leaving group; and

[0409] n is at least 1 (e.g., 1, 2 or 3; preferably 1).

[0410] In another preferred embodiment, (LG) n -R 1F is selected from the following:

[0411]

[0412] wherein x is at least 1 (e.g., 1-3), preferably 1 or 2, even more preferably 2.

[0413] More preferably (LG) n -R 1F is selected from the following:

[0414]

[0415] wherein x is 1 or 2, more preferably 2.

[0416] Even more preferably (LG) n -R 1F is:

[0417]

[0418] In another embodiment, the present invention also relates to a compound of formula (III-F’), which is a precursor of a compound of formula (I-F’):

[0419]

[0420] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0421] is a 6-membered heteroaryl, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0422] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or

[0423] R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR4 R 5 is C1-C4 alkyl; or

[0424] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, where the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen;

[0425] R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl; and

[0426] R 2F is a 5- or 6-membered heteroaryl, which is optionally substituted by 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl; and

[0427] LG is a leaving group.

[0428] In a preferred embodiment, -R 2F -( LG ) is selected from the following: where R 2b is -CH2-CH2-LG or -CH2-CH2-CH2-LG; or

[0429] Preferably, the leaving group (LG) in (III-F) or (III-F’) is halogen, C1-C4 alkyl sulfonate, C1-C4 alkyl ammonium, or C6-C 10 aryl sulfonate, where the C6-C 10 aryl sulfonate can be optionally substituted by -CH3 or NO2. More preferably, the leaving group (LG) is bromine, chlorine, iodine, C6-C4 alkyl sulfonate, or C6-C 10 aryl sulfonate, where the C6-C 10 aryl sulfonate can be optionally substituted by -CH3 or -NO2. Even more preferably, the leaving group (LG) is mesylate, tosylate, or nosylate. Even more preferably, the leaving group (LG) is mesylate or tosylate. More preferably, the leaving group (LG) is tosylate.

[0430] In another embodiment, the present invention relates to a compound of formula (III-H), a precursor of the compound of formula (I-H):

[0431]

[0432] or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates, where

[0433] is a 6-membered heteroaryl group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0434] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably optionally substituted by at least one halogen; or

[0435] R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0436] R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen;

[0437] R 2 is a 5- or 6-membered heteroaryl group, which is optionally substituted by 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0438] R 4 and R 5 are independently selected from H, C1-C4 alkyl and halo C1-C4 alkyl;

[0439] m is 0, 1, 2 or 3;

[0440] p is 0, 1, 2 or 3; and

[0441] X is bromine, chlorine or iodine;

[0442] provided that the compound of formula (III-H) contains at least one X (for example, 1, 2 or 3 X, preferably 1 or 2 X).

[0443] In formula (III-H), the halogen is preferably F, 18 F or 19 F.

[0444] X is connected to the 6-membered heteroaryl group and / or R 2a 5- or 6-membered heteroaryl. If a halogen is present as a substituent and X is present, then in addition to the halogen, X may also be present.

[0445] In a preferred embodiment, R 2 is selected from the following:

[0446]

[0447] Preferably

[0448] wherein

[0449] R 2a is independently selected from X, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; wherein the halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkyl, or C1-C4 alkoxy is optionally substituted with one or more X;

[0450] s is 0, 1, or 2 (preferably 0 or 1); and

[0451] R 2b is selected from H, X, halo-C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl.

[0452] Preferably R 2 is selected from the following:

[0453]

[0454] Preferably

[0455] wherein

[0456] R 2a is X;

[0457] R 2b is selected from H, X, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl, preferably H, X, halo-C1-C4 alkyl, and C1-C4 alkyl, more preferably X. In another preferred embodiment, R 2b is selected from halo-C1-C4 alkyl and halo-C1-C4 alkoxy;

[0458] s is 0, 1, or 2 (preferably 0); and

[0459] wherein the C1-C4 alkyl is optionally substituted with one or more X.

[0460] In a preferred embodiment, the detectable labeled compound of formula (III-H) contains one, two or three Xs. In a preferred embodiment, the detectable labeled compound of formula (III-H) contains one or two Xs. In a more preferred embodiment, the detectable labeled compound of formula (III-H) contains two Xs. X is selected from bromine, chlorine and iodine. In a preferred embodiment, X is bromine.

[0461] Synthesis method of compounds with detectable labels

[0462] The present invention also relates to a method for preparing a compound of formula (I) or its sub-formulas (such as (I-F), (I-F'), (I-H*), (I-H)), and in particular a compound of formula (III-F), (III-F') or (III-H).

[0463] In one embodiment, the present invention relates to a method for preparing a compound of formula (I-F), which is carried out by reacting a compound of formula (III-F) with 18 an F-fluorinating agent such that LG is 18 replaced by F.

[0464]

[0465] Wherein , R 1F , R 2 , n and LG are as defined above.

[0466] In another embodiment, the present invention relates to a method for preparing a compound of formula (I-F'), which is carried out by reacting a compound of formula (III-F') with 18 an F-fluorinating agent such that LG is 18 replaced by F.

[0467]

[0468] Wherein , R 1 , R2 F and LG are as defined above.

[0469] Suitable solvents for 18 F-fluorination include DMF, DMSO, acetonitrile, DMA or mixtures thereof, preferably acetonitrile or DMSO. Suitable reagents for 18 F-fluorination are selected from K 18 F, Rb 18 F, Cs 18 F, Na 18 F, 18 tetrakis(C 1-6alkyl)ammonium salts, kryptofix

[222] 18 F and 18 F] tetrabutylammonium fluoride.

[0470] In one embodiment, the present invention relates to a method for preparing a compound of formula (I-H), which is carried out by reacting a compound of formula (III-H) with 3 a H radiolabeling reagent.

[0471]

[0472] wherein , R 1 , R 2 , X, Y, m and p are as defined above.

[0473] In one embodiment, the present invention relates to a method for preparing a compound of formula (I-H*), which is carried out by reacting a compound of formula (III-H)* with 3 a H or D radiolabeling reagent.

[0474]

[0475] wherein , R 1 , R 2 , X, m and p are as defined herein, and wherein Y is D, CD3, T or CT3.

[0476] 3 The H radiolabeling reagent can be tritium gas. The method can be carried out in the presence of a catalyst such as palladium / carbon (Pd / C), a solvent such as dimethylformamide (DMF) and a base such as N,N-diisopropylethylamine (DIEA).

[0477] In another embodiment, the compound of formula (III-H*) can be reacted with a 2 H radiolabeling reagent containing D (such as D2O, D4-methanol or other suitable reagents), preferably in the presence of a catalyst such as Pd / C, such that X is replaced by D (D is deuterium, 2 H).

[0478] Alternatively, in another embodiment, the present invention relates to a method for preparing a compound of formula (I-H*), which is carried out by radiolabeling a compound of formula (III-H*) with a 3 H radiolabeling reagent such as a CT3 radiolabeling reagent (reacting a compound of formula (III-H*)), wherein T is 3 H, such that X is replaced by CT3. The CT3 radiolabeling reagent can be ICT3 (having 3Iodomethane derivatives of H). This method can be carried out in the presence of a solvent such as dimethylformamide (DMF) and a base such as cesium carbonate or sodium hydride.

[0479] Kit

[0480] The precursor compounds of the present invention can also be used in a kit for preparing a radiopharmaceutical preparation. Due to radioactive decay, radiopharmaceuticals are usually prepared immediately before use. The kit typically contains a precursor of the compound of the present invention and a reagent that reacts with the precursor to introduce a radioactive label into the compound of the present invention. The precursor of the compound of the present invention can be, for example, a compound having the formula (III-F), (III-H*) or (III-H). The reagent can be a reagent for introducing a radioactive label such as 18F, 3H or D.

[0481] In one embodiment, the kit is a test kit for detecting and / or diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the test kit contains at least one precursor of the compound of the present invention (e.g., a compound having the formula (III-F), (III-H*) or (III-H)).

[0482] In another embodiment, the kit is a kit for preparing a radiopharmaceutical preparation, wherein the kit contains a sealed vial containing at least one precursor of the compound of the present invention (e.g., a compound having the formula (III-F), (III-H*) or (III-H)).

[0483] In a preferred embodiment, the kit is used for imaging α-synuclein aggregates, wherein the imaging is preferably carried out by positron emission tomography, or for in vitro imaging, ex vivo imaging or in vivo imaging, preferably for in vivo imaging. More preferably, the use is for brain imaging.

[0484] Diagnostic composition

[0485] The compounds of the present invention are particularly suitable for, including, imaging α-synuclein aggregates. With respect to α-synuclein aggregates, the compounds are particularly suitable for binding to different types of α-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites. Imaging can be carried out in mammals, preferably in humans. Imaging is preferably in vitro imaging, ex vivo imaging or in vivo imaging. More preferably, the imaging is in vivo imaging; even more preferably, the imaging is preferably brain imaging. Imaging can also be eye / retinal imaging. The compounds of the present invention are particularly suitable for diagnosis.

[0486] Diagnosis can be performed on mammals, preferably humans. The tissue of interest for which the diagnosis is performed can be brain, central nervous system tissue, eye tissue (e.g., retinal tissue), peripheral organ tissue, such as intestinal or other tissue, or body fluid, such as cerebrospinal fluid (CSF) or blood. The tissue is preferably brain tissue.

[0487] In one embodiment, the present invention provides a diagnostic composition comprising a compound of the present invention and optionally at least one pharmaceutically acceptable excipient, carrier, diluent, and / or adjuvant.

[0488] Due to its design and binding properties, the compound of the present invention is suitable for diagnosing diseases, disorders, and abnormalities associated with α-synuclein aggregates. In another embodiment, the diagnostic composition comprising the compound of the present invention is also suitable for diagnosing diseases, disorders, and abnormalities associated with α-synuclein aggregates.

[0489] In another embodiment, the compound of the present invention or the diagnostic composition comprising the compound of the present invention is suitable for imaging, such as in vitro imaging, ex vivo imaging, or in vivo imaging, preferably for in vivo imaging, more preferably for brain imaging. In particular, this use is for humans.

[0490] In another embodiment, the compound or diagnostic composition of the present invention is particularly suitable for positron emission tomography imaging of α-synuclein aggregates.

[0491] Diseases involving α-synuclein aggregates are generally classified as synucleinopathies (or α-synucleinopathies). The compounds of the present invention are suitable for the diagnosis of diseases, disorders or abnormalities associated with α-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites or their susceptibility, wherein the diseases, disorders or abnormalities are selected from (including but not limited to) Parkinson's disease (sporadic, familial with α-synuclein mutations or familial with mutations other than α-synuclein, pure autonomic failure and Lewy body dysphagia), SNCA repeat carriers, Lewy body dementia ("pure" Lewy body dementia), Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease and normal aging in Down syndrome). The compounds of the present invention are suitable for the diagnosis of diseases, disorders or abnormalities associated with α-synuclein aggregates, including but not limited to α-synuclein aggregates with neurons and glia, including multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy).Other diseases that may have α-synuclein immunoreactive lesions include traumatic brain injury, chronic traumatic encephalopathy, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Niemann-Pick disease type C1), motor neuron diseases, amyotrophic lateral sclerosis (sporadic, familial, and the ALS-dementia syndrome in Guam), neuroaxonal dystrophy, type 1 neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome), prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gaucher disease, and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder (Jellinger, Mov Disord 2003, 18 Suppl 6, S2-12; Galvin et al., JAMA Neurology 2001, 58(2), 186-190; Kovari et al., Acta Neuropathol. 2007, 114(3), 295-8; Saito et al., J Neuropathol Exp Neurol. 2004, 63(4), 323-328; McKee et al., Brain, 2013, 136(Pt 1), 43-64; Puschmann et al., Parkinsonism Relat Disord 2012, 18S1, S24-S27; Usenovic et al., J Neurosci. 2012, 32(12), 4240-4246; Winder-Rhodes et al., Mov Disord. 2012, 27(2), 312-315; Ferman et al., J Int Neuropsychol Soc. 2002, 8(7), 907-914). Preferably, the compounds of the present invention are suitable for diagnosing Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease dementia, SNCA repeat carriers, or Alzheimer's disease, more preferably Parkinson's disease (PD) or multiple system atrophy (MSA).

[0492] In a method for diagnosing a disease, disorder, or abnormality associated with α-synuclein aggregates, such as Parkinson's disease or MSA, or the susceptibility of a subject, the method comprises the following steps:

[0493] (a) Administering to the subject a diagnostically effective amount of a compound of the present invention or a diagnostic composition comprising a compound of the present invention;

[0494] (b) Distributing the compound of the present invention into a tissue of interest (such as brain tissue, central nervous system (CNS) tissue, eye tissue, peripheral organ tissue, or other tissues) or a body fluid (such as cerebrospinal fluid (CSF) or blood); and

[0495] (c) Image the tissue or body fluid of interest.

[0496] If the amount of the compound that binds to α-synuclein aggregates is increased compared to the normal control level, the subject has a disease, disorder or abnormality associated with α-synuclein aggregates or is at risk of developing a disease, disorder or abnormality associated with α-synuclein aggregates.

[0497] The compounds of the present invention can be used to image α-synuclein aggregates in any sample of a patient or in a specific body part or body region of the patient, and any sample of the patient or the specific body part or body region is suspected of containing α-synuclein aggregates. These compounds can cross the blood-brain barrier. Therefore, they are particularly suitable for imaging α-synuclein aggregates in the brain, central nervous system (CNS) tissue, eye tissue (such as retinal tissue), peripheral organ tissue such as the intestine or other tissues or body fluids such as cerebrospinal fluid (CSF) or blood.

[0498] In diagnostic applications, the compounds of the present invention are preferably administered in the form of a diagnostic composition comprising the compound of the present invention. A "diagnostic composition" is defined in the present invention as a composition comprising one or more compounds of the present invention, which is suitable for administration to a patient, such as a mammal, such as a human, and is suitable for diagnosing the specific disease, disorder or abnormality described above. Preferably, the diagnostic composition further comprises a pharmaceutically acceptable excipient, carrier, diluent or adjuvant. Preferably, the administration is carried out as defined below. More preferably, the composition is injected as an aqueous solution. Such compositions may also optionally contain additional ingredients, such as buffers; pharmaceutically acceptable solubilizers (such as cyclodextrins or surfactants, such as Pluronic, Tween or phospholipids); and pharmaceutically acceptable stabilizers or antioxidants (such as ascorbic acid, gentisic acid or p-aminobenzoic acid). The dose of the compound of the present invention varies depending on the exact compound administered, the patient's weight and other variables that are obvious to an experienced physician in the art.

[0499] Although the compounds of the present invention can be administered alone, they are preferably formulated into diagnostic compositions according to standard pharmaceutical practice. Therefore, the present invention also provides a diagnostic composition comprising a diagnostically effective amount of the compound of the present invention and optionally at least one pharmaceutically acceptable excipient, carrier, diluent or adjuvant.

[0500] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., New Jersey (1975). The pharmaceutical excipients can be selected according to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense that it is not harmful to its recipient.

[0501] Pharmaceutically useful excipients, carriers, adjuvants and diluents that can be used in the preparation of the diagnostic compositions of the present invention can include solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as diols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickeners, stabilizers, disintegrants, glidants, lubricants, buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorants, coating materials, preservatives, antioxidants, processing aids, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point waxes and ion exchange resins.

[0502] The route(s) of administration (delivery) of the compounds of the present invention include, but are not limited to, one or more of the following: intravenous, gastrointestinal, intrathecal, intraperitoneal, intramuscular, oral (e.g., as tablets, capsules or ingestible solutions), topical, mucosal (e.g., as nasal sprays or inhalation aerosols), nasal, parenteral (e.g., by injectable form), transdermal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, oral, epidural and sublingual. Preferably, the route of administration (delivery) of the compounds of the present invention is intravenous.

[0503] For example, the compounds can be administered orally in the form of tablets, capsules, vaginal suppositories, elixirs, solutions or suspensions, which can contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled-release applications.

[0504] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine, disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type can also be used as fillers in gelatin capsules. In this regard, preferred excipients include starch, cellulose, milk sugar (lactose), or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the agent can be combined with various sweetening or flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin and combinations thereof.

[0505] Preferably, for diagnostic applications, the compounds of the present invention are administered parenterally. If the compounds of the present invention are administered parenterally, examples of such administration include one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, or subcutaneous administration of the compound; and / or by using infusion techniques. For parenteral administration, the compound is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose to render the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0506] As shown, the compounds of the present invention can be administered intranasally or by inhalation and can conveniently be delivered from a pressurized container, pump, nebulizer, or atomizer in the form of a dry powder inhaler or aerosol spray using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes, such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, nebulizer, or atomizer can contain a solution or suspension of the active compound, for example, using a mixture of ethanol and a propellant as a solvent, which may also contain a lubricant, such as sorbitan trioleate. Capsules and cartridges (e.g., prepared from gelatin) for use in an inhaler or insufflator can be formulated to contain a mixture of the compound and a suitable powder matrix, such as lactose or starch.

[0507] Alternatively, the compounds of the present invention can be administered in the form of suppositories or vaginal suppositories, or can be administered topically in the form of gels, hydrogels, emulsions, solutions, creams, ointments or powders. The compounds of the present invention can also be administered transdermally or percutaneous, for example, by using a skin patch.

[0508] They can also be administered by the pulmonary or rectal route. They can also be administered by the ocular route. For ophthalmic use, these compounds can be formulated as an isotonic micronized suspension, pH-adjusted sterile saline or, preferably as an isotonic solution, pH-adjusted, sterile physiological saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be formulated as an ointment such as petrolatum.

[0509] For topical administration to the skin, the compounds of the present invention can be formulated as an ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in a mixture of one or more of the following, for example: mineral oil, sorbitan stearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0510] Typically, a clinician will determine the exact dosage most suitable for an individual subject. The specific dosage level and dosage frequency for any particular individual may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health status, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disorder and the individual undergoing the diagnosis.

[0511] The diagnostic compositions of the present invention can be produced in a manner known per se to those skilled in the art, for example as described in Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., New Jersey (1975).

[0512] The compounds of the present invention can be used as in vitro analytical reference substances or in vitro screening tools. They are also useful in in vivo diagnostic methods.

[0513] The compounds of the present invention can also be provided in the form of a mixture, pharmaceutical composition or combination, which comprises a compound of the present invention and at least one compound selected from imaging agents, pharmaceutically acceptable excipients, carriers, diluents or adjuvants different from the compounds of the present invention. The imaging agent different from the compound of the present invention is preferably present in a diagnostically effective amount. More preferably, the imaging agent different from the compound of the present invention is an Abeta or Tau imaging agent.

[0514] Method of use of the present invention

[0515] In one embodiment, the present invention provides a method for diagnosing a disease, disorder, or abnormality associated with α-synuclein aggregates in a subject, the method comprising the steps of:

[0516] (a) administering to the subject a compound of the present invention or a diagnostic composition comprising a compound of the present invention;

[0517] (b) allowing the compound to bind to α-synuclein aggregates; and

[0518] (c) detecting the compound that binds to α-synuclein aggregates.

[0519] Optionally, the method may further comprise the steps of:

[0520] (d) generating an image representative of the location and / or amount of the compound that binds to α-synuclein aggregates, including.

[0521] In another embodiment, the present invention provides a method for positron emission tomography (PET) imaging of α-synuclein aggregates in a subject's tissue, the method comprising the steps of:

[0522] (a) administering to the subject a compound of the present invention or a diagnostic composition comprising a compound of the present invention

[0523] (b) allowing the compound to bind to α-synuclein aggregates; and

[0524] (c) detecting the compound that binds to α-

[0525] synuclein aggregates by acquiring a positron emission tomography (PET) image of the subject's tissue.

[0526] In another embodiment, the present invention relates to a method for detecting and optionally quantifying (e.g., in vivo or in vitro methods) α-synuclein aggregates in a subject's tissue, the method comprising the steps of:

[0527] (a) contacting a sample, a specific body part, or a body region suspected of containing α-synuclein aggregates with a compound of the present invention or a diagnostic composition comprising a compound of the present invention;

[0528] (b) allowing the compound to bind to α-synuclein aggregates;

[0529] (c) detecting the compound that binds to α-synuclein aggregates; and

[0530] (d) Optionally, quantify the amount of the compound that binds to α-synuclein aggregates.

[0531] In one embodiment, the present invention relates to a method of collecting data for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, the method comprising the following steps:

[0532] (a) Contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with the compound of the present invention or a diagnostic composition comprising the compound of the present invention;

[0533] (b) Binding the compound to α-synuclein aggregates;

[0534] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0535] (d) Optionally, correlating the presence or absence of the compound that binds to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample or the specific body part or body region.

[0536] If the amount of the compound that binds to α-synuclein aggregates is higher than the normal control value, it can be presumed that the patient has a disease, disorder or abnormality associated with α-synuclein aggregates.

[0537] Another embodiment of the present invention relates to a method of collecting data for determining the susceptibility to a disease, disorder or abnormality associated with α-synuclein aggregates, the method comprising the following steps:

[0538] (a) Contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with the compound of the present invention or a diagnostic composition comprising the compound of the present invention;

[0539] (b) Binding the compound to α-synuclein aggregates;

[0540] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0541] (d) Optionally, correlating the presence or absence of the compound that binds to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample or the specific body part or body region.

[0542] If the amount of the compound that binds to α-synuclein aggregates is higher than the normal control value of healthy / reference subjects, this indicates that the patient has a disease, disorder or abnormality associated with α-synuclein aggregates, or is at risk of developing a disease, disorder and abnormality associated with α-synuclein aggregates. In particular, if the amount of the compound that binds to α-synuclein aggregates is higher than that expected in a person without clinical evidence of a disease, disorder or abnormality associated with α-synuclein aggregates, it can be presumed that the patient has a predisposition to a disease, disorder and abnormality associated with α-synuclein aggregates.

[0543] In another aspect, the present invention relates to a method of collecting data for predicting the prognosis of a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the method comprises the following steps:

[0544] (a) contacting a sample, a particular body part or body region suspected of containing α-synuclein aggregates with a compound of the present invention or a diagnostic composition comprising the compound of the present invention;

[0545] (b) binding the compound to α-synuclein aggregates;

[0546] (c) detecting the compound that binds to α-synuclein aggregates;

[0547] (d) optionally correlating the presence or absence of the compound bound to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample or the particular body part or body region; and

[0548] (e) optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0549] Medical workers can evaluate the prospects (e.g., probability, duration and / or degree) of the progression and / or recovery of a disease, disorder or abnormality based on the presence or absence of the compound bound to α-synuclein aggregates, the amount of the compound bound to α-synuclein aggregates, etc. If desired, steps (a)-(c) and, if present, the optional step (d) can be repeated over time to monitor the progression of the disease, disorder or abnormality and thus allow a more reliable evaluation.

[0550] Another aspect relates to a method of collecting data for monitoring the progression (or evolution) of a disease, disorder or abnormality associated with α-synuclein aggregates in a patient, the method comprising the following steps:

[0551] (a) contacting a sample, a particular body part or body region suspected of containing α-synuclein aggregates with a compound of the present invention or a diagnostic composition comprising the compound of the present invention;

[0552] (b) binding the compound to α-synuclein aggregates;

[0553] (c) detecting the compound that binds to α-synuclein aggregates;

[0554] (d) optionally correlating the presence or absence of the compound that binds to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in a sample or a specific body part or body region; and

[0555] (e) optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0556] In a method for monitoring progression, the amount of the compound that binds to α-synuclein aggregates can optionally be compared at different time points during treatment, such as before and after the start of treatment or at different time points after the start of treatment.

[0557] Typically, the patient has or is receiving treatment for a disease, disorder or abnormality associated with α-synuclein aggregates, or is receiving / has received treatment for synucleinopathy. In particular, the treatment can involve administering a drug suitable for treating a disease, disorder or abnormality associated with α-synuclein aggregates.

[0558] In another embodiment, the present invention relates to a method for collecting data for predicting the responsiveness of a patient suffering from a disease, disorder or abnormality associated with α-synuclein aggregates to drug treatment, the method comprising the following steps:

[0559] (a) contacting a sample, a specific body part or body region suspected of containing α-synuclein aggregates with a compound of the present invention or a diagnostic composition comprising the compound of the present invention;

[0560] (b) binding the compound to α-synuclein aggregates;

[0561] (c) detecting the compound that binds to α-synuclein aggregates;

[0562] (d) optionally correlating the presence or absence of the compound that binds to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in a sample or a specific body part or body region; and

[0563] (e) optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once. In the method for predicting responsiveness, the method can further comprise steps (i)-(vi) before step (a):

[0564] (i) contacting a sample, or a specific body part or body region, suspected of containing α-synuclein aggregates with a compound of the invention that specifically binds to α-synuclein aggregates;

[0565] (ii) binding the compound to the α-synuclein aggregates;

[0566] (iii) detecting the formation of a compound bound to the α-synuclein aggregates;

[0567] (iv) optionally correlating the presence or absence of a compound bound to the α-synuclein aggregates with the presence or absence of α-synuclein aggregates in the sample, or specific body part or body region;

[0568] (v) optionally comparing the amount of the compound bound to the α-synuclein aggregates with a normal control value; and

[0569] (vi) treating a patient with a medicament.

[0570] Optionally, the method may further comprise step (A) after step (d) or step (e):

[0571] (A) comparing the amount of the compound bound to the α-synuclein aggregates determined in step (iv) with the amount of the compound bound to the α-synuclein aggregates determined in step (d).

[0572] In a method for predicting responsiveness, the amount of the compound bound to the α-synuclein aggregates may optionally be compared at different time points during treatment, such as before and after the start of treatment or at different time points after the start of treatment. A change in the amount of the compound bound to the α-synuclein aggregates, in particular a decrease, may indicate a high response potential of the patient to the corresponding treatment.

[0573] If the amount of the compound bound to the α-synuclein aggregates decreases over time, it may be presumed that the patient is responsive to the treatment. If the amount of the compound bound to the α-synuclein aggregates is substantially constant or increases over time, it may be presumed that the patient is non-responsive to the treatment.

[0574] Alternatively, responsiveness can be evaluated by measuring the amount of a compound that binds to α-synuclein aggregates. The amount of the compound that binds to α-synuclein aggregates can be compared to a control value, such as a normal control value, a preclinical control value, or a clinical control value. Alternatively, the control value can be a control value of a subject known to respond to a certain therapy, or the control value can be a control value of a subject known not to respond to a certain therapy. The results regarding responsiveness can be "responsive" to a certain therapy, "non-responsive" to a certain therapy, or "uncertain response" to a certain treatment. The response to a therapy may vary from patient to patient.

[0575] Optionally, the diagnostic composition can be used before, during, and after a surgical procedure (such as deep brain stimulation (DBS)) and non-invasive brain stimulation (such as repetitive transcranial magnetic stimulation (rTMS)) to visualize α-synuclein aggregates before, during, and after these procedures. Surgical techniques, including DBS, have improved the late-stage symptoms of PD on the basis of the best medical therapies currently in use. In the past 20 years, rTMS has been closely studied as a possible treatment for PD (Ying-hui Chou et al. JAMA Neurol. April 1, 2015; 72(4): 432-440).

[0576] In any of the above methods, optionally, the step of correlating the presence or absence of a compound that binds to α-synuclein aggregates with the presence or absence of α-synuclein aggregates in a sample or a specific body part or body region; comprises

[0577] - measuring the amount of the compound that binds to α-synuclein aggregates;

[0578] - correlating the amount of the compound that binds to α-synuclein aggregates with the amount of α-synuclein aggregates in a sample or a specific body part or body region; and

[0579] - optionally comparing the amount of the compound that binds to α-synuclein aggregates in a sample or a specific body part or body region with a normal control value of a healthy control subject.

[0580] The control value can be, for example, a normal control value, a preclinical control value, and / or a clinical control value.

[0581] A "healthy control subject" or a "healthy volunteer (HV) subject" is a person without clinical evidence of a disease, disorder, or abnormality related to α-synuclein aggregates.

[0582] In an embodiment of any of the above methods, the α-synuclein aggregates include but are not limited to Lewy bodies and / or Lewy neurites.

[0583] If, in any of the methods outlined above, the amount of the compound that binds to α-synuclein aggregates is higher than the normal control value, it can be expected that the patient has or may have a disease, disorder or abnormality associated with α-synuclein aggregation or may have an α-synucleinopathy.

[0584] Contact a sample or a specific body part or body region suspected of containing α-synuclein aggregates with the compound of the present invention.

[0585] Any compound of the present invention can be used in the methods outlined above. Preferably, a compound of the present invention with a detectable label is used in the methods outlined above.

[0586] The specific body part or body region is preferably mammalian, more preferably human, and includes the whole body or a part of the body region or body part of a patient suspected of containing α-synuclein aggregates. The specific body part or body region can be the brain, central nervous system, eye or peripheral organs such as the gut, preferably the brain.

[0587] The tissue can be brain tissue, central nervous system (CNS) tissue, eye tissue (such as retinal tissue), tissue of peripheral organs such as the gut or other tissues, or a body fluid, such as cerebrospinal fluid or blood. The tissue is preferably brain tissue. Preferably, the sample is an in vitro sample from a patient.

[0588] In the above methods, the compound of the present invention can be brought into contact with a sample or a specific body part or body region suspected of containing α-synuclein aggregates by any suitable method.

[0589] In an in vitro method, the compound of the present invention and a liquid sample can simply be mixed.

[0590] In an in vivo method, a specific body part or body region can be brought into contact with the compound of the present invention by administering an effective amount of the compound of the present invention to the patient.

[0591] The effective amount of the compound of the present invention is an amount suitable for enabling the determination of the presence or absence of α-synuclein aggregates in a sample, a specific body part or body region using the selected analytical technique. There is no particular limitation on this amount and it will depend on the compound of formula (I), the type of detectable label, the sensitivity of the corresponding analytical method and the corresponding apparatus. This amount can be appropriately selected by a person skilled in the art.

[0592] Then the compound is brought into binding with α-synuclein aggregates. The step of bringing the compound into binding with α-synuclein aggregates includes allowing the compound of the present invention sufficient time to bind to the α-synuclein aggregates. The time period required for binding depends on the type of test (e.g., in vitro or in vivo) and can be determined by those skilled in the art through routine experimentation. In an in vivo method, the time period depends on the time required for the compound to reach a specific body part or body region suspected of containing α-synuclein aggregates. This time period should not be too long so as to avoid clearance and / or metabolism of the compound of the present invention.

[0593] Subsequently, the compound bound to the α-synuclein aggregates can be detected by any suitable method. There is no particular limitation on the method for detecting the compound bound to the α-synuclein aggregates, and it depends on factors such as the detectable label, sample type, specific body part or body region, and whether the method is an in vitro or in vivo method. Examples of possible methods include but are not limited to fluorescence imaging techniques or nuclear imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). These have been described and enable visualization of α-synuclein biomarkers. Fluorescence imaging techniques and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the detectable labeled compound in a sample or a specific body part or body region. The imaging system provides an image of the boundary detectable label, such as a radioisotope, particularly a positron emitter or a γ emitter, as present in the test sample, the specific body part being tested, or the body region being tested. Preferably, the compound bound to the α-synuclein aggregates is detected by an imaging device such as a PET or SPECT scanner, more preferably PET.

[0594] The amount of the compound bound to the α-synuclein aggregates can be determined visually or by quantitative analysis, such as using PET scan images.

[0595] The compound of the present invention or its precursor can also be incorporated into a test kit for detecting α-synuclein protein aggregates. The test kit typically contains a container holding one or more compounds of the present invention or their precursors, as well as instructions for using the compound to bind to the α-synuclein aggregates and detect the compound formed by binding to the α-synuclein aggregates, such that the presence or absence of the compound bound to the α-synucleic acid protein aggregates is correlated with the presence or absence of the α-synucleic acid protein aggregates.

[0596] The term "test kit" generally refers to any diagnostic kit known in the art. More specifically, the latter term refers to a diagnostic kit as described by Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.

[0597] The compounds of the invention which are detectable labels, preferably with 18 compounds of formula (III-F) labeled with F or with 3 the dose of the compounds of formula (I-H*) or (I-H) labeled with H will vary depending on the exact compound to be administered, the weight of the patient, the size and type of the sample, and other variables which will be apparent to a physician experienced in the art. Generally, the dose can preferably be in the range of 0.001 μg / kg - 10 μg / kg, preferably 0.01 μg / kg - 1.0 μg / kg. The radioactive dose can be, for example, 100 - 600 MBq, more preferably 150 - 450 MBq.

[0598] Synthesis method of the compounds of the present invention

[0599] The compounds of the invention can be prepared by the routes described in the following schemes or examples according to the definition of the compounds of formula (I). All methods described herein can be carried out in any suitable order, except as otherwise indicated herein or as is clearly inconsistent with the context. The use of any and all examples or exemplary language (e.g., "for example") provided herein is only intended to better illustrate the invention and does not limit the scope of the invention otherwise claimed. In the following general methods, R 1 、R 2 、 、LG and Hal are as previously defined in the above embodiments, or are limited to the names in the schemes. Unless otherwise indicated, the starting materials are commercially available or are prepared by known methods.

[0600] General synthetic schemes for preparing the compounds of the invention:

[0601] Scheme 1

[0602]

[0603] Commercially available or custom-made aldehyde derivatives containing an acid-sensitive protecting group (Pg) on the triazolo- moiety can react with a suitable amine through reductive amination. After purification, intermediate A is obtained. Then, through Suzuki coupling, the halogen atom is replaced by a heteroarylboronic acid derivative containing a leaving group (LG). After purification, intermediate B is obtained. Then, LG is replaced by a suitable amine derivative through aromatic nucleophilic substitution. After purification, intermediate C is obtained. Pg is removed by acid treatment. After purification, intermediate D is obtained. Alternatively, the halogen atom of a commercially available or custom-made aldehyde derivative containing an acid-sensitive Pg on the triazolo- moiety is replaced by a heteroarylboronic acid derivative through Suzuki coupling. After purification, intermediate E is obtained. Intermediate E is subjected to reductive amination with a suitable amine. After purification, intermediate F is obtained. Pg of intermediate F is removed by acid treatment. After purification, intermediate D is obtained. 1,1'-Carbonyldiimidazole (CDI) is used to cyclize intermediate D in a suitable solvent to obtain a compound of formula G as the free base. Acid treatment of the compound of formula G is used to obtain the salt of the compound of formula (I).

[0604] Scheme 2

[0605]

[0606] A commercially available or custom-made triazolo derivative containing an ester moiety is treated with a suitable reagent. After purification, an acid-sensitive Pg is introduced. Then, the halogen atom is replaced by a heteroarylboronic acid derivative containing a leaving group (LG) through Suzuki coupling. After purification, intermediate B is obtained. Then, LG is replaced by a suitable amine derivative through aromatic nucleophilic substitution. After purification, intermediate C is obtained. The ester moiety is reduced to the corresponding alcohol to obtain intermediate D after purification. The alcohol moiety is moderately oxidized with a reagent such as Dess-Martin reagent (DMP) to obtain an intermediate E containing an aldehyde. Intermediate E is subjected to reductive amination with a suitable amine. After purification, intermediate F is obtained. Pg of intermediate F is removed by acid treatment. After purification, intermediate D is obtained. 1,1'-Carbonyldiimidazole (CDI) is used to cyclize intermediate D in a suitable solvent to obtain a compound of formula H as the free base. Acid treatment of the compound of formula H can be used to obtain the salt of the compound of formula (I).

[0607] 1 8 General synthesis of the F-labeled compounds of the present invention :

[0608] It can be prepared by reacting a precursor compound (III-F) as described below with 18 an F-fluorinating agent such that the LG contained in the precursor compound is replaced by 18 F to thereby prepare 18 an F-labeled compound of formula (I).

[0609] It can be used for 18F-fluorination reagents, solvents and conditions are well known to those skilled in the art (L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, 2853-2873; J. Fluorine Chem., 27(1985):177-191; Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006),: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp.15-50). Preferably, for 18 F-fluorination, the solvent is DMF, DMSO, acetonitrile, DMA or a mixture thereof. Preferably, the solvent is acetonitrile or DMSO.

[0610] Any suitable 18 F-fluorinating agent can be used. Typical examples include H 18 F, alkali metal or alkaline earth metal 18 F-fluorides (such as K 18 F, Rb 18 F, Cs 18 F and Na 18 F). Optionally, 18 the F-fluorinating agent can be used in combination with a chelating agent, such as a cryptand (such as: 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane- ).) or a crown ether (such as: 18-crown-6). Alternatively, 18 the F-fluorinating agent can be 18 a tetraalkylammonium salt of 18 F or 18 a tetraalkylphosphonium salt of 1-6 F; for example 18 a tetra(C 1-6 alkyl)ammonium salt of 18 F or 1-6 a tetra(C 18 alkyl)phosphonium salt of 18 F. Preferably, 18 the F-fluorinating agent is K 18 F, H 18 F, Cs 18 F, Na 18 F, 18 a tetra(C 1-6 alkyl)ammonium salt of 1-6 F, kryptofix

[222] 18 F or 18 tetrabutylammonium 18 F] fluoride.

[0611] Although the above regarding 18 F as a radioactive label shows the reaction, other radioactive labels can be introduced in a similar manner.

[0612] The present invention is illustrated by the following examples. However, these examples should not be construed as limiting. Examples

[0613] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. In all methods, it should be understood that, in accordance with the general principles of chemistry, protecting groups for sensitive or reactive groups can be used when necessary. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed using methods obvious to those skilled in the art at a convenient stage of the compound synthesis.

[0614] Unless otherwise stated, all reagents and solvents are obtained from commercial sources and can be used without further purification.

[0615] These chemical names were generated using ChemBioDraw Ultra v20 from CambridgeSoft.

[0616] Temperatures are given in degrees Celsius. Unless otherwise mentioned, all evaporations are carried out under reduced pressure, typically at about 15 mmHg - 100 mmHg (= 20 - 133 mbar). The structures of the end products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopic features, such as MS, IR, NMR.

[0617] Abbreviation:

[0618] The abbreviations used are those conventional in the art.

[0619]

[0620]

[0621] Analysis details, preparation and analysis methods

[0622] NMR measurements were carried out in deuterated solvents on a DRX-400 MHz NMR spectrometer or a Bruker AV-400 MHz NMR spectrometer, with or without TMS as an internal standard. Chemical shifts (δ) from low field of TMS are given in ppm, and the spectral splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), septet (sept), multiplet, unresolved or overlapping signals (m), or broad signals (br). The deuterated solvents are given in parentheses and have a chemical shift of dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR spectral data.

[0623] MS was recorded on an Advion CMS mass spectrometer or on a UPLC H-Class Plus with a photodiode array detector and a Qda mass spectrometer from Waters.

[0624] Column chromatography was performed using silica gel (Fluka: silica gel 60, 0.063 - 0.2 mm) and a suitable solvent as indicated in the specific examples.

[0625] Flash column chromatography system: Flash purification was carried out using a Biotage Isola One flash purification system, which uses HP Sil or KP-NH SNAP columns (Biotage) and a solvent gradient as indicated in the specific examples.

[0626] TLC was performed on silica gel plates using UV detection.

[0627] Preparation examples

[0628] Preparation example 1

[0629]

[0630] The compound was purchased from the commercial supplier Aurum Pharmatech LLC.

[0631] Preparation example 2

[0632]

[0633] Step - A:At 0 °C under a nitrogen atmosphere, 5-bromo-2-fluoropyridine (5.0 g, 28.4 mmol) was added portionwise to a stirred solution of 2-fluoroethanol (1.82 mL, 31.2 mmol) and sodium hydride (60% dispersed in mineral oil) (1.25 g, 31.2 mmol) in THF (100 mL) over 15 min. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (5.0 g, 79%).

[0634] 1 H NMR (CDCl3) δ 8.17 (dd, 1H), 7.66 (dd, 1H), 6.73 (dd, 1H), 4.80 (m, 1H), δ 4.68 (m, 1H), 4.57 (m, 1H), 4.50 (m, 1H).

[0635] Step - B: Under an argon atmosphere, the title compound from the above Step A (5.0 g, 22.7 mmol), bis(pinacolato)diboron (11.5 g, 45.4 mmol), KOAc (6.7 g, 68.9 mmol) and 1,4-dioxane (250 mL) were added to a dried flask. The reaction mixture was degassed with argon for 15 min. Then [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1.8 g, 22.7 mmol) was added and the reaction mixture was heated to 60 °C for 5 h. The solvent was removed under reduced pressure and the crude material was treated with a 40% EtOAc in hexane solution (200 mL) and filtered through a Celite pad. The filtrate was dried over Na2SO4, concentrated and the residue was purified by silica gel chromatography (100 - 200 mesh) using a 10% EtOAc in hexane solution to give the title compound as a pale yellow solid (3.5 g, 57%).

[0636] 1 H NMR (CDCl3) δ 8.51 (q, 1H), 7.94 (dd, 1H), 6.78 (dd, 1H), δ 4.81 (m, 1H), 4.69 (m, 1H), 4.64 (m, 1H), 4.57 (m, 1H), δ 1.35 (d, 1H), 1.34 (s, 12H).

[0637] Preparation example 3

[0638]

[0639] The compound was purchased from the commercial supplier SV ChemBioTech, Inc.

[0640] Preparation example 4

[0641]

[0642] (2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol), pyrrolidine (0.7 mL, 8.2 mmol), DIPEA (1.6 mL, 9.4 mmol) and NMP (10 mL, 10 vol) were heated at 160 °C under microwave irradiation for 1 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL), and the crude reaction mass was filtered through a Buchner funnel. The crude solid was washed with pentane (5 mL x 3) and dried under high vacuum to give the desired intermediate as a yellow solid (80 mg, 70%).

[0643] 1 H NMR (DMSO-d6) δ 8.59 (s, 2H), 7.97 (s, 2H), 3.48 (t, 4H), 1.91 (m, 4H).

[0644] MS (ESI): 193.73 [M+H].

[0645] Preparation example 5

[0646]

[0647] Step - A: 2,5-Dibromopyrazine (5.0 g, 21 mmol), pyrrolidine (1.8 g, 25.2 mmol), CS2CO3 (6.8 g, 21 mmol) and DMSO (50 mL, 10 vol) were heated at 100 °C under microwave irradiation for 16 h. After completion, the reaction mixture was quenched with ice-cold water (60 mL), and the crude reaction mass was filtered through a Buchner funnel. The solid was dried under high vacuum to give the desired product as a yellow solid (4.3 g, 90%).

[0648] 1 H NMR (CDCl3) δ 8.10 (d, 1H), 7.61 (d, 1H), 3.44 (t, 4H), 2.06 - 2.02 (m, 4H).

[0649] MS (ESI): 229.9 [M+H].

[0650] Step - B:At -78 °C under a N2 atmosphere, nBuLi (2.5 M hexane solution) (4.2 mL, 10.5 mmol) was added dropwise to a stirred solution of the product of Step A (2.0 g, 8.77 mmol) in THF (80 mL, 40 vol.). The mixture was stirred for 1 h. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 mL, 10.5 mmol) was added and the mixture was stirred at -78 °C for 2 h and at rt for 3 h. The reaction time was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Without further purification, the crude reaction product was used directly in the next step as such.

[0651] MS(ESI): 276.3 [M+H].

[0652] Preparation example 6

[0653]

[0654] Step - A: To a solution of 4-nitro-1H-pyrazole (2.5 g, 21.9 mmol) in DMF (50 mL, 20 vol.) was added Cs2CO3 (21.5 g, 65.9 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (10.2 g, 43.9 mmol). The mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated in vacuo and water (100 mL) was added to the residue. The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 - 200 mesh) eluting with a 50% EtOAc in hexane solution to give the desired product as a yellow oil (3.0 g, 78%).

[0655] 1 1H NMR (CDCl3) δ 8.18 (s, 1H), 8.10 (s, 1H), 4.52 (t, 1H), 4.41 (t, 1H), 4.33 (t, 2H), 2.37 - 2.25 (m, 2H).

[0656] MS(ESI) 174.05 [M+H].

[0657] Step - B:To a solution of the product of Step A (3.2 g, 18.48 mmol) in methanol (96 mL, 30 vol.) under N2 atmosphere was gradually added 10% Pd / C (640 mg, 20% w / w). Then the vessel was filled with H2 gas and the mixture was stirred at rt for 20 h. The progress of the reaction was monitored by TLC. After completion, the mixture was filtered through celite and the celite was washed with MeOH (3 x 100 mL). The combined filtrate was concentrated in vacuo to give the desired product as a yellow oil (2.6 g, 93%).

[0658] 1 1H NMR (CDCl3) δ 7.04 (s, 1H), 6.91 (s, 1H), 4.43 (t, 1H), 4.33 (t, 1H), 4.01 (t, 2H), 3.89 (s, 2H), 2.06 (tt, 2H).

[0659] MS (ESI) 144.0 [M+H].

[0660] Preparation example 7

[0661]

[0662] Step - A: To a solution of 3-nitro-1H-pyrazole (2.0 g, 17.6 mmol) in DMF (40 mL, 20 vol.) was added Cs2CO3 (17.3 g, 53.1 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (8.2 g, 35.4 mmol). The mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated in vacuo and water (80 mL) was added to the residue. The aqueous layer was extracted with EtOAc (2 x 80 mL), the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material obtained was purified by silica gel column chromatography (100 - 200 mesh), eluting with a hexane solution of 50% EtOAc to give the desired product as a yellow oil (2.3 g, 75%).

[0663] 1 1H NMR (CDCl3) δ 7.50 (d, 1H), 6.91 (d, 1H), 4.51 (t, 1H), 4.40 - 4.36 (m, 3H), 2.45 - 2.27 (m, 2H).

[0664] MS (ESI) 174.11 [M+H].

[0665] Step - B:Under a N2 atmosphere, 10% Pd / C (230 mg, 10% w / w) was gradually added to a solution of the product from step A (2.3 g, 13.2 mmol) in methanol (70 mL, 30 vol.). The reaction vessel was filled with H2 gas, and the mixture was stirred at rt for 21 h. The progress of the reaction was monitored by TLC. After completion, the mixture was filtered through Celite, and the Celite was washed with MeOH (3 x 100 mL). The combined filtrate was concentrated in vacuo to give the desired product as a yellow oil (1.7 g, 86%). The compound was pure enough to be used directly in the next step without further purification.

[0666] 1 1H NMR (DMSO-D6) δ 7.32 (d, 1H), 5.40 - 5.39 (m, 1H), 4.87 (s, 2H), 4.45 (t, 1H), 4.33 (t, 1H), 3.93 (t, 2H), 2.11 - 2.08 (m, 1H), 2.06 - 1.98 (m, 1H).

[0667] MS (ESI) 144.01 [M+H].

[0668] Examples of the present invention

[0669] Example 1: (R)-2-(6-(3-fluoropyrrolidin-1-yl)-2-methylpyridin-3-yl)-6-(pyridin-3-yl)-6, 7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one hydrochloride

[0670]

[0671] Step A: At 0 °C under a nitrogen atmosphere, molecular sieves and glacial AcOH (7.5 mL) were added to a stirred solution of (3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-carbaldehyde (3.0 g, 9.6 mmol) and pyridin-3-amine (1.17 g, 12.5 mmol) in 1,2-dichloroethane (120 mL). The reaction mixture was stirred for 4 h to reach room temperature. Then sodium triacetoxyborohydride (4.0 g, 19.2 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 (100 mL), and the product was extracted with a DCM solution of 5% MeOH (3 x 250 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (100 - 200 mesh) using silica gel and a DCM solution of 2% MeOH to give the title compound as a yellow liquid (3.0 g, 76%).

[0672] 1 ​1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, 1H), 7.81 (dd, 1H), 7.09 (dd, 1H), 6.99 (dq, 1H), 6.49 (t, 1H), 5.70 (dd, 1H), 4.53 (m, 2H), 3.88 (m, 1H), 3.69 (m, 1H), 2.09 (m, 1H), 1.93 (m, 2H), 1.60 (m, 3H).

[0673] MS: 338.24 [M+H] + .

[0674] Step B: In an argon atmosphere, in a dried screw-cap vial, add the title compound from the above step A (0.6 g, 1 - 78 mmol), (6-fluoro-2-methylpyridin-3-yl)boronic acid (0.55 g, 3.5 mmol), K2CO3 (0.49 g, 3.5 mmol) and a mixture of 1,4-dioxane and water (30 mL, 4 / 1). Degas the reaction mixture with argon for 15 min. Then add the complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with dichloromethane (0.145 g, 0.178 mmol), and heat the reaction mixture to 90 °C for 4 h. Quench the reaction mixture with ice-water and extract with a DCM solution of 10% MeOH (3 x 30 mL). Dry the organic layer over Na2SO4, concentrate, and purify by silica gel chromatography (100 - 200 mesh) using a DCM solution of 4% MeOH to obtain the title compound as a light brown liquid (0.45 g, 68%).

[0675] 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, 1H), 8.09 (d, 1H), 7.81 (q, 1H), 7.09 (m, 1H), 6.51 (t, 1H), 5.78 (m, 1H), 4.60 (ddd, 2H), 3.91 (d, 1H), 3.73 (m, 1H), 2.70 (s, 3H), 2.24 (m, 1H), 2.01 (m, 3H), 1.69 (t, 1H), 1.57 (q, 2H), 1.34 (s, 1H), 1.23 (d, 4H), 1.17 (q, 1H).

[0676] MS: 369.15 [M+H] + .

[0677] Step - C: In an argon atmosphere, combine the title compound from step B above (0.1 g, 0.27 mmol), (R)-3-fluoropyrrolidine hydrochloride (0.051 g, 0.40 mmol), DIPEA (0.14 mL, 0.8 mmol), and NMP (5 mL) in a dried microwave vial. Heat the reaction mixture in a microwave oven at 160 °C for 4 h. Quench the reaction mixture with ice-cold water (10 mL) and extract with a DCM solution of 5% MeOH (3 x 10 mL). Wash the combined organic layers with a cold brine solution (2 x 10 mL), dry over Na2SO4, and concentrate in vacuo. Purify the crude material by column chromatography using silica gel (100 - 200 mesh) with a DCM solution of 3% MeOH to obtain the title compound as a white solid (0.050 g, 42%).

[0678] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.99 (d, 1H), 7.80 (q, 1H), 7.08 (dd, 2H), 6.44 (m, 2H), 5.71 (dd, 1H), 5.44 (m, 1H), 4.54 (ddd, 2H), 3.91 (d, 1H), 3.67 (m, 4H), 3.43 (td, 1H), 2.63 (s, 3H), 2.20 (m, 3H), 1.98 (m, 2H), 1.63 (m, 3H).

[0679] Step - D : At 0 °C under a nitrogen atmosphere, add a solution of 4 M HCl in 1,4-dioxane (0.5 mL) to a stirred solution of the title compound from step c above (0.050 g, 0.11 mmol) in DCM (2.5 mL). Stir the reaction mixture for 6 h and allow it to reach room temperature. Remove the solvent in vacuo to obtain the title compound as a hydrochloride salt. Wash the yellow solid with hexane (3 x 5 mL) and dry in vacuo.

[0680] MS: 354.25 [M+H] + 。

[0681] Step - E: Under a nitrogen atmosphere, sodium hydride (60% dispersed in mineral oil) (0.004 g, 0.17 mmol) was added to a cold solution of the title compound from the above step D (0.04 mg, 0.1 mmol) in 1,2-DCE (2 mL). The reaction mixture was stirred at room temperature for 30 min. Then, 1,1'-carbonyldiimidazole (0.16 g, 1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with ice-cold water, and the product was extracted with a DCM solution of 5% MeOH. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh) using a DCM solution of 4% MeOH to give the title compound as a white solid (0.02 mg, 51%).

[0682] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, 1H), 8.46 (m, 1H), 8.19 (d, 1H), 8.16 (d, 1H), 7.54 (d, 1H), 6.51 (d, 1H), 5.46 (d, 1H), 5.26 (s, 2H), 3.72 (m, 3H), 3.48 (m, 1H), 2.73 (s, 3H), 2.22 (m, 2H).

[0683] MS: 379.9 [M + H] + 。

[0684] Step - F : At 0 °C under a nitrogen atmosphere, a solution of 4M HCl in 1,4-dioxane (0.2 mL) was added to a stirred solution of the title compound from the above step E (0.020 g, 0.05 mmol) in DCM (2 mL). The reaction mixture was stirred for 6 h and warmed to room temperature. The solvent was evaporated, and the residue was treated with pentane and dried in vacuo to give the title compound as a yellow solid (0 - 015 g, 71%).

[0685] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (d, 1H), 8.57 (m, 1H), 8.40 (d, 1H), 7.74 (q, 1H), 6.94 (s, 1H), 5.55 (d, 1H), 5.34 (s, 2H), 3.77 (m, 4H), 3.57 (s, 1H), 2.91 (s, 3H), 2.30 (m, 2H).

[0686] MS: 379.9 [M + H] + 。

[0687] Examples 2 - 5

[0688] Following a method similar to that described for Example 1, except using the reagents indicated in the specific steps of Table 1 below, the following examples were prepared.

[0689] Table 1 :

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702] Example 7: (S)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)- 6,7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one hydrochloride

[0703]

[0704] Step A:To a cold solution of ethyl 5-bromo-1H-1,2,4-triazole-3-carboxylate (2.5 g, 11.3 mmol) in THF (50 mL) under a nitrogen atmosphere was added sodium hydroxide (60% dispersed in mineral oil) (0.59 g, 14.7 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0 °C, and 2-(trimethylsilyl)ethoxymethyl chloride (2.4 mL, 13.6 mmol) was added dropwise. The reaction mixture was stirred for 16 h to reach room temperature. The reaction mixture was quenched with ice-water, and the reaction mixture was extracted with EtOAc (3 x 75 mL). The combined organic phases were washed with brine (2 x 25 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh) using a hexane solution of 10% EtOAc to give the title compound as a yellow oil (0.96 g, 24%).

[0705] 1 H NMR (400 MHz, CDCl3) δ 5.86 (s, 2H), 4.48 (q, 2H), 3.67 (m, 2H), 1.45 (d, 3H), 0.92 (m, 2H), -17.45 (s, 9H).

[0706] MS: 352.79 [M + 2H] + 。

[0707] Step B: To a dried screw-cap vial under an argon atmosphere was added the title compound from the above Step A (0.2 g, 0.57 mmol), (6-fluoropyridin-3-yl)boronic acid (0.096 g, 0.68 mmol), Cs2CO3 (0.371 g, 1.14 mmol), and 1,4-dioxane (8 mL). The reaction mixture was degassed with argon for 15 min. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.048 g, 0.06 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.023 g, 0.06 mmol) were added, and the reaction mixture was heated to 80 °C for 3 h. The reaction system was quenched with ice-water, and the reaction mixture was extracted with DCM (3 x 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100 - 200 mesh) using a hexane solution of 20% EtOAc to give the title compound as a yellow liquid (0.170 g, 81%).

[0708] 11H NMR (400 MHz, CDCl3) δ 9.01 (d, 1H), 8.54 (td, 1H), 7.02 (dd, 1H), δ 5.95 (s, 2H), 4.54 (q, 2H), 3.71 (t, 2H), 1.48 (t, 3H), 0.95 (t, 2H), -22.7 (s, 9H).

[0709] MS: 367.25 [M+H] + 。

[0710] Step C: In an argon atmosphere, the title compound from the above step B (3.0 g, 8.2 mmol), (S)-3-fluoropyrrolidine hydrochloride (2.0 g, 16.3 mmol), DIPEA (7.13 mL, 41 mmol), and ethanol (30 mL) were combined in a dried microwave vial. The reaction mixture was heated at 130 °C in a microwave oven for 3 h. The solvent was removed in vacuo, and the resulting crude material was purified by silica gel column chromatography (100 - 200 mesh) using a hexane solution of 50% EtOAc to give the title compound as a white solid (1.8 g, 50%).

[0711] 1 1H NMR (400 MHz, CDCl3) δ 8.94 (d, 1H), 8.20 (dd, 1H), 6.44 (d, 1H), 5.92 (s, 2H), 5.40 (dt, 1H), 4.52 (q, 2H), 3.91 (q, 1H), 3.69 (m, 4H), 3.64 (m, 2H), 2.41 (m, 1H), 2.17 (m, 1H), 1.48 (t, 3H), -23.4 (s, 9H).

[0712] MS: 436.58 [M+H] + 。

[0713] Step D: At 0 °C under a nitrogen atmosphere, sodium borohydride (1.25 g, 33 mmol) was added portionwise to a cold solution of the title compound from the above step C (1.8 g, 4.13 mmol) in MeOH (90 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, and the reaction system was quenched by adding ammonium chloride (effervescence!). The solvent was removed in vacuo, the crude material was diluted with water, and extracted with DCM (3 x 100 mL). The combined organic layers were washed with a cold brine solution (100 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound as a white solid (1.6 g, 98%).

[0714] 11H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H), 8.11 (dd, 1H), 6.44 (d, 1H), 5.55 (s, 2H), 5.39 (dt, 1H), 4.88 (s, 2H), 3.90 (q, 1H), 3.80 (s, 1H), 3.68 (m, 6H), 2.41 (m, 1H), 2.17 (m, 1H), 0.93 (t, 2H), 0.85 (m, 1H), -16.2 (s, 9H).

[0715] MS: 394.62 [M+H] + 。

[0716] Step E: At 0 °C under a nitrogen atmosphere, the Dess-Martin reagent (3.45 g, 8.14 mmol) was added portionwise to a cold solution of the title compound from the above step D (1.6 g, 4.0 mmol) in DCM (48 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and the reaction system was quenched by adding saturated NaHCO3 (50 mL). The reaction mixture was extracted with DCM (3 x 80 mL). The combined organic layers were washed with a cold brine solution (80 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography (100 - 200 mesh) using silica gel and a hexane solution of 50% EtOAc to give the title compound as a white solid (1.3 g, 82%).

[0717] 1 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.95 (d, 1H), 8.18 (dd, 1H), 6.47 (d, 1H), 5.86 (s, 2H), 5.41 (dt, 1H), 3.93 (q, 1H), 3.71 (m, 6H), 2.43 (m, 1H), 2.18 (m, 1H), 0.94 (t, 2H), -22.03 (s, 9H).

[0718] MS: 392.26 [M+H] + 。

[0719] Step F: Under a nitrogen atmosphere, molecular sieves were added to a stirred solution of the title compound from the above step E (0.4 g, 1.0 mmol) and 1-methyl-1H-pyrazol-4-amine (0.1 g, 1.0 mmol) in 1,2-dichloroethane (16 mL) And ice AcOH (0.8 mL). The reaction mixture was stirred at room temperature for 2 h. Then sodium triacetoxyborohydride (0.43 g, 2.0 mmol) was added, and the compound was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL), and the reaction mixture was extracted with a 5% MeOH in DCM solution (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (100 - 200 mesh) using silica gel and a 3% MeOH in DCM solution to give the title compound as a yellow liquid (0.4 g, 83%).

[0720] MS: 473.59 [M+H] + 。

[0721] Step G: To a stirred solution of the title compound from the above step F (0.4 mg, 0.85 mmol) in DCM (8.0 mL) at 0 °C under a nitrogen atmosphere was added a solution of 4M HCl in 1,4 - dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 2 h, the solvent was evaporated under reduced pressure, the residue was washed with pentane and dried in vacuo to give the title compound as a yellowish - white solid (0.28 g, 97%).

[0722] MS: 341.13 [M+H] + 。

[0723] Step H: To a cold solution of the title compound from the above step G (0.28 g, 0.82 mmol) in 1,2 - dichloroethane (17 mL) under a nitrogen atmosphere was added sodium hydride (60% dispersed in mineral oil) (0.033 g, 0.82 mmol). The reaction mixture was stirred at room temperature for 30 min. Then 1,1′ - carbonyldiimidazole (1.33 g, 8.2 mmol) was added to the reaction mixture, and the compound was stirred at room temperature for 24 h. The reaction mixture was quenched with ice - cold water, and the reaction mixture was extracted with a 5% MeOH in DCM solution (3 x 40 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC using a 5% MeOH in DCM solution as the mobile phase. The solvent was removed in vacuo to give the title compound as a yellowish - white solid (0.009 g, 3%).

[0724] 11H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 6.61 (d, 1H), 5.44 (d, 1H), 4.99 (s, 2H), 3.83 (m, 3H), 3.68 (m, 3H), 3.45 (m, 1H), 2.19 (m, 2H).

[0725] MS: 368.95 [M+H] + 。

[0726] Step I: At 0 °C under a nitrogen atmosphere, a solution of 4M HCl in 1,4-dioxane (0.6 mL) was added to a stirred solution of the title compound from the above step H (0.006 g, 0.024 mmol) in DCM (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the hydrochloride salt. The off-white solid was washed with n-hexane (2 mL) and then dried in vacuo to give the title compound as a white solid (0.004 g, 40%).

[0727] 1 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, 1H), 8.70 (d, 1H), 8.56 (d, 1H), 8.38 (dd, 2H), 7.72 (q, 1H), 7.00 (d, 1H), 5.54 (d, 1H), 5.32 (s, 2H), 3.85 (m, 3H), 3.61 (td, 1H), 2.26 (m, 2H).

[0728] MS: 368.90 [M+H] + 。

[0729] Examples 8 - 10

[0730] Following the same method as described for Example 7, except using the reagents indicated in the specific steps in Table 2 below, the following examples were prepared.

[0731] Table 2:

[0732]

[0733]

[0734]

[0735] Example 11: (2-(6-(2-Fluoroethoxy)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one

[0736]

[0737] Step A: 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-carbaldehyde (1.5 g, 5.7 mmol), the title compound from Preparation Example 2 (3.1 g, 11.5 mmol), K2CO3 (1.6 g, 11.5 mmol), and a mixture of 1,4-dioxane and water (5 mL, 4 / 1) were added to a dried screw-cap vial under an argon atmosphere. The reaction mixture was degassed with argon for 15 min. Then a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (0.47 g, 0.57 mmol) was added, and the reaction mixture was heated to 60 °C for 5 h. The reaction mixture was quenched with ice water and extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over Na2SO4, concentrated, and the residue was purified by silica gel chromatography (100 - 200 mesh) using a hexane solution of 25% EtOAc to give the title compound as a light brown solid (1.0 g, 55%).

[0738] 1 H NMR (400 MHz, CDCl3) δ 10.7 (s, 1H), 8.92 (d, 1H), 8.33 (dd, 1H), 6.89 (d, 1H), 6.25 (dd, 1H), 4.83 (t, 1H), 4.74 (t, 1H), 4.68 (t, 1H), 4.62 (t, 1H), 4.12 (m, 1H), 3.78 (td, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.77 (m, 2H), 1.66 (m, 1H).

[0739] MS: 321.35 [M+H] + 。

[0740] Step B: Molecular sieves were added to a stirred solution of the title compound from the above Step A (0.4 g, 1.3 mmol) and 1-methyl-1H-pyrazol-4-amine (0.18 g, 1.9 mmol) in 1,2-dichloroethane (16 mL) under a nitrogen atmosphere And ice AcOH (1.2 mL). The reaction mixture was stirred at room temperature for 4 h. Then sodium triacetoxyborohydride (0.55 g, 2.6 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (60 mL) and the product was extracted with DCM solution of 5% MeOH (3 x 60 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel (100 - 200 mesh) with DCM solution of 4% MeOH to give the title compound as a brown liquid (0.34 g, 65%).

[0741] 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.23 (dd, 1H), 7.16 (s, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 5.72 (dd, 1H), 5.02 (s, 1H), 4.81 (t, 1H), 4.72 (t, 1H), 4.56 (dt, 2H), 4.28 (dd, 2H), 3.94 (d, 1H), 3.70 (m, 1H), 3.68 (s, 3H), 2.22 (ddd, 1H), 2.01 (m, 1H), 1.89 (td, 1H), 1.65 (m, 1H), 1.58 (m, 2H).

[0742] MS: 402.43 [M + H] + 。

[0743] Step C: To a stirred solution of the title compound from the above step B (0.26 g, 0.65 mmol) in DCM (13 mL) at 0 °C under a nitrogen atmosphere was added a solution of 4 M HCl in 1,4-dioxane (2.6 mL). The reaction mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure to give the hydrochloride salt. The yellow solid was washed with n-hexane (3 x 5 mL) and dried in vacuo to give the title compound (0.2 g, 87%).

[0744] 1 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, 1H), 8.29 (dd, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.07 (d, 1H), 4.82 (t, 1H), 4.73 (dd, 1H), 4.61 (t, 1H), 4.54 (s, 4H), 3.82 (s, 3H).

[0745] MS: 318.35 [M + H] + 。

[0746] Step D: Under a nitrogen atmosphere, sodium hydride (60% dispersed in mineral oil) (0.04 g, 0.95 mmol) was added to a cold solution of the title compound from the above step C (0.2 mg, 0.63 mmol) in 1,2-dichloroethane (12 mL). The reaction mixture was stirred at room temperature for 30 min. Then 1,1'-carbonyldiimidazole (1.02 g, 6.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water and the mixture was extracted with a DCM solution of 5% MeOH (3 x 20 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100 - 200 mesh), using a DCM solution of 3% MeOH, to give the title compound as a white solid (0.09 g, 42%).

[0747] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, 1H), 8.36 (dd, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.05 (d, 1H), 5-07 (s, 2H), 4.79 (m, 2H), 4.60 (m, 2H), 3.88 (s, 3H).

[0748] MS: 344.15 [M+H] + 。

[0749] Step E: At 0 °C under a nitrogen atmosphere, a solution of 4M HCl in 1,4-dioxane (0.8 mL) was added to a stirred solution of the title compound from the above step D (0.08 g, 0.23 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 5 h and the solvent was evaporated under reduced pressure. The residue was treated with pentane and dried in vacuo to give the title compound as a white solid (0.08 g, 92%).

[0750] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, 1H), 8.36 (dd, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.05 (d, 1H), 5.07 (s, 2H), 4.83 (t, 1H), 4.74 (t, 1H), 4.63 (t, 1H), 4.57 (t, 1H), 3.88 (s, 3H).

[0751] MS: 344.20 [M+H] + 。

[0752] Example 12

[0753] Following the same method as described for Example 11, except using the reagents indicated in the specific steps in Table 3 below, the following examples were prepared.

[0754] Table 3 :

[0755]

[0756] Biological assay description and corresponding results

[0757] 1. Preparation of α-synuclein (α-syn) aggregates from human Parkinson's disease (PD) brain

[0758] This method was adapted from the protocol described by Spillantini et al., 1998. Frozen tissue blocks from PD donors were thawed on ice and homogenized using a glass Dounce homogenizer. The homogenate was then centrifuged in an ultracentrifuge (Beckman, XL100K) at 4 °C at 11,000 x g (12,700 RPM) for 20 minutes using a pre-cooled 70.1 rotor (Beckman, 342184). The pellet was resuspended in extraction buffer [10 mM Tris-HCl pH 7.4, 10% sucrose, 0.85 mM NaCl, 1% protease inhibitor (Calbiochem 539131), 1 mM EGTA, 1% phosphatase inhibitor (Sigma P5726 and P0044)] and centrifuged at 4 °C at 15,000 x g (14,800 rpm, 70.1Ti rotor) for 20 minutes. The pellet was discarded, and sodium lauroyl sarcosinate (20% stock solution, Sigma L7414) was added to the supernatant to a final concentration of 1% at room temperature and stirred for 1 hour. The solution was then centrifuged at 4 °C at 100,000 x g (38,000 rpm, 70.1Ti rotor) for 1 hour. The pellet containing enriched α-synuclein aggregates was resuspended in PBS and stored at -80 °C until use.

[0759] 2. Micro-radioactive binding competition assay for determining the binding affinity in α-synuclein aggregates from PD brain

[0760] The α-synuclein aggregates from PD brain were spotted onto microarray slides. The slides were incubated with 25 nM, 30 nM, or 40 nM of 3[[3H]]-α-synuclein reference was incubated with the example compounds (non-radiolabeled) at 1 μM and 100 nM. In some cases, different concentrations of the non-radiolabeled example compounds varying between 0.05 nM - 2 μM were further evaluated. After incubation, the slides were washed and scanned by a real-time autoradiography system (BeaQuant, ai4R). Quantification of the signal was performed by using the image analysis software Beamage (ai4R). Non-specific signal was determined with an excess of non-radiolabeled α-synuclein ligand (2 μM), and specific binding was calculated by subtracting the non-specific signal from the total signal. Competition was calculated as a percentage, where 0% was defined as specific binding in the presence of vehicle and 100% was defined as the value obtained in the presence of an excess of non-radiolabeled reference α-synuclein ligand. Ki values were calculated by applying non-linear regression curve fitting using a one-site specific binding model in GraphPad Prism 7. All measurements were performed with at least two technical replicates, and all measurements were performed with at least two technical reproductions. For compounds tested in more than one experiment, the mean of the replicates or the Ki values in independent experiments were reported.

[0761] Results : The potency of the example compounds to compete with a [[3H]]-radiolabeled reference ligand for binding to α-synuclein aggregates from the brains of PD patients was evaluated. The results of the micro-radioligand binding competition assays for the example compounds tested are shown in Table 4 as the percentage of competition at 1 μM and 100 nM. Table 4 also shows the Ki values. Ki measurements for example compounds 1 - 11 were performed on the same PD brain-derived α-synuclein aggregates, while Ki measurements for example compounds 13 - 17 and 25 were performed on PD brain-derived α-synuclein aggregates from different donors. The data show that the compounds of the present invention bind to α-synuclein aggregates from human brains. Example compounds 4, 5, 11, and 17 have very high affinity (Ki < 100 nM) for α-synuclein aggregates from the brains of human PD patients.

[0762] Table 4

[0763]

[0764]

[0765] Table 4: Binding affinity was evaluated by micro-radioligand binding competition assay on human PD brain-derived α-synuclein aggregates. For the selected compounds, the percentage of competition (%) and K 3 [[3H]] reference α-synuclein ligand over tritiated iValue. (n.d. = not determined; * = two independent experiments were conducted).

Claims

1. A compound of formula (I): a compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof or a detectable label thereof, wherein is a 6-membered heteroaryl which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl.

2. The compound according to claim 1, which has the formula (Ia): or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1 and R 2 as defined in claim 1, R 3 is a halogen or a C1-C4 alkyl group; and q is 0, 1 or 2.

3. A compound according to claim 1 or 2, wherein R 1 is a 4- to 6-membered heterocyclic group selected from the following: where R 1a is F or H; or R 1 is halo C1-C4 alkoxy-.

4. The compound according to claim 3, wherein R 1 is a 5-membered heterocyclic group, which is: Preferably, F is 19 F or 18 F, more preferably 18 F; or R 1 is -OCH2-CH2-F.

5. A compound according to claim 1 or 2, wherein R 2 is a 5- or 6-membered heteroaryl selected from the following: wherein R 2a Preferably halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; R 2b selected from H, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and s is 0, 1 or 2.

6. The compound according to claim 5, wherein R 2 is a 5- or 6-membered heteroaryl selected from the following: wherein R 2b Preferably a halogenated C1-C4 alkyl group, a halogenated C1-C4 alkoxy group, an alkoxy group, H or a C1-C4 alkyl group.

7. The compound according to claim 1, wherein the compound is selected from: or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The compound according to claim 1, wherein the compound is selected from: or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. The compound according to any one of the above claims, wherein the compound is a detectably labeled compound.

10. The compound according to claim 9, wherein the compound with a detectable label comprises a radioactive isotope selected from 18 F, 2 H, and 3 H.

11. A compound according to claim 9 or 10, wherein R 1 is 12. A diagnostic composition comprising the compound according to any one of claims 9 - 11, and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and / or adjuvant.

13. The compound according to any one of claims 9 - 11 or the diagnostic composition according to claim 12, which is used for imaging of α - synuclein aggregates.

14. The compound according to any one of claims 9 - 11 or the diagnostic composition according to claim 12, which is used for positron emission tomography imaging of α - synuclein aggregates.

15. The compound or diagnostic composition for use in the use of claim 13 or 14, wherein the use is for in vitro imaging, ex vivo imaging or in vivo imaging, preferably, the use is for in vivo imaging, more preferably, the use is for brain imaging.

16. The compound according to any one of claims 9 - 11 or the diagnostic composition according to claim 12, which is used for diagnosis.

17. A compound or diagnostic composition for use in the use of claim 16, wherein the diagnosis is a diagnosis of a disease, disorder or abnormality associated with α-synuclein aggregates or susceptibility thereto, wherein the disease, disorder or abnormality is optionally selected from Parkinson's disease (including sporadic, familial with α-synuclein mutations, familial with mutations other than α-synuclein, pure autonomic failure and Lewy body dysphagia), SNCA repeat carriers, Lewy body dementia (LBD), dementia with Lewy bodies (DLB) (including "pure" Lewy body dementia), Parkinson's disease dementia (PDD), diffuse Lewy body disease (DLBD), Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer's disease, Down syndrome, multiple system atrophy (MSA) (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, boxer's dementia, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Niemann-Pick disease, type C1, frontotemporal dementia with parkinsonism linked to chromosome 17), Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial and Guam ALS-dementia syndrome), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gerstmann-Straussler-Scheinker syndrome, inclusion body myositis, Gaucher's disease, Krabbe's disease and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder.

18. A compound or diagnostic composition for use in the use of claim 17, wherein the disease is Parkinson's disease.

19. A compound or diagnostic composition for use in the use of claim 17, wherein the disease is multiple system atrophy.

20. A compound or diagnostic composition for use in the use of claim 17, wherein the disease is dementia with Lewy bodies.

21. A compound or diagnostic composition for use in the use of claim 17, wherein the disease is Parkinson's disease dementia.

22. A compound or diagnostic composition for use in the use of claim 16, wherein the disease is SNCA repeat carriers.

23. A compound or diagnostic composition for use in the use of claim 17, wherein the disease is Alzheimer's disease.

24. A compound or diagnostic composition for use in the use of any one of claims 13-23, wherein the use is for humans.

25. A method of diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates in a subject, the method comprising the following steps: (a) Administering to a subject a compound according to any one of claims 1-11, or a diagnostic composition according to claim 12, said diagnostic composition comprising a compound according to any one of claims 1-11; (b) Binding the compound to α-synuclein aggregates; and (c) Detecting the compound bound to α-synuclein aggregates.

26. The diagnostic method according to claim 24, the method further comprising the following steps: (d) Generating an image representative of the location and / or amount of the compound bound to α-synuclein aggregates.

27. A method for positron emission tomography (PET) imaging of α-synuclein aggregates in a subject's tissue, the method comprising the following steps: (a) Administering to a subject a compound according to any one of claims 1-11, or a diagnostic composition according to claim 12, said diagnostic composition comprising a compound according to any one of claims 1-11; (b) Binding the compound to α-synuclein aggregates; and (c) Detecting, by acquiring a positron emission tomography (PET) image of the subject's tissue, the compound bound to α- synuclein aggregates.

28. The positron emission tomography imaging method according to claim 27, wherein the tissue is central nervous system (CNS) tissue, eye tissue, peripheral organ tissue, or brain tissue, preferably wherein the tissue is brain tissue.

29. A method for detecting and optionally quantifying α-synuclein aggregates in a subject's tissue, the method comprising the following steps: (a) Contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound according to any one of claims 1-11 or a diagnostic composition according to claim 12, said diagnostic composition comprising a compound according to any one of claims 1-11; (b) Binding the compound to α-synuclein aggregates; (c) Detecting, using positron emission tomography, the compound bound to α-synuclein aggregates; and (d) Optionally quantifying the amount of the compound bound to α-synuclein aggregates.

30. A method for collecting data for diagnosing or determining the susceptibility to a disease, disorder, or abnormality associated with α-synuclein aggregates, the method comprising the following steps: (a) Contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound according to any one of claims 1-11 or a diagnostic composition according to claim 12, said diagnostic composition comprising a compound according to any one of claims 1-11; (b) Binding the compound to α-synuclein aggregates; (c) Detecting the compound bound to α-synuclein aggregates; and (d) Optionally, correlating the presence or absence of the compound bound to α-synuclein aggregates with the presence or absence of α-synuclein in the sample or the specific body part or body region.

31. A method for collecting data for predicting the prognosis of a disease, disorder, or abnormality associated with α-synuclein aggregates, For monitoring the progression of a disease, disorder or abnormality associated with α-synuclein aggregates in a patient; or for predicting the responsiveness of a patient having a disease, disorder or abnormality associated with α-synuclein aggregates to treatment of said disease, disorder and abnormality associated with α-synuclein aggregates, wherein the method comprises the following steps: (a) Contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound according to any one of claims 1-11 or a diagnostic composition according to claim 12, said diagnostic composition comprising a compound according to any one of claims 1-11; (b) Binding said compound to α-synuclein aggregates; (c) Detecting the compound bound to α-synuclein aggregates; (d) Optionally, correlating the presence or absence of the compound bound to α-synuclein aggregates with the presence or absence of α-synuclein in the sample or specific body part or body region; and (e) Optionally repeating steps (a)-(c), and if present, repeating the optional step (d) at least once.

32. The method of claim 30 or 31, wherein the step of optionally correlating the presence or absence of the compound bound to α-synuclein aggregates with the presence or absence of α-synuclein in the sample or specific body part or body region comprises the following steps: - Determining the amount of the compound bound to α-synuclein aggregates; - Correlating the amount of the compound bound to α-synuclein aggregates with the amount of α-synuclein aggregates in the sample or specific body part or body region; and - Optionally comparing the amount of the compound bound to α-synuclein aggregates in the sample or specific body part or body region with a normal control value of a healthy control subject.

33. A compound of formula (III-F) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1F is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one C1-C4 alkoxy group, NR 4 R 5 or a C1-C4 alkyl group; or R 1F is a C1-C4 alkoxy group, NR 4 R 5 or a C1-C4 alkyl group; or R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl; and R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; LG is a leaving group; and n is at least 1.

34. A compound of formula (III-F) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl; and R 2F is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl; and LG is a leaving group.

35. A compound of formula (III-F) according to claim 33 or a compound of formula (III-F') according to claim 34, wherein LG is selected from bromine, chlorine, iodine, C1-C4 alkylsulfonates and C6-C 10 arylsulfonates, wherein the C6-C 10 arylsulfonate may optionally be substituted by -CH3 or -NO2.

36. A compound of formula (I-F) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1F is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one C1-C4 alkoxy group, NR 4 R 5 or a C1-C4 alkyl group; or R 1F is a C1-C4 alkoxy group, NR 4 R 5 or a C1-C4 alkyl group; or R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl; R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; and n is at least 1; preferably 1.

37. A compound of formula (I-F’) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl; and R 2F is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl.

38. A compound of formula (III-H) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is a 6-membered heteroaryl optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted by at least one halogen; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; and R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl; X is bromine, chlorine or iodine; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; and provided that the compound of formula (III-H) contains at least one X.

39. A compound of formula (I-H) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is a 6-membered heteroaryl which is optionally substituted with at least one halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl; or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl is optionally substituted with at least one halogen; and R 2 is a 5- or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and halo C1-C4 alkyl; Y is D, CD3, T or CT3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; Provided that the compound of formula (I-H) comprises at least one D, CD3, T or CT3, where D is deuterium and T is 3 H (tritium).

40. A process for preparing a compound of formula (I-F) according to claim 36, the process comprising reacting a compound of formula (III-F) according to claim 33 or 34 with 18 an F-fluorinating agent such that LG is 18 replaced by F.

41. A process for preparing a compound of formula (I-F’) according to claim 37, the process comprising reacting a compound of formula (III-F’) according to claim 35 with 1 8 F-fluorinating agent such that LG is 18 replaced by F.

42. The method according to claim 40 or 41, wherein 18 the F-fluorinating agent is selected from K 18 F, Rb 18 F, Cs 18 F, Na 18 F, Rb 18 F, Kryptofix[222] 18 F, 18 tetra(C 1-6 alkyl)ammonium salts of F and 18 tetrabutylammonium fluoride.

43. A method for preparing a compound of formula (I-H) according to claim 39, the method comprising reacting a compound of formula (III-H) according to claim 38 with 2 a H-radiolabeling reagent such that X is replaced by D or CD3.

44. A method for preparing a compound of formula (I-H) according to claim 39, comprising reacting a compound of formula (III-H) according to claim 38 with a 3H radiolabeling reagent such as CT3 so that X is replaced by T or CT3.

45. A compound according to any one of claims 1-11, which is used as an in vitro analysis reference or an in vitro screening tool.

46. A test kit for detecting and / or diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the test kit comprises at least one compound as defined in any one of claims 9-11.

47. A kit for preparing a radiopharmaceutical formulation, wherein the kit comprises a sealed vial containing at least one compound as defined in any one of claims 33, 34, 35 or 38.

48. The kit according to claim 46, wherein the radiopharmaceutical formulation is used for imaging α-synuclein aggregates, and the imaging is preferably performed by positron emission tomography.

49. The kit according to claim 46, wherein the radiopharmaceutical formulation is used for in vitro imaging, ex vivo imaging or in vivo imaging, preferably for in vivo imaging.

50. The kit according to claim 46, wherein the radiopharmaceutical formulation is used for brain imaging.

Images