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., multi-system atrophy (MSA)), to determine the susceptibility to the disease, disorder or disorder, to predict the prognosis of the disease, disorder or disorder, to monitor disease evolution in a patient suffering from the disease, disorder or disorder, and to determine the prognosis of the disease, disorder or disorder. Monitoring the progression of the disease, disorder, or abnormality, and predicting the responsiveness of a patient suffering from the disease, disorder, or abnormality to its treatment.

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 amounts. 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 (MSA), determine 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, disorders or abnormalities, 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 (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, pugilistic dementia, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal ganglionic degeneration, and Niemann-Pick disease type C1, frontotemporal dementia with parkinsonism linked to chromosome 17), motor neuron disease, Huntington's disease, amyotrophic lateral sclerosis (sporadic, familial, and 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 natural 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) the 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) the hydrophobic non-β-amyloid component (NAC) domain spans residues 61-95, which is crucial for the protofibrillation of α-synuclein; and 3) the 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-mediated 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. U S A 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. It has been demonstrated that α-synuclein is 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). α-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 α-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 at Ser-129 (McLean et al., Neurosci Lett 2002, 323(3), 219-223) and nitration at Tyr-125, -133, and -136 (Takahashi et al., Brain Res 2002, 938(1-2), 73-80), can affect the aggregation of α-synuclein. Truncation of the carboxyl-terminal region by proteolysis has been reported to play a role in α-synuclein fibril formation in various neurodegenerative diseases (Rochet et al., Biochemistry 2000, 39(35), 10619-10626). Full-length as well as partially truncated and insoluble α-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 of multiple 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, yielding 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 the 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 feature 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 dot-like 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 diseases include Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy. Depending on the predominant motor phenotype, the disease can be clinically classified into the parkinsonian (MSA-P) or cerebellar (MSA-C) variant (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 are mainly composed of the fibrillar form of α-synuclein and 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 considered a central player in the pathogenesis of MSA. A correlation has been reported between the 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] Furthermore, 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 considered 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, 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 confirmation by pathology can only be made by postmortem 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 for differentiating typical from atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured using 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 stages (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 OpinNeurol 2013;26(4):395 - 400), but so far, none of these biomarkers alone or in combination can be used for a definitive diagnostic test. To our knowledge, despite the urgent need in Parkinson's disease research and drug development, there are currently no approved diagnostic reagents for α - synuclein 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, including Parkinson's disease (PD) and MSA research, diagnosis, and drug development, of α-synucleinopathies. 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 the disease at an early stage, (ii) evaluate disease progression, and (iii) serve as a pharmacodynamic tool for drug development. Today, 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 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 18 F]ACI-12589, 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 18 F]ACI-12589, 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 (MSA), 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 targeting 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 the 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] US2014 / 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 studying amyloid deposits in the brain in vivo for the diagnosis of 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 which can be used for diagnosing diseases, disorders or abnormalities associated with α-synuclein aggregates, such as Parkinson's disease or MSA, predicting the prognosis of such diseases, disorders or abnormalities, and monitoring 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 diseases, disorders or abnormalities, or predicting the responsiveness of patients suffering from such diseases, disorders or abnormalities 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 detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0032] 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;

[0033] R 1 is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one halogen; or

[0034] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0035] 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;

[0036] 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

[0037] Z is CH or N.

[0038] In another aspect, the present invention also relates to compounds having the following sub-formula (Ia)

[0039]

[0040] or a compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof that is detectably labeled,

[0041] wherein R 3 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 hydroxy, preferably R 3 is halogen or C1-C4 alkyl; and r is 0, 1 or 2, preferably 0.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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 and more preferably for brain imaging.

[0046] In yet another aspect, the compound of formula (I) or the diagnostic composition as defined herein can be used for diagnosis.

[0047] 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:

[0048] (a) administering to the subject a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0049] (b) binding the compound to α-synuclein aggregates; and

[0050] (c) detecting the compound bound to α-synuclein aggregates.

[0051] 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:

[0052] (a) Administering to a subject a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0053] (b) Binding the compound to α-synuclein aggregates; and

[0054] (c) Detecting, by collecting a positron emission tomography (PET) image of a subject's tissue, the compound that binds to α-synuclein aggregates.

[0055] 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 following steps:

[0056] (a) Contacting a sample suspected of containing α-synuclein aggregates or a specific body part or body region with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0057] (b) Binding the compound to α-synuclein aggregates;

[0058] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0059] (d) Optionally, quantifying the amount of the compound that binds to α-synuclein aggregates.

[0060] The present invention also relates to a method for collecting data for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, wherein the method comprises the following steps:

[0061] (a) Contacting a sample suspected of containing α-synuclein aggregates or a specific body part or body region with a compound of formula (I) as defined herein or a diagnostic composition comprising a compound of formula (I);

[0062] (b) Binding the compound to α-synuclein aggregates;

[0063] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0064] (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 specific body part or body region.

[0065] The present invention also relates to a method for collecting data for determining the susceptibility to a disease, disorder or abnormality associated with α-synuclein aggregates, the method comprising the following steps:

[0066] (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);

[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, 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 specific body part or body region.

[0070] 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:

[0071] (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);

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

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

[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 specific body part or body region; and

[0075] (e) Optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0076] 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:

[0077] (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);

[0078] (b) Binding the compound to the α-synuclein aggregates;

[0079] (c) Detecting the compound bound to the α-synuclein aggregates;

[0080] (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; and

[0081] (e) Optionally repeat steps (a)-(c), and if present, optionally repeat step (d) at least once.

[0082] In another aspect, the present invention relates to a method of 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:

[0083] (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);

[0084] (b) Binding the compound to α-synuclein aggregates;

[0085] (c) Detecting the compound that binds to α-synuclein aggregates;

[0086] (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; and

[0087] (e) Optionally repeat steps (a)-(c), and if present, optionally repeat step (d) at least once.

[0088] In another aspect, the present invention further relates to a compound of formula (III-F):

[0089]

[0090] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0091] 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;

[0092] R 1F is a 4- to 6-membered heterocyclic group; or

[0093] R 1F is C1-C4 alkoxy or C1-C4 alkyl; or

[0094] R 1Fis -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl;

[0095] R 2 is 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; Z is CH or N;

[0096] LG is a leaving group;

[0097] q is 0 or 1; and

[0098] n is at least 1 (e.g., 1, 2 or 3), preferably 1.

[0099] In another aspect, the present invention also relates to a compound of formula (I), wherein the compound is a detectable labeled compound of formula (I-F):

[0100]

[0101] or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, wherein

[0102] 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;

[0103] R 1F is a 4- to 6-membered heterocyclic group, or

[0104] R 1F is C1-C4 alkoxy or C1-C4 alkyl; or

[0105] R 1F is -NH-C3-C6 cycloalkyl or C3-C6 cycloalkyl;

[0106] R 2 is 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;

[0107] Z is CH or N;

[0108] q is 0 or 1; and

[0109] n is at least 1 (e.g., 1, 2 or 3), preferably 1.

[0110] In another aspect, the present invention also relates to a compound of formula (III-H)

[0111]

[0112] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof,

[0113] wherein

[0114] 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;

[0115] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted with at least one halogen; or

[0116] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0117] 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;

[0118] 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;

[0119] Z is CH or N;

[0120] X is bromine, chlorine or iodine;

[0121] m is 0, 1, 2 or 3;

[0122] p is 0, 1, 2 or 3; and

[0123] provided that the compound of formula (III-H) contains at least one X.

[0124] Another aspect of the present invention also relates to a compound of formula (I-H)

[0125]

[0126] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof,

[0127] wherein

[0128] 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;

[0129] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0130] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0131] 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;

[0132] 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; Z is CH or N;

[0133] Y 1 is D, CD3, T or CT3;

[0134] m is 0, 1, 2 or 3;

[0135] p is 0, 1, 2 or 3; and

[0136] 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.

[0137] 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 tetra(C 1-6 alkyl)ammonium salt, Kryptofix

[222] 18 F, 18 F] tetrabutylammonium fluoride or any other suitable reagent) so that the leaving group (LG) is18 Replacement with F.

[0138] 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 a radioactive H-labeling reagent (such as tritium gas or any other suitable reagent) such that X is replaced by T or CT3.

[0139] 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 a radioactive H-labeling reagent containing D 2 (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).

[0140] 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.

[0141] 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).

[0142] The present invention also relates to a kit for preparing a radiopharmaceutical preparation, wherein the kit comprises a sealed vial containing at least one compound of formula (III-F) or (III-H).

[0143] Definitions

[0144] For the purpose of interpreting this specification, unless otherwise specified, 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 in this text and the appended claims include plural referents. Thus, for example, reference to "a compound" includes reference to one or more compounds, etc.

[0145] The term "C1-C4 alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon chain consisting only of carbon and hydrogen atoms, having no unsaturation, having 1-4 carbon atoms, and being generally connected to the rest 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.

[0146] 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.

[0147] The term "halo C1-C4 alkyl" or "halogenated 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 "halogenated 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.

[0148] 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 "halogenated 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.

[0149] 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.

[0150] 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 heterocyclic ring 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, and most preferably pyridyl.

[0151] 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).

[0152] 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, for example, 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 0f 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 halogens (bromine, chlorine, iodine), nitro, C 1-4 alkylsulfonates and C 6-10 arylsulfonates, where the C 6-10 arylsulfonates may optionally be substituted with -CH3 or -NO2.

[0153] Unless otherwise specified, the term "compounds of the invention" refers to compounds of formula (I) or its sub-formulas (such as (Ia), (I-F), (I-H*), (I-H)) or their 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 (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.

[0154] The compounds of the present 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 present invention.

[0155] ″Pharmaceutically acceptable salts″ are defined as derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; 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.

[0156] ″Pharmaceutically acceptable″ is defined as those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for 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.

[0157] ″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).

[0158] The patient or subject in the present invention is typically an animal, particularly a mammal, and more particularly a human.

[0159] 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 spectrum of Lewy pathologies in Parkinson's disease and other synucleinopathies. The α-synuclein aggregates that make up the Lewy pathological condition can be detected as having the following morphologies: Lewy bodies, Lewy neurites, preformed Lewy bodies or globose 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 referred to as glial cytoplasmic inclusions) and neuronal somata, axons and nuclei (termed neuronal cytoplasmic inclusions), which are histological hallmarks of multiple system atrophy. The α-synuclein aggregates in Lewy pathologies typically show a significant increase in post-translational modifications such as phosphorylation, ubiquitination, nitration and truncation.

[0160] 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 5-10-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.

[0161] 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.

[0162] 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 GCI, inclusions composed of α-synuclein filaments are detected in the cytoplasm or in neurons under the nuclear membrane, termed neuronal cytoplasmic inclusions and intranuclear inclusions, respectively. GCI are regarded as a defining morphological feature of MSA; their widespread distribution is a definitive criterion for the postmortem neuropathological diagnosis of MSA.

[0163] The terms "disease", "disorder" or "abnormality" are used interchangeably herein.

[0164] 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 to be considered limited to any particular type of binding.

[0165] Unless otherwise stated, 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

[0167] Compounds of the present invention

[0168] 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 formulae (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 formulae (I-H) and (I-H*), respectively, and vice versa.

[0169] The present invention relates to compounds of formula (I):

[0170]

[0171] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0172] 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, provided that when substituted, is substituted by 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;

[0173] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0174] R 1is a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0175] 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;

[0176] 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

[0177] Z is CH or N.

[0178] In one embodiment, selected from:

[0179]

[0180] which can be attached to the heterocycle at any available position;

[0181] and wherein can be optionally substituted with one or more substituents selected from halogen; halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl.

[0182] In a preferred embodiment, is a 6-membered heteroaryl containing at least one N, preferably is pyridyl, most preferably is pyridyl and is unsubstituted.

[0183] The optional substituent of (if present) is preferably halogen or C1-C4 alkyl.

[0184] Preferably, is unsubstituted.

[0185] In another embodiment, the present invention provides a compound having the formula (Ia):

[0186]

[0187] or a detectable labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof,

[0188] wherein Z, R 1 and R 2 are as defined above, and R3 is a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl, preferably R 3 is a halogen or halo-C1-C4 alkyl; and

[0189] r is 0, 1 or 2; preferably 0.

[0190] In one embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen (e.g., 1 to 3, preferably 1 or 2, more preferably 1 halogen). In a preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group, which is substituted by at least one halogen. Preferably, the heterocyclic group is substituted by at least one halogen, more preferably by one or two halogens, even more preferably by one halogen.

[0191] In another embodiment, R 1 is substituted by a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl. Preferably, R 1 is halo-C1-C2 alkoxy, more preferably -OCH2-CH2-F.

[0192] In one embodiment, R 1 is selected from the following:

[0193]

[0194] wherein R 1’ is independently a halogen; and s = 0, 1, 2 or 3.

[0195] In a preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group selected from the following:

[0196]

[0197] wherein R 1a is F.

[0198] Preferably, R 1 is a 4- or 5-membered heterocyclic group selected from the following:

[0199]

[0200] wherein R 1a is F.

[0201] In another embodiment, R 1 is a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl. Preferably, R 1is a halogenated C1-C4 alkyl or a halogen, more preferably R 1 is -O-CH2-CH2-F or F. More preferably, R 1 is a halogen, and even more preferably, R 1 is F.

[0202] In another most preferred embodiment, R 1 is a 5-membered heterocyclic group, which is:

[0203]

[0204] or R 1 is F.

[0205] In 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.

[0206] In each of the embodiments, F is preferably 19 F or 18 F.

[0207] In one embodiment, R 2 is a 5- or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents independently selected from halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl.

[0208] In a preferred embodiment, R 2 is a 5- or 6-membered heteroaryl, which is selected from the following:

[0209]

[0210] wherein

[0211] R 2a is selected from halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0212] R 2b is selected from H, halogenated C1.C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; and

[0213] s is 0, 1 or 2 (preferably 0 or 1, more preferably 0).

[0214] Preferably, R 2 is a 5- or 6-membered heteroaryl, which is selected from the following:

[0215]

[0216] wherein

[0217] R 2b is selected from H or C1-C4 alkyl.

[0218] More preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0219]

[0220] wherein

[0221] R 2a is independently selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl;

[0222] R 2b is selected from H, halo C1-C4 alkyl and C1-C4 alkyl, where halo C1-C4 alkyl and C1-C4 alkyl; and

[0223] s is 0, 1 or 2 (preferably 0 or 1, more preferably 0).

[0224] Even more preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0225]

[0226] wherein

[0227] R 2b is selected from C1-C4 alkyl.

[0228] In a most preferred embodiment, R 2 is an unsubstituted 6-membered heteroaryl or R 2 is a 5-membered heteroaryl substituted with C1-C4 alkyl.

[0229] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is selected from

[0230]

[0231]

[0232] or a detectable labeled compound, stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0233] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is selected from

[0234]

[0235]

[0236] or a compound, pharmaceutically acceptable salt, hydrate or solvate thereof that is detectably labeled.

[0237] In one embodiment, the present invention provides a compound of formula (I) that 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 selected from 18 F, 2 H, and 3 H. Most preferably, the radioisotope is selected from 18 F and 3 H.

[0238] In one embodiment, the present invention provides a compound of formula (I) wherein R 1 is or 18 F, preferably

[0239] In one embodiment, the present invention provides a compound of formula (I) that is a detectably labeled compound of formula (I-F):

[0240]

[0241] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0242] 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;

[0243] R 1F is a 4- to 6-membered heterocyclic group; or

[0244] R 1F is C1-C4 alkoxy or C1-C4 alkyl; and R 1F is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl;

[0245] 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;

[0246] Z is CH or N;

[0247] q is 0 or 1; and

[0248] n is at least 1 (for example, n is 0, 1, 2, or 3), preferably 1.

[0249] 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:

[0250]

[0251] wherein R 1’ is 18 F; and s = 1, 2, or 3, preferably s = 1.

[0252] In a preferred embodiment, -R 1F -( 18 F) n is selected from the following:

[0253]

[0254] More preferably, -R 1F -( 18 F) n is selected from the following:

[0255]

[0256] Even more preferably, -R 1F -( 18 F) n is:

[0257]

[0258] In another embodiment, -R 1F -( 18 F) n is a halogenated C1-C4 alkoxy, such as -O-CH2-CH2- 18 F.

[0259] In another preferred embodiment, q is 0, i.e., R 1F -( 18 F) n is 18 F.

[0260] The detectable-labeled compound of formula (I-F) contains at least one 18 F. Preferably, the detectable-labeled compound of formula (I-F) contains one 18 F.

[0261] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is a compound of formula (I-H*).

[0262]

[0263] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0264] 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; and

[0265] R 1 is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0266] R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0267] 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

[0268] 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; and

[0269] Z is CH or N; and

[0270] Y 1 is D, CD3, T or CT3;

[0271] m is 0, 1, 2 or 3; and

[0272] p is 0, 1, 2 or 3; and

[0273] 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 may be present as T or as -CT3.2 H can exist as D or as -CD3.

[0274] In a preferred embodiment, the compound is a detectable-labeled compound of formula (I-H)

[0275]

[0276] or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0277] 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;

[0278] R 1 is a 4- to 6-membered heterocyclic group which is optionally substituted with at least one halogen; or

[0279] R 1 is a halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0280] 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

[0281] 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; Z is CH or N;

[0282] Y 1 is D, CD3, T or CT3;

[0283] m is 0, 1, 2 or 3;

[0284] p is 0, 1, 2 or 3; and

[0285] 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 D or CD3. In another embodiment, the compound of formula (I-H) contains at least one T or CT3.

[0286] 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 a 5- or 6-membered heteroaryl (e.g., in the form of D or T), or can be present in a 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, for example, be directly bonded to the 4- to 6-membered heterocyclic group.

[0287] In one embodiment, is a 6-membered heteroaryl, which is optionally substituted by one halogen or C1-C4 alkyl, and m is 1, 2, or 3, preferably 1 or 2.

[0288] More preferably, is unsubstituted.

[0289] In one embodiment, 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, and p is 1, 2, or 3, preferably 1.

[0290] Preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0291]

[0292] wherein

[0293] R 2a is independently selected from T, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl (e.g., CT3);

[0294] 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 is selected from T or CT3); and s is 0, 1, or 2 (preferably 0 or 1, more preferably 0).

[0295] Preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0296]

[0297] wherein

[0298] R 2bSelected from H, T or C1-C4 alkyl (e.g., CT3).

[0299] More preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0300]

[0301] wherein

[0302] R 2a is independently selected from T, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl (e.g., CT3);

[0303] 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 is selected from T or CT3); and s is 0, 1 or 2 (preferably 0).

[0304] Even more preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0305]

[0306] wherein

[0307] R 2b is selected from C1-C4 alkyl, wherein the C1-C4 alkyl optionally contains one or more T.

[0308] Preferably, R 2a is -T, -OCH3, -CH3 or -H; and R 2b is selected from -H, -T or -CT3.

[0309] In a preferred embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) contains one, two or three Ts. 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 Ts. In another embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) contains three Ts, such as -CT3.

[0310] In another embodiment, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0311]

[0312] wherein

[0313] R 2a is independently selected from D, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl (such as CD3);

[0314] R 2b is 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).

[0315] More preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0316]

[0317] wherein

[0318] R 2a is independently selected from D, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl (such as CD3);

[0319] R 2b is 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).

[0320] Even more preferably, R 2 is a 5- or 6-membered heteroaryl selected from the following:

[0321]

[0322] wherein

[0323] R 2b is selected from C1-C4 alkyl, wherein the C1-C4 alkyl optionally contains one or more D.

[0324] Preferably, R 2a is -D, -OCH3, -CH3 or -H; and R 2b is selected from -H, -D or -CD3.

[0325] In one embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) comprises one, two or three Ds. Preferably, the detectable-labeled compound of formula (I-H*) or (I-H) comprises one D. In another embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) comprises two Ds. In another embodiment, the detectable-labeled compound of formula (I-H*) or (I-H) comprises three Ds, such as -CD3.

[0326] In another embodiment, the present invention provides a detectable-labeled compound of formula (I-H*) or (I-H), wherein 3 H tritium (“T”) can be 2 replaced by 2 H deuterium (“D”). The deuterated compound can be prepared by reacting a compound of formula (III-H) with

[0327] 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, preferably the detectable label is a radioisotope. With regard to the detectable-labeled compounds and their 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 a certain amount that is different from the natural amount of the corresponding radioisotope, positron emitter, or gamma emitter. In addition, the amount used should allow 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, more preferably 2 H, 3 H, and 18 F.

[0328] 18 F-labeled compounds are particularly suitable for imaging applications such as PET. The corresponding compounds including those with the natural 19 F isotope are also of particular interest because they can be used as analytical standards and reference substances during the manufacture, quality control, release, and clinical use of their 18 F-analogues.

[0329] In addition, isotopes such as deuterium (i.e., 2Substitution with H or D can provide certain diagnostic and therapeutic advantages due to greater metabolic stability obtained, for example, by reducing defluorination, increasing in vivo half-life or reducing dose requirements, while maintaining or improving the efficacy of the original compound.

[0330] Isotopically varied forms of the compounds of the invention and their precursors 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 varied forms of suitable reagents, which are commercially available or prepared by known synthetic techniques.

[0331] Radionuclides, positron emitters and gamma emitters can be included in the compounds of the invention and their precursors by methods commonly used in the field of organic synthesis. Typically, when preparing the desired compounds and their precursors of the 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.

[0332] There is no particular limitation on the position where the detectable label binds to the compounds of the invention and their precursors. 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 with 3 F. 2 H can be attached at any available position where H is present. If

[0333] In another embodiment, the invention also relates to compounds of formula (III-F), which are precursors of compounds of formula (I-F)

[0334]

[0335] or their stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, wherein

[0336] 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;

[0337] R 1F is a 4- to 6-membered heterocyclic group; or

[0338] R 1Fis a C1-C4 alkoxy group or a C1-C4 alkyl group; or

[0339] R 1F is -NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl; and

[0340] R 2 is a 5- or 6-membered heteroaryl group, 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; Z is CH or N;

[0341] LG is a leaving group;

[0342] q is 0 or 1; and

[0343] n is at least 1 (e.g., 1, 2, or 3).

[0344] In one embodiment, (LG) n -(R 1F ) q is -NH-C3-C6 cycloalkyl-LG, C3-C6 cycloalkyl-LG, or heterocyclic-LG. Preferably, (LG) n -R 1F is selected from the following:

[0345]

[0346] wherein n is at least 1 (e.g., 1, 2, or 3, preferably 1).

[0347] In a preferred embodiment, (LG) n -(R 1F ) q is selected from the following:

[0348]

[0349] More preferably, (LG) n -R 1F is selected from the following:

[0350]

[0351] Even more preferably, (LG) n -(R 1F ) q is (LG) n (q is 0) or is:

[0352]

[0353] Preferably, the leaving group (LG) is halogen, C6-C4 alkyl sulfonate, C1-C4 alkyl ammonium, or C6-C10 Aryl sulfonate, wherein C6-C 10 The aryl sulfonate may optionally be substituted by -CH3 or -NO2. More preferably, the leaving group (LG) is nitro, bromine, chlorine, iodine, C1-C4 alkyl sulfonate or C6-C 10 Aryl sulfonate, wherein C6-C 10 The aryl sulfonate may optionally be 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 nitro, mesylate or tosylate. More preferably, the leaving group (LG) is mesylate or nitro.

[0354] In another embodiment, the present invention relates to a compound of formula (III-H), which is a precursor of the compound of formula (I-H):

[0355]

[0356] Or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, wherein

[0357] Is a 6-membered heteroaryl, which is optionally substituted by at least one halogen, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl;

[0358] R 1 Is a 4- to 6-membered heterocyclic group, which is optionally substituted by at least one halogen; or

[0359] R 1 Is halogen, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; or

[0360] 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

[0361] R 2 Is a 5- or 6-membered heteroaryl, which is optionally substituted by 1 or 2 substituents independently selected from halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; Z is CH or N;

[0362] X is bromine, chlorine or iodine;

[0363] m is 0, 1, 2 or 3;

[0364] p is 0, 1, 2 or 3; and

[0365] provided that the compound of formula (III-H) contains at least one X (for example 1, 2 or 3 Xs, preferably 1 or 2 Xs).

[0366] In formula (III-H), the halogen is preferably F, 18 F or 19 F.

[0367] X is attached to the 6-membered heteroaryl and / or R 2 the 5- or 6-membered heteroaryl. If the halogen is present as a substituent and X is present, then in addition to the halogen, X may also be present.

[0368] In a preferred embodiment, R 2 is selected from the following:

[0369]

[0370] wherein

[0371] 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 Xs;

[0372] s is 0, 1 or 2 (preferably 0 or 1, more preferably 0); and R 2b is selected from H, X, halo C1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl.

[0373] Preferably, R 2 is a 5- or 6-membered heteroaryl, which is selected from the following:

[0374]

[0375] wherein

[0376] R 2b is selected from H or C1-C4 alkyl.

[0377] More preferably, R 2 is selected from the following:

[0378]

[0379] wherein

[0380] R 2a is X;

[0381] R2b Selected from H, X, halo C1-C4 alkyl, and C1-C4 alkyl, preferably X;

[0382] s is 0, 1, or 2 (preferably 0); and

[0383] wherein the C1-C4 alkyl is optionally substituted with one or more X.

[0384] In a preferred embodiment, the detectable labeled compound of formula (III-H) contains one, two, or three X. In a preferred embodiment, the detectable labeled compound of formula (III-H) contains one X. In another preferred embodiment, the detectable labeled compound of formula (III-H) contains two X. X is selected from bromine, chlorine, and iodine. In a preferred embodiment, X is bromine.

[0385] Synthetic methods of compounds with detectable labels

[0386] The present invention also relates to a method for preparing a compound of formula (I) or its sub-formulas (such as (I-F), (I-H*), (I-H)), and in particular a compound of formula (III-F) or (III-H).

[0387] 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.

[0388]

[0389] wherein R 1F 、R 2 、Z, n, q, and G are as defined above.

[0390] Suitable solvents for 18 F-fluorination include DMF, DMSO, acetonitrile, DMA, or a mixture 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 tetra(C 1-6 alkyl)ammonium salts of F, kryptofix

[222] 18 F, and 18 tetrabutylammonium fluoride.

[0391] In one embodiment, the present invention relates to a process for preparing a compound of formula (IH) by reacting a compound of formula (III-H) with 3 The reaction was carried out using a H radiolabeling reagent.

[0392]

[0393] in R 1 , R 2 , Z, X, Y 1 , m and p are as defined above.

[0394] In one embodiment, the present invention relates to a process for preparing a compound of formula (IH*) by reacting a compound of formula (III-H*) with 3 The reaction is carried out using H or D radiolabeled reagents.

[0395]

[0396] in R 1 , R 2 , Z, X, m and p are as defined above, and wherein Y 1 It is D, CD3, T or CT3.

[0397] 3 The H radiolabeling agent may be tritium gas. The method may be carried out in the presence of a catalyst such as palladium on carbon (Pd / C), a solvent such as dimethylformamide (DMF) and a base such as N,N-diisopropylethylamine (DIEA).

[0398] In another embodiment, the compound of formula (III-H*) can be combined with a 2 H radiolabeling reagent (such as D2O, D4-methanol or any other suitable reagent), preferably in the presence of a catalyst such as Pd / C, so that X is replaced by D (D is deuterium, 2 H).

[0399] Alternatively, in another embodiment, the invention relates to a process for preparing a compound of formula (IH*) or (IH) by using 3 H radiolabeling reagents such as CT3 radiolabeling reagents (where T is 3 H) respectively radiolabel the compound of formula (III-H*) or (III-H) (reacting the compound of (III-H*) or (III-H) respectively) so that X is replaced by CT3. The CT3 radiolabeling (DMF) reagent can be ICT3. 3 The process can be carried out in the presence of a solvent such as dimethylformamide and a base such as cesium carbonate or sodium hydride.

[0400] Kit

[0401] 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 typically 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 formula (III-F), (III-H*), or (III-H). The reagent can be a reagent for introducing a radioactive label such as 18 F, 3 H or D.

[0402] 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 formula (III-F), (III-H*), or (III-H)).

[0403] 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 formula (III-F), (III-H*), or (III-H)).

[0404] In a preferred embodiment, the kit is for imaging α-synuclein aggregates, wherein the imaging is preferably performed by positron emission tomography, or 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.

[0405] Diagnostic compositions

[0406] 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 different types of α-synuclein aggregates. Imaging can be performed in a mammal, preferably in a human. 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 / retina imaging. The compounds of the present invention are particularly suitable for diagnosis.

[0407] Diagnosis can be performed in a mammal, preferably in a human. The tissue of interest for the diagnosis can be brain, central nervous system tissue, eye tissue (e.g., retina 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.

[0408] 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.

[0409] Due to its design and binding properties, the compounds of the present invention are 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.

[0410] 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.

[0411] In another embodiment, the compound or diagnostic composition of the present invention is particularly suitable for positron emission tomography imaging of α-synuclein aggregates.

[0412] 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 disease, amyotrophic lateral sclerosis (sporadic, familial, and the ALS-dementia syndrome in Guam), neuronal axonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gaucher'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). 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).

[0413] In the present invention, the disease, disorder or abnormality may be selected from 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 (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 and olivopontocerebellar atrophy), traumatic brain injury, chronic traumatic encephalopathy, pugilistic dementia, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Niemann-Pick disease, type C1, Parkinsonian frontotemporal dementia associated with chromosome 17), Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial and Guam ALS-dementia syndrome), neuronal ceroid lipofuscinosis, neurodegeneration with brain iron accumulation, type 1 (including Hallervorden-Spatz syndrome), prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gerstmann-Straussler-Scheinker disease, inclusion body myositis, Gaucher's disease, Krabbe disease and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder.

[0414] In a method for diagnosing a disease, disorder or abnormality (such as Parkinson's disease) or susceptibility to MSA associated with α-synuclein aggregates in a subject, the method comprises the following steps:

[0415] (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;

[0416] (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 tissue) or a body fluid (such as cerebrospinal fluid (CSF) or blood); and

[0417] (c) Imaging the tissue or body fluid of interest.

[0418] If the amount of a compound that binds to an α-synuclein aggregate is increased compared to a normal control level, the subject has a disease, disorder, or abnormality associated with an α-synuclein aggregate or is at risk of developing a disease, disorder, or abnormality associated with an α-synuclein aggregate.

[0419] The compounds of the 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 that is suspected of containing α-synuclein aggregates. These compounds are capable of crossing the blood-brain barrier. Thus, they are particularly suitable for imaging α-synuclein aggregates in the brain, central nervous system (CNS) tissue, eye tissue (e.g., retinal tissue), peripheral organ tissue such as intestinal tissue or other tissues, or body fluids such as cerebrospinal fluid (CSF) or blood.

[0420] In diagnostic applications, the compounds of the invention are preferably administered in the form of a diagnostic composition comprising a compound of the invention. A "diagnostic composition" is defined in the present invention as a composition comprising one or more compounds of the invention that 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. The preferred diagnostic composition also comprises a pharmaceutically acceptable excipient, carrier, diluent, or adjuvant. Administration is preferably carried out as defined below. More preferably, the composition is administered by injection as an aqueous solution. Such compositions may also optionally contain additional ingredients, such as buffers; pharmaceutically acceptable solubilizers (e.g., cyclodextrins or surfactants, such as Pluronics, Tweens, or phospholipids); and pharmaceutically acceptable stabilizers or antioxidants (e.g., ascorbic acid, gentisic acid, or para-aminobenzoic acid). The dose of the compound of the invention varies depending on the exact compound administered, the patient's weight, and other variables that are obvious to a physician skilled in the art.

[0421] Although the compounds of the invention can be administered alone, they are preferably formulated into diagnostic compositions according to standard pharmaceutical practice. Accordingly, the present invention also provides a diagnostic composition comprising a diagnostically effective amount of a compound of the invention optionally in combination with at least one pharmaceutically acceptable excipient, carrier, diluent, or adjuvant.

[0422] 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). Medicinal 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.

[0423] Pharmaceutically useful excipients, carriers, adjuvants, and diluents for the diagnostic composition formulations of the present invention may include solvents such as monohydric alcohols, e.g., ethanol, isopropanol, and polyhydric alcohols, e.g., diols, and edible oils, e.g., soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, oily esters, e.g., 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, e.g., 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.

[0424] Routes 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 forms), 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.

[0425] For example, the compounds may be administered orally in the form of tablets, capsules, vaginal suppositories, elixirs, solutions, or suspensions, which may contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed, or controlled-release applications.

[0426] 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. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type may 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 may 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 glycerol and combinations thereof.

[0427] Preferably, in 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, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous administration of the compounds; and / or by using infusion techniques. For parenteral administration, it is preferred to use the compounds in the form of a sterile aqueous solution, which may contain other substances, for example, 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.

[0428] As shown, the compounds of the present invention can be administered intranasally or by inhalation and can be conveniently 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 (HFA134A) 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 which contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0429] Alternatively, the compounds of the present invention can be administered in the form of a suppository or vaginal pessary, or can be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the present invention can also be administered transdermally or percutaneous, for example, by using a skin patch.

[0430] 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.

[0431] For topical administration to the skin, the compounds of the present invention can be formulated into 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 into a suitable lotion or cream, suspended or dissolved in a mixture of one or more of, for example, the following: mineral oil, sorbitan stearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0432] 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 upon a variety of factors including the activity of the specific 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.

[0433] The diagnostic compositions of the present invention can be produced in a manner well 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).

[0434] The compounds of the present invention can be used as in vitro assay reference standards or in vitro screening tools. They can also be used in in vivo diagnostic methods.

[0435] The compounds of the present invention can also be provided in the form of a mixture, pharmaceutical composition, or combination, which contains a compound of the present invention and at least one compound selected from imaging agents different from the compounds of the present invention, pharmaceutically acceptable excipients, carriers, diluents, or adjuvants. 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.

[0436] Methods of use of the present invention

[0437] 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 following steps:

[0438] (a) administering to the subject a compound of the present invention or a diagnostic composition containing a compound of the present invention; (b) allowing the compound to bind to α-synuclein aggregates; and

[0439] (c) detecting the compound that has bound to the α-synuclein aggregates.

[0440] Optionally, the method may further comprise the following steps:

[0441] (d) Generating an image representative of the location and / or amount of a compound that binds to α-synuclein aggregates.

[0442] 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 following steps:

[0443] (a) Administering to the subject a compound of the present invention or a diagnostic composition comprising a compound of the present invention;

[0444] (b) Allowing the compound to bind to α-synuclein aggregates; and

[0445] (c) Detecting the compound that binds to α-synuclein aggregates by acquiring a positron emission tomography (PET) image of the subject's tissue.

[0446] 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 following steps:

[0447] (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 a compound of the present invention;

[0448] (b) Allowing the compound to bind to α-synuclein aggregates;

[0449] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0450] (d) Optionally quantifying the amount of the compound that binds to α-synuclein aggregates.

[0451] In one embodiment, the present invention relates to a method of acquiring data for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates, including the method comprising the following steps:

[0452] (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 a compound of the present invention;

[0453] (b) Allowing the compound to bind to α-synuclein aggregates;

[0454] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0455] (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.

[0456] 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.

[0457] 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:

[0458] (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;

[0459] (b) Binding the compound to α-synuclein aggregates;

[0460] (c) Detecting the compound that binds to α-synuclein aggregates; and

[0461] (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.

[0462] If the amount of the compound that binds to α-synuclein aggregates is higher than the normal control value of a healthy / reference subject, 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 what would be 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.

[0463] In another aspect, the present invention 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:

[0464] (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;

[0465] (b) Binding the compound to α-synuclein aggregates;

[0466] (c) Detecting a compound that binds to α-synuclein aggregates;

[0467] (d) Optionally 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; and

[0468] (e) Optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0469] 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 a compound that binds to α-synuclein aggregates, the amount of the compound that binds 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 for a more reliable evaluation.

[0470] 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:

[0471] (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;

[0472] (b) Binding the compound to α-synuclein aggregates;

[0473] (c) Detecting a compound that binds to α-synuclein aggregates;

[0474] (d) Optionally 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; and

[0475] (e) Optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once.

[0476] In a method for monitoring progression, the amount of a compound that binds to α-synuclein aggregates can optionally be compared at different time points during treatment, e.g., before and after the start of treatment or at different time points after the start of treatment.

[0477] Typically, the patient is 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 may involve administering a drug suitable for treating a disease, disorder or abnormality associated with α-synuclein aggregates.

[0478] In another embodiment, the present invention relates to a method of 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:

[0479] (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 a compound of the present invention;

[0480] (b) binding the compound to α-synuclein aggregates;

[0481] (c) detecting the compound bound to α-synuclein aggregates;

[0482] (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 specific body part or body region; and

[0483] (e) optionally repeating steps (a)-(c), and if present, optionally repeating step (d) at least once. In the method for predicting responsiveness, the method may further comprise steps (i)-(vi) before step (a):

[0484] (i) contacting a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound of the present invention that specifically binds to α-synuclein aggregates;

[0485] (ii) binding the compound to α-synuclein aggregates;

[0486] (iii) detecting the formation of the compound bound to α-synuclein aggregates;

[0487] (iv) 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 specific body part or body region;

[0488] (v) optionally comparing the amount of the compound bound to α-synuclein aggregates with a normal control value; and

[0489] (vi) treating the patient with a drug.

[0490] Optionally, the method may further comprise step (A) after step (d) or step (e):

[0491] (A) comparing the amount of the compound that binds to α-synuclein aggregates as determined in step (iv) with the amount of the compound that binds to α-synuclein aggregates as determined in step (d).

[0492] In the method for predicting responsiveness, the amount of the compound that binds to 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 that binds to α-synuclein aggregates, particularly a decrease, may indicate that the patient has a high response potential to the corresponding treatment.

[0493] If the amount of the compound that binds to α-synuclein aggregates decreases over time, it may be presumed that the patient is responsive to the treatment. If the amount of the compound that binds to α-synuclein aggregates is substantially constant or increases over time, it may be presumed that the patient is non-responsive to the treatment.

[0494] Alternatively, responsiveness may be evaluated by determining the amount of the compound that binds to α-synuclein aggregates. The amount of the compound that binds to α-synuclein aggregates may be compared with a control value, such as a normal control value, a preclinical control value, or a clinical control value. Alternatively, the control value may refer to the control value of a subject known to respond to a certain therapy, or the control value may refer to the control value of a subject known not to respond to a certain therapy. The result regarding responsiveness may 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.

[0495] Optionally, the diagnostic composition may 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 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).

[0496] In any of the above methods, optionally, the step of 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; comprises

[0497] - Determine the amount of a compound that binds to α-synuclein aggregates;

[0498] - Establish a correlation between the amount of the compound that binds to α-synuclein aggregates and the amount of α-synuclein aggregates in a sample or a specific body part or body region; and

[0499] - Optionally, compare 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.

[0500] The control value can be, for example, a normal control value, a preclinical control value, and / or a clinical control value.

[0501] A "healthy control subject" or "healthy volunteer (HV) subject" is a person without clinical evidence of a disease, disorder, or abnormality associated with α-synuclein aggregates.

[0502] 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.

[0503] If, in any of the above-described methods, 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 synucleinopathy.

[0504] Contact a sample or a specific body part or body region suspected of containing α-synuclein aggregates with a compound of the present invention.

[0505] Any compound of the present invention can be used in the methods outlined above. Preferably, a detectably labeled compound of the present invention is used in the methods outlined above.

[0506] The specific body part or body region is preferably mammalian, more preferably human, and includes the whole body or a partial 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 intestine, preferably the brain.

[0507] The tissue can be brain tissue, central nervous system (CNS) tissue, eye tissue (e.g., retinal tissue), tissue of a peripheral organ such as the intestine, 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.

[0508] In the above methods, the compound of the present invention can be contacted with a sample or a specific body part or body region suspected of containing α-synuclein aggregates by any suitable method.

[0509] In an in vitro method, the compounds of the present invention and a liquid sample can simply be mixed.

[0510] In an in vivo method, a particular body part or body region can be brought into contact with the compounds of the present invention by administering to a patient an effective amount of the compounds of the present invention.

[0511] The effective amount of the compounds of the present invention is an amount suitable for enabling determination, using a selected analytical technique, of the presence or absence of α-synuclein aggregates in a sample, a particular body part or body region. There is no particular limitation on this amount and it will depend on the compound of formula (I), the type of detectable label, the corresponding analytical method and the sensitivity of the corresponding device. This amount can be appropriately selected by a person skilled in the art.

[0512] The compound is then bound to the α-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites. The step of binding the compound to the α-synuclein aggregates includes allowing the compounds 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 a person 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 the particular 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 compounds of the present invention.

[0513] 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 the detectable label, the sample type, the particular body part or body region, and whether the method is an in vitro or in vivo method, etc. 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 label compound within a sample or a particular body part or body region. The imaging system provides an image of the bound detectable label, such as a radioisotope, particularly a positron emitter or a γ emitter, as present in the test sample, the particular 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.

[0514] The amount of the compound that binds to the α-synuclein aggregate can be determined visually or by quantitative analysis, such as using PET scan images.

[0515] 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 includes a container containing one or more compounds of the present invention or their precursors, and instructions for using the compound to bind to α-synuclein aggregates and detect the compound bound to the α-synuclein aggregates formed, such that the presence or absence of the compound bound to the α-synuclein aggregate is correlated with the presence or absence of the α-synuclein aggregate.

[0516] 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 in Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.

[0517] The detectable-labeled compound of the present invention, preferably 18 the compound of formula (III-F) labeled with 3 F or the compound of formula (I-H*) or (I-H) labeled with

[0518] Synthetic methods of the compounds of the present invention

[0519] The compounds of the present invention can be prepared according to 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, unless otherwise stated or 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 present invention and does not limit the scope of the present invention otherwise claimed. In the following general methods, R 1 、R 2 、 Z, Y 1 、LG, Hal, m and n are as previously defined in the above embodiments, or are limited to the names in the schemes. Unless otherwise stated, the starting materials are commercially available or prepared by known methods.

[0520] General synthetic schemes for preparing the compounds of the present invention:

[0521] Scheme 1

[0522]

[0523] A commercially available or custom aldehyde derivative can react with a suitable amine through reductive amination, and after purification, intermediate A is obtained. Then the halogen atom is replaced by a heteroarylboronic acid derivative containing a leaving group (LG) through Suzuki coupling, and after purification, intermediate B is obtained. The LG is then replaced by a suitable amine derivative through aromatic nucleophilic substitution, and after purification, intermediate C is obtained. Intermediate C can be cyclized using 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to obtain the compound of formula (I). Alternatively, a custom aldehyde can be cyclized using 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to obtain intermediate D. Then the halogen atom is replaced by a heteroarylboronic acid derivative containing a leaving group (LG) through Suzuki coupling, and after purification, intermediate E is obtained. Then the LG is replaced by a suitable amine derivative through aromatic nucleophilic substitution to obtain the compound of formula (I).

[0524] 1 8 General Synthesis of the F-Labeled Compounds of the Invention :

[0525] 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 18 replaced by F, thereby preparing 18 an F-labeled compound having formula (I).

[0526] It can be used for 18 The reagents, solvents, and conditions for F-fluorination are well known to those skilled in the art (L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, 2853 - 2873; J. Fluorine Chem., 27(1985): 177 - 191; Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of BasicReactions, (2006),: Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-TheDriving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15 - 50). Preferably, for 18The F-fluorinated solvent is DMF, DMSO, acetonitrile, DMA or a mixture thereof. Preferably, the solvent is acetonitrile or DMSO.

[0527] Any suitable 18 F-fluorinating agent can be used. Typical examples include H 18 F, alkali metal or alkaline earth metal 18 F-fluorides (e.g., 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 (e.g., 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane- ). Or a crown ether (e.g., 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; e.g., 18 a tetra(C 1-6 alkyl)ammonium salt of 18 F or 18 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

[0528] Although the above shows reactions with 18 F as a radiolabel, other radiolabels can be introduced in a similar manner.

[0529] The present invention is illustrated by the following examples. However, these examples should not be construed as limiting. Examples

[0530] 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 general chemical principles, protecting groups for sensitive or reactive groups may be used when necessary. Manipulate protecting groups 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). Remove these groups using methods obvious to those skilled in the art at a convenient stage of compound synthesis.

[0531] Unless otherwise specified, all reagents and solvents are obtained from commercial sources and can be used without further purification.

[0532] These chemical names were generated using ChemBioDraw Ultra v20 from CambridgeSoft.

[0533] 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 characteristics, such as MS, IR, NMR.

[0534] Abbreviations

[0535] The abbreviations used are those conventional in the art.

[0536] CDI Carbonyl diimidazole DCM Dichloromethane DMSO Dimethyl sulfoxide DTT Dithiothreitol EGTA Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid HPLC High performance liquid chromatography LCMS Liquid chromatography-mass spectrometry LG Leaving group MS Mass spectrometry NMR Nuclear magnetic resonance Pg Protecting group <![CDATA[S N Ar]]> Nucleophilic aromatic substitution THF Tetrahydrofuran TMS Tetramethylsilane RT Room temperature

[0537] Analytical details, preparation and analytical methods

[0538] NMR measurements are carried out in deuterated solvents on a DRX - 400 MHz NMR spectrometer or a Spinsolve 80 MHz NMR spectrometer, on a Bruker AV - 400 MHz NMR spectrometer, with or without tetramethylsilane as an internal standard. Chemical shifts (δ) from the 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.

[0539] Mass spectrometry (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.

[0540] Column chromatography was performed using silica gel (Fluka: silica gel 60, 0.063 - 0.2 mm) and appropriate solvents as indicated in the specific examples.

[0541] Flash chromatography system: Flash purification was carried out using a Biotage Isola One flash purification system, which used HP Sil or KP-NH SNAP columns (Biotage) and the solvent gradients indicated in the specific examples.

[0542] Thin-layer chromatography (TLC) was performed on silica gel plates using UV detection.

[0543] Example 1: (R)-6-(6-(3-Fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1H-pyrrolo [1,2-c]imidazol-3(2H)-one hydrochloride

[0544]

[0545] Step A: To a solution of 4-bromo-1H-pyrrole-2-carbaldehyde (1.5 g, 8.62 mmol) in tetrahydrofuran (60 mL) was added titanium(IV) isopropoxide (2.53 mL, 8.62 mmol), followed by 3-aminopyridine (2.434 g, 25.9 mmol). The reaction mixture was stirred at room temperature for 40 min, and then sodium cyanoborohydride (0.813 g, 12.93 mmol) was added. The reaction mixture was stirred for 40 min, but the starting material was still present. Therefore, another batch of titanium(IV) isopropoxide (2.53 mL, 8.62 mmol) was added, and the reaction mixture was stirred for an additional 1 h. Water and ethyl acetate were added, and the mixture was filtered through a pad of diatomaceous earth. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with a brine solution, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography (silica gel, HP-Sil 100 g column, dichloromethane solution of 0 - 10% methanol) and further purified by flash chromatography (silica gel, HP-Sil 100 g column, heptane solution of 40 - 100% ethyl acetate) to give N-((4-bromo-1H-pyrrol-2-yl)methyl)pyridin-3-amine as an orange solid (1.19 g, 55%).

[0546] 11H NMR (80 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.00 (d, 1H), 7.77 (dd, 1H), 7.18 - 6.91 (m, 2H), 6.77 (t, 1H), 6.23 - 5.94 (m, 2H), 4.14 (d, 2H).

[0547] MS: 253.94 [M+H] + 。

[0548] Step B: In a flask under an argon atmosphere, the compound from step A (250 mg, 0.992 mmol), (R)-2-(3-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (319 mg, 1.091 mmol), bis(tri-tert-butylphosphine)palladium(0) (50.7 mg, 0.099 mmol) and cesium carbonate (969 mg, 2.97 mmol) were added, followed by the addition of a mixture of dry 1,4-dioxane (16 mL) / degassed water (4 mL). The reaction mixture was stirred at 85 °C for 4 h. The crude product was evaporated under reduced pressure, dissolved in water, and extracted twice with a mixture of dichloromethane / methanol (9:1). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was triturated in ethyl acetate and the solid was triturated in dichloromethane to give (R)-N-((4-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-pyrrol-2-yl)methyl)pyridin-3-amine as a dark brown solid (80.1 mg, 24%).

[0549] 1 1H NMR (80 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.28 (d, 1H), 8.03 (s, 1H), 7.86 - 7.52 (m, 2H), 7.13 - 6.89 (m, 2H), 6.74 - 6.22 (m, 3H), 6.06 (t, 1H), 5.43 (d, 1H), 4.19 (s, 2H), 3.92 - 3.42 (m, 4H), 2.23 - 1.81 (m, 2H).

[0550] MS: 339.10 [M+H] + 。

[0551] Step C:Dissolve the compound from step B (40 mg, 0.119 mmol) in dichloroethane (3 mL), and add 1,1′-carbonyldiimidazole (192 mg, 1.186 mmol). Stir the mixture at RT. After 24 h, add 1,1′-carbonyldiimidazole (192 mg, 1.186 mmol). Stir the mixture for 24 h to complete. Filter the crude reaction mixture and triturate in water to obtain (R)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1H-pyrrolo[1,2-c]imidazol-3(2H)-one as a brown solid (25.2 mg, 58.5%).

[0552] 1 1H NMR (80 MHz, DMSO-d6) δ 8.96 (d, 1H), 8.53 - 8.32 (m, 2H), 8.19 (dd, 1H), 7.85 (dd, 1H), 7.64 (s, 1H), 7.48 (dd, 1H), 6.71 - 6.39 (m, 2H), 5.91 - 4.89 (m, 3H), 3.75 - 3.35 (m, 4H), 2.23 - 1.80 (m, 2H).

[0553] MS: 364.12 [M + H] + 。

[0554] Step D: To a solution of the compound from step C (25 mg, 0.069 mmol) in dioxane (7 mL) at RT, add a dioxane solution of 4 M hydrochloric acid (0.5 mL, 2.00 mmol). Stir the mixture at RT for 22 h. Evaporate the solvent and triturate the solid with acetonitrile and then with ethyl acetate to obtain (R)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1H-pyrrolo[1,2-c]imidazol-3(2H)-one hydrochloride as a brown solid (17.1 mg, 62%).

[0555] 1 1H NMR (80 MHz, DMSO-d6) δ 9.07 (d, 1H), 8.60 - 8.19 (m, 4H), 7.99 (s, 1H), 7.70 (dd, 1H), 7.17 (d, 1H), 6.80 (s, 1H), 5.57 (d, 1H), 5.10 (s, 2H), 4.21 - 3.35 (m, 4H), 2.33 - 1.84 (m, 2H).

[0556] MS: 261.03 [M + H] + 。

[0557] Example 2:(R)-2-(6-(3-Fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one hydrochloride

[0558]

[0559] Step A: To a solution of 4-bromo-1H-imidazole-2-carbaldehyde (1 g, 5.71 mmol) in tetrahydrofuran (60 mL) was added titanium(IV) isopropoxide (6.70 mL, 22.86 mmol), followed by 3-aminopyridine (1.614 g, 17.14 mmol). The mixture was stirred at RT for 1 h 30, then titanium(IV) isopropoxide (6.70 mL, 22.86 mmol) was added. After 1 h, sodium cyanoborohydride (0.813 g, 12.93 mmol) was added and the reaction was complete after 2 h. Water and ethyl acetate were added and the mixture was filtered through a pad of diatomaceous earth. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated to dryness. The crude product was triturated in ethyl acetate to give N-((4-bromo-1H-imidazol-2-yl)methyl)pyridin-3-amine as a pale pink solid (460 mg, 32%).

[0560] 1 1H NMR (80 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.00 (d, 1H), 7.78 (dd, 1H), 7.16 (s, 1H), 7.11 - 6.90 (m, 2H), 6.35 (t, 1H), 4.24 (d, 2H).

[0561] MS: 254.97 [M+H] + 。

[0562] Step B: The compound from step A (460 mg, 1.817 mmol) was dissolved in dichloroethane (50 mL) and 1,1′-carbonyldiimidazole (2947 mg, 18.17 mmol) was added. The mixture was stirred at RT for 1 h. The solvent was evaporated and the crude product was purified by flash chromatography (silica gel, HP-Sil 100 g column, dichloromethane solution of 0 - 10% methanol) to give 2-bromo-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one as a white solid (412 mg, 81%).

[0563] 11H NMR (80 MHz, DMSO-d6) δ 8.94 (d, 1H), 8.44 (dd, 1H), 8.25 - 8.05 (m, 1H), 7.97 (s, 1H), 7.50 (dd, 1H), 5.10 (s, 2H).

[0564] MS: 280.95 [M+H] + 。

[0565] Step C : In a flask under an argon atmosphere, the compound from step B (275 mg, 0.985 mmol), (6-fluoropyridin-3-yl)boronic acid (208 mg, 1.478 mmol), tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol), and sodium carbonate (209 mg, 1.971 mmol) were added to a mixture of dry 1,4-dioxane (10 mL) / degassed water (2.50 mL). The mixture was heated at 85 °C for 3 h. The crude product was evaporated under reduced pressure, dissolved in water, and extracted three times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was triturated in ethyl acetate to give 2-(6-fluoropyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one as a white solid (128.8 mg, 44.3%).

[0566] 1 1H NMR (80 MHz, DMSO-d6) δ 8.98 (d, J = 2.7 Hz, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.57 - 8.33 (m, 3H), 8.20 (d, J = 8.9 Hz, 1H), 7.52 (dd, J = 8.4, 4.7 Hz, 1H), 7.28 (dd, J = 8.6, 2.8 Hz, 1H), 5.17 (s, 2H).

[0567] MS: 296.08 [M+H] + 。

[0568] Step D: In a vial under an argon atmosphere, the compound from step C (40 mg, 0.135 mmol), (R)-3-fluoropyrrolidine hydrochloride (68.0 mg, 0.542 mmol), and cesium fluoride (123 mg, 0.813 mmol) were mixed in dry dimethyl sulfoxide (3 mL). The mixture was purged with argon and stirred at 120 °C for 18 h. The reaction mixture was cooled and poured into cold water pre-cooled with an ice bath. The resulting solution was filtered and rinsed with water and isopropanol. The solid was dried to obtain (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one as a white solid (36.6 mg, 74%).

[0569] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, 1H), 8.64 (s, 1H), 8.42 (d, J = 4.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 7.3 Hz, 1H), 6.57 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 53.6 Hz, 1H), 5.12 (s, 2H), 3.87 - 3.51 (m, 4H), 2.18 (d, J = 77.1 Hz, 2H).

[0570] MS: 365.22 [M+H] + 。

[0571] Step E : To a solution of the compound from step D (35 mg, 0.096 mmol) in dioxane (7 mL) at RT was added a dioxane solution of 4 M hydrochloric acid (0.7 ml, 2.80 mmol). The mixture was stirred at RT for 13 h. The solvent was evaporated to obtain (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one hydrochloride as a light brown solid (45.4 mg, 118%).

[0572] 1 H NMR (80 MHz, DMSO-d6) δ 9.09 (d, J = 2.6 Hz, 1H), 8.64 - 8.29 (m, 5H), 7.74 (dd, J = 8.7, 4.8 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 6.01 - 5.08 (m, 3H), 3.99 - 3.52 (m, 4H), 2.22 - 1.81 (m, 2H).

[0573] MS: 365.19 [M+H] + 。

[0574] Example 3 : (S)-2-(6-(3-Fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one hydrochloride

[0575]

[0576] Step A: In a vial under an argon atmosphere, the compound from Step C of Example 2 (40 mg, 0.135 mmol), (S)-3-fluoropyrrolidine hydrochloride (68.0 mg, 0.542 mmol), and cesium fluoride (123 mg, 0.813 mmol) were mixed in dry dimethyl sulfoxide (3 mL). The mixture was purged with argon and stirred at 120 °C for 6 h. The reaction mixture was cooled and poured into cold water pre-cooled with an ice bath. The resulting solution was filtered, and the solid was washed with water and isopropanol and dried to give (S)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one as a light brown solid (32.9 mg, 67%).

[0577] 1 H NMR (80 MHz, DMSO-d6) δ 8.95 (d, 1H), 8.62 (d, 1H), 8.41 (dd, J = 4.4 Hz, 1H), 8.19 (d, 1H), 8.08 - 7.88 (m, 2H), 7.50 (dd, J = 8.3, 5.0 Hz, 1H), 6.57 (d, J = 9.0 Hz, 1H), 5.89 - 5.02 (m, 3H), 3.97 - 3.44 (m, 4H), 2.32 - 1.91 (m, 2H).

[0578] MS: 365.15 [M+H] + 。

[0579] Step B: To a solution of the compound from Step D (32.9 mg, 0.090 mmol) in dioxane (7 mL) at RT was added a 4 M solution of hydrochloric acid in dioxane (0.7 mL, 2.80 mmol). The mixture was stirred at RT for 5 h. The solvent was evaporated to give (S)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-a]imidazol-5-one hydrochloride as a light brown solid (41.3 mg, 114%).

[0580] 1 1H NMR (80 MHz, DMSO-d6) δ 9.04 (d, J = 2.7 Hz, 1H), 8.60 - 8.21 (m, 5H), 7.64 (dd, J = 8.4, 4.8 Hz, 1H), 7.19 (d, J = 9.5 Hz, 1H), 6.00 - 5.07 (m, 3H), 4.47 - 3.93 (m, 4H), 2.29 - 1.84 (m, 2H).

[0581] MS: 365.20 [M+H] + .

[0582] Example 4 : 6-(6-Fluoropyridin-3-yl)-2-(pyridin-3-yl)-1H-pyrrolo[1,2-c]imidazol-3(2H)-one

[0583]

[0584] Step A : In a flask under an argon atmosphere, 4-bromo-1H-pyrrole-2-carbaldehyde (5 g, 28.7 mmol), (6-fluoropyridin-3-yl)boronic acid (6.07 g, 43.1 mmol), tetrakis(triphenylphosphine)palladium(0) (4.98 g, 4.31 mmol) and sodium carbonate (6.09 g, 57.5 mmol) were added to a mixture of dry 1,4-dioxane (100 mL) / degassed water (25 mL). The mixture was heated at 85 °C for 3 h, then tetrakis(triphenylphosphine)palladium(0) (4.98 g, 4.31 mmol) was added. The mixture was stirred at 85 °C overnight. The crude product was evaporated under reduced pressure, dissolved in water, and extracted three times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The product was triturated in dichloromethane, the filtrate was evaporated, and the product was triturated in ethyl acetate. The filtrate was triturated more than once in dichloromethane, and the solids were combined to give 4-(6-fluoropyridin-3-yl)-1H-pyrrole-2-carbaldehyde as a white solid (730 mg, 13%).

[0585] 1 1H NMR (80 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.54 (s, 1H), 8.56 (d, 1H), 8.24 (td, 1H), 7.84 (s, 1H), 7.48 (d, 1H), 7.18 (dd, 1H).

[0586] MS: 191.00 [M+H] + .

[0587] Step B: To a solution of the compound from step A (500 mG, 2.63 mmol) in tetrahydrofuran (25 mL) was added titanium(IV) isopropoxide (1.541 mL, 5.26 mmol), followed by 3-aminopyridine (247 mg, 2.63 mmol). The mixture was stirred at RT for 1 h, then 1 mL of titanium(IV) isopropoxide was added. After 15 min, a spatula tip of 3-aminopyridine was added. After 40 min, sodium cyanoborohydride (330 mg, 5.26 mmol) was added. Water and ethyl acetate were added, and the mixture was filtered through a diatomaceous earth pad. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered, and concentrated to dryness. The solid crude product was triturated successively in ethyl acetate, dichloromethane, and acetonitrile to give N-((4-(6-fluoropyridin-3-yl)-1H-pyrrol-2-yl)methyl)pyridin-3-amine as a pale yellow solid (359 mg, 50.9%).

[0588] 1 H NMR (80 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.36 (d, 1H), 8.20 - 7.91 (m, 2H), 7.77 (dd, 1H), 7.31 - 6.93 (m, 4H), 6.42 (d, 1H), 6.14 (t, 1H), 4.19 (d, 2H).

[0589] MS: 269.03 [M+H] + 。

[0590] Step C : The compound from step B (140 mg, 0.522 mmol) was dissolved in dimethyl sulfoxide (20 mL) and 1,1′-carbonyldiimidazole (846 mg, 5.22 mmol). The mixture was stirred at RT for 20 h. The reaction mixture was cooled and poured into ice-cold water pre-cooled with an ice bath. The resulting solution was filtered, and the solid was washed with water. The solid was dried to give 6-(6-fluoropyridin-3-yl)-2-(pyridin-3-yl)-1H-pyrrolo[1,2-c]imidazol-3(2H)-one as a light brown solid (97.6 mg, 63.6%).

[0591] 1 H NMR (80 MHz, DMSO-d6) δ 8.96 (d, J = 2.7 Hz, 1H), 8.61 (d, 1H), 8.47 - 8.08 (m, 3H), 7.93 (s, 1H), 7.49 (dd, J = 8.5, 4.7 Hz, 1H), 7.21 (dd, J = 8.5, 3.0 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 5.08 (s, 2H).

[0592] MS: 295.02 [M+H] + 。

[0593] Example 5 : (S)-6-(6-(3-Fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride

[0594]

[0595] Step A : Under an argon atmosphere, in a dried screw-cap vial, 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (150 mg, 0.53 mmol), boronic ester (311 mg, 1.06 mmol), Na2CO3 (170 mg, 1.6 mmol) and (1,4-dioxane: H2O) (4:1, 7.5 mL) were added. The reaction mixture was degassed with argon for 15 min. Then Pd(PPh3)4 (62 mg, 0.053 mmol) was added and the mixture was heated to 85 °C for 5 h. As monitored by TLC, the reactants were exhausted. Thereafter, the reaction mixture was quenched with ice-water (10 mL) and extracted with a DCM solution of 5% MeOH (30 mL × 3). The organic layer was dried over Na2SO4, concentrated, purified by silica gel chromatography (100 - 200 mesh), eluted with a DCM solution of 2% MeOH to obtain (S)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one as a yellowish-white solid (40 mg, 20%).

[0596] 1 1H NMR (DMSO-d6) δ 8.44 (d, 1H), 7.98 (s, 1H), 7.83 (dd, 1H), 7.64 (d, 1H), 7.60 (d, 1H), 6.56 (m, 1H), 6.52 (d, 1H), 5.45 (m, 1H), 4.81 (s, 2H), 3.86 (s, 3H), 3.66 (m, 3H), 3.44 (m, 1H), 2.20 (m, 2H).

[0597] LCMS: 366.9 [M] + 。

[0598] Step B: At 0 °C under a N2 atmosphere, a 1,4-dioxane solution of 4 M HCl (0.2 mL) was added to a stirred solution of the compound from step A (40 mg, 0.11 mmol) in 1,4-dioxane (1.2 mL). The mixture was stirred at RT for 16 h. After completion of the reaction, the solvent was evaporated, the residue was washed with pentane, and dried in vacuo to give (S)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride as a white solid (10 mg, 25%).

[0599] 1 1H NMR (DMSO-d6) δ 8.28 (d, 2H), 8.02 (s, 1H), 7.89 (s, 1H), 7.66 (s, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 5.55 (d, 1H), 4.84 (s, 2H), 3.84 (m, 7H), 2.25 (m, 2H).

[0600] LCMS: 366.9 [M] + .

[0601] Example 6: (R)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride

[0602]

[0603] Step A:In an argon atmosphere, in a dried screw-cap vial, 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one (150 mg, 0.53 mmol), boronic ester (311 mg, 1.1 mmol), Na2CO3 (170 mg, 1.6 mmol) and dioxane:H2O (4:1, 7.5 mL) were added. The reaction mixture was degassed with argon for 15 min. Then Pd(PPh3)4 (62 mg, 0.053 mmol) was added and the mixture was heated to 85 °C for 4 h. As monitored by TLC, the reactants were exhausted. Thereafter, the reaction mixture was quenched with ice-water (15 mL) and extracted with a DCM solution of 5% MeOH (15 mL × 3). The organic layer was dried over Na2SO4, concentrated, purified by silica gel chromatography (100 - 200 mesh), eluted with a DCM solution of 3% MeOH to give (R)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one as a yellow solid (40 mg, 20%).

[0604] 1 1H NMR (DMSO-D6) δ 8.44 (d, 1H), 7.98 (s, 1H), 7.83 (dd, 1H), 7.61 (d, 2H), 6.54 (m, 2H), 5.45 (m, 1H), 4.81 (s, 2H), 3.86 (s, 3H), 3.66 (m, 3H), 3.44 (m, 1H), 2.20 (m, 2H).

[0605] LCMS: 366.9 (M) + 。

[0606] Step B: To a stirred solution of the compound from step A (40 mg, 0.1 mmol) in DCM (0.8 mL) at 0 °C under a N2 atmosphere was added a 1,4-dioxane solution of 4M HCl (0.2 mL) and the mixture was stirred at rt for 16 h. Then the solvent was evaporated, the residue was washed with pentane and dried in vacuo to give (R)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride as a white solid (40 mg, 90%).

[0607] 11H NMR (DMSO-d6) δ 8.40 (dd, 1H), 8.20 (d, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.20 (d, 1H), 6.74 (d, 1H), 5.57 (d, 1H), 4.85 (s, 2H), 3.94 (m, 2H), 3.86 (s, 3H), 3.67 (m, 2H), 2.30 (m, 2H).

[0608] LCMS: 366.9 (M) + .

[0609] Example 7 : (S)-6-(6-(3-Fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride

[0610]

[0611] Step A : Under a N2 atmosphere, NaH (60% dispersed in mineral oil) (24 mg, 0.98 mmol) was added to a solution of Example 1 Step A (500 mg, 1.9 mmol) in 1,2-DCE (5.0 mL) cooled in ice. Then the mixture was warmed to RT and kept for 30 min. Then CDI (3.2 g, 19.6 mmol) was added to the reaction mixture, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice-cold water, and the product was extracted with EtOAc (40 mL × 3). The extract was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh), eluting with a hexane solution of 20% EtOAc to give 6-bromo-2-(pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one as a yellow solid (250 mg, 45%).

[0612] 1 1H NMR (DMSO-d6) δ 8.92 (d, 1H), 8.40 (d, 1H), 8.15 (m, 1H), 7.50 (m, 2H), 6.34 (s, 1H), 5.03 (s, 2H).

[0613] MS (ESI): 280.15 (M + H) + .

[0614] Step B:In an argon atmosphere, in a dried screw-cap vial, add the compound from step A (100 mg, 0.35 mmol), boronic ester (210 mg, 0.72 mmol), Cs2CO3 (233 mg, 0.72 mmol) and dioxane:H2O (4:1, 5 mL). Degas the reaction mixture with argon for 15 min. Then add Pd(dPPf)Cl2.DCM (30 mg, 0.036 mmol), and heat the mixture to 90 °C for 12 h. As monitored by TLC, the reactants were exhausted. Thereafter, quench the reaction mixture with ice-water (15 mL), and extract with DCM solution of 5% MeOH (50 mL X 3). Dry the organic layer with Na2SO4, concentrate, purify by silica gel chromatography (100 - 200 mesh), elute with DCM solution of 4% MeOH to obtain (S)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one as a yellowish-white solid (25 mg, 19%).

[0615] 1 1H NMR (DMSO-d6) δ 8.96 (d, 1H), 8.47 (d, 1H), 8.39 (d, 1H), 8.19 (d, 1H), 7.86 (dd, 1H), 7.65 (s, 1H), 7.49 (q, 1H), 6.61 (s, 1H), 6.53 (d, 1H), 5.46 (d, 1H), 5.05 (s, 2H), 3.67 (m, 3H), 3.44 (m, 1H), 2.21 (m, 2H).

[0616] LCMS: 364.0 (M+H) + 。

[0617] Step C: At 0 °C in an N2 atmosphere, add a 1,4-dioxane solution of 4M HCl (0.12 mL) to a stirred solution of the compound from step B (25 mg, 0.07 mmol) in DCM (0.7 mL), and stir the mixture at RT for 10 h. After the reaction is complete, evaporate the solvent, wash the residue with pentane, and dry in vacuo to obtain (S)-6-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-2-(pyridin-3-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one hydrochloride as a white solid (15 mg, 55%).

[0618] 11H NMR (DMSO-d6) δ 8.50 (d, 1H), 8.42 (d, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.20 (d, 1H), 6.82 (s, 1H), 5.58 (d, 1H), 5.11 (s, 2H), 3.90 (m, 3H), 3.67 (td, 1H), 2.30 (m, 2H).

[0619] LCMS: 363.9 (M) + 。

[0620] Biological assay description and corresponding results

[0621] 1. Preparation of α-synuclein (α-syn) aggregates from human Parkinson's disease (PD) brain

[0622] This method was adapted from the protocol described in Spillantini et al., 1998. Frozen tissue blocks from PD donors were thawed on ice and homogenized using a glass Dounce homogenizer. Then, using a pre-cooled 70.1 rotor (Beckman, 342184), the homogenate was centrifuged in an ultracentrifuge (Beckman, XL100K) at 4 °C at 11,000 x g (12,700 RPM) for 20 minutes. 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 × g (14,800 rpm, 70.1Ti rotor) for 20 minutes. The pellet was discarded, and sodium dodecyl 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. Then the solution was centrifuged at 4 °C at 100,000 × g (38,000 rpm, 70.1Ti rotor) for 1 hour. The pellet containing enriched α-syn aggregates was resuspended in PBS according to each gram of brain initially used and stored at -80 °C until use.

[0623] 2. Microscopic radioactivity binding competition assay for determining binding affinity in α-synuclein aggregates from PD brain

[0624] The α-synuclein aggregates from PD brain were spotted onto a microarray slide. The slide was incubated with 20 nM or 30 nM of 3H]-α-synuclein reference was incubated with the example compounds (non-radiolabeled) at 1 μM and 100 nM. In some cases, different concentrations of 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 using the image analysis software Beamage (ai4R). Non-specific signal was determined using an excess of non-radiolabeled α-synuclein reference compound (2 μM), and specific binding was calculated by subtracting the non-specific signal from the total signal. Competition was calculated as a percentage, where 0% was defined as specific binding in the presence of vehicle and 100% was defined as the value obtained in the presence of an excess of non-radiolabeled α-synuclein reference compound. Ki values were calculated by applying non-linear regression curve fitting using the one-site specific binding model in GraphPad Prism 7. All measurements were performed with at least two technical replicates, and all measurements were performed at least twice with technical replication. For compounds tested in more than one experiment, the mean of replicates or the Ki value in independent experiments was reported.

[0625] Results : To evaluate the competitive potency of the example compounds against 3 H]-reference α-synuclein ligand binding to α-synuclein aggregates derived from the brains of PD patients. The results of the micro-radioligand binding competition assay for the example compounds tested are shown in Table 3: % competition percentages at 1 μM and 100 nM. Table 3 also shows the K i i values.

[0626] Table 3

[0627]

[0628] Table 3: Binding affinities for α-synuclein aggregates derived from human PD brains were evaluated by micro-radioligand binding competition assay. Percent competition (%) of tritiated 3 H]-α-synuclein reference ligand in the presence of 1 μM and 100 nM of example compounds 1 - 7. Ki values for the selected example compounds are also shown. These examples are the mean of Ki values in two independent experiments using PD brain homogenates from two different donors. As shown in Table 3, example compounds 1 - 7 of the present invention showed potent binding to α-synuclein aggregates derived from PD brains (n.d. = not determined).

Claims

1. A compound of formula (I): or a detectably labeled compound, 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; or R 1 is a halogen, halo C1-C4 alkyl, halo C1-C4 alkoxy, C1-C4 alkoxy 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 Z is CH or N.

2. The compound according to claim 1, having the formula (Ia): or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 3 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; and r is 0, 1 or 2.

3. A compound according to any one of the preceding claims, wherein R 1 is a 4- to 6-membered heterocyclic group selected from the following: wherein R 1a is F; or R 1 is a halogen.

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

5. A compound according to any one of the preceding claims, wherein R 2 is a 5- or 6-membered heteroaryl group selected from the following: wherein R 2a selected from halo C1-C4 alkyl, halo 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 R2 is a 5- or 6-membered heteroaryl selected from the following: wherein R 2b selected from H or C1-C4 alkyl.

7. The compound according to any one of the above claims, 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 7, wherein the compound is selected from: or a detectably labeled compound, 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 label selected from 18 F, 2 H, and 3 H.

11. A compound according to claim 9 or 10, wherein R 1 is or 18 F.

12. A diagnostic composition comprising a compound according to any one of claims 9 - 11 and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and / or adjuvant.

13. A compound according to any one of claims 9 - 11 or a diagnostic composition according to claim 12 for imaging α-synuclein aggregates.

14. A compound according to any one of claims 9 - 11 or a diagnostic composition according to claim 12 for positron emission tomography imaging of α-synuclein aggregates.

15. A compound or diagnostic composition for use in the use according to 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. A compound according to any one of claims 9 - 11 or a diagnostic composition according to claim 12 for use in diagnosis.

17. A compound or diagnostic composition for use according to the use of claim 16, wherein the diagnosis is of a disease, disorder or abnormality associated with α-synuclein aggregates or a 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 and 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 disease, 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 according to the use of claim 17, wherein the disease is Parkinson's disease.

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

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

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

22. A compound or diagnostic composition for use according to claim 17, wherein the disease is SNCA repeat carriers.

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

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

25. A method for diagnosing a disease, disorder or abnormality associated with α-synuclein aggregates in a subject, the method comprising the following steps: (a) Administering to the 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 25, 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 performing positron emission tomography (PET) imaging of α-synuclein aggregates in a subject's tissue, the method comprising the following steps: (a) Administering to the 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 by acquiring a positron emission tomography (PET) image of the subject's tissue.

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, including but not limited to Lewy bodies and / or Lewy neurites; (c) Detecting the compound bound to α-synuclein aggregates using positron emission tomography; 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 propensity for 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, 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.

31. A method for collecting data, the method being used to predict 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 suffering from a disease, disorder or abnormality associated with α-synuclein aggregates to treatment of the 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, the 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 that binds to α-synuclein aggregates; (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 in a sample or a specific body part or body region; and (e) Optionally repeat steps (a)-(c), and if present, repeat the optional step (d) at least once.

32. The method of claim 30 or 31, wherein the step of optionally establishing a correlation between the presence or absence of a compound that binds to α-synuclein aggregates and the presence or absence of α-synuclein in a sample or a specific body part or body region comprises the following steps: - Determining the amount of the compound that binds to α-synuclein aggregates; - Establishing a correlation between the amount of the compound that binds to α-synuclein aggregates and the amount of α-synuclein aggregates in a sample or a specific body part or body region; and - 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.

33. A compound of formula (III-F) or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, 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; or R 1F is a C1-C4 alkoxy group 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; Z is CH or N; LG is a leaving group; q is 0 or 1; and n is at least 1.

34. A compound of formula (III-F) according to claim 33, wherein LG is selected from nitro, bromo, chloro, iodo, C1-C4 alkylsulfonate and C6-C 10 arylsulfonate, wherein C6-C 10 arylsulfonate may optionally be substituted by -CH3 or -NO2.

35. A compound of formula (I-F) or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, 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; or R 1F is a C1-C4 alkoxy group 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; Z is CH or N; q is 0 or 1; and n is at least 1, preferably 1.

36. A compound of formula (III-H) or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, 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 with at least one halogen; or R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy 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; Z is CH or N; 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.

37. A compound of formula (I-H) or its stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, 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; or R 1 is halogen, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C1-C4 alkoxy 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; Z is CH or N; Y 1 is D, CD3, T or CT3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; and Provided that the compound of formula (I-H) contains at least one D, CD3, T or CT3, where D is 2 D (deuterium), and T is 3 H (tritium).

38. A process for preparing a compound of formula (I-F) according to claim 35, 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.

39. The method according to claim 38, 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(C1-6 alkyl)ammonium salts of F and 18 tetrabutylammonium fluoride.

40. A process for preparing a compound of formula (I-H) according to claim 37, wherein Y 1 is D or CD3, the process comprising reacting a compound of formula (III-H) according to claim 36 with 2 a H-radiolabeling reagent such that X is replaced by D or CD3.

41. A process for preparing a compound of formula (I-H) according to claim 37, wherein Y 1 is T or CT3, comprising reacting a compound of formula (III-H) according to claim 36 with a 3H-radiolabeling reagent such as a CT3 radiolabeling reagent such that X is replaced by T or CT3.

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

43. 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.

44. 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 or 36.

45. The kit according to claim 44, wherein the radiopharmaceutical formulation is for imaging α-synuclein aggregates, wherein the imaging is preferably performed by positron emission tomography.

46. The kit according to claim 44, wherein the radiopharmaceutical formulation is for in vitro imaging, ex vivo imaging or in vivo imaging, preferably the use is for in vivo imaging.

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

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