Novel compounds for diagnostics

Abstract

The present invention relates to novel compounds of formula (I), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, which can be used to image and quantify alpha-synuclein aggregates. Furthermore, the compounds can be used to diagnose diseases, disorders, or conditions associated with alpha-synuclein aggregates (e.g., Parkinson's disease or multiple system atrophy (MSA)), determine a predisposition to such diseases, disorders, or conditions, prognose such diseases, disorders, or conditions, monitor the progression of such diseases, disorders, or conditions in patients suffering from such diseases, disorders, or conditions, monitor the progression of such diseases, disorders, or conditions, and predict the responsiveness of patients suffering from such diseases, disorders, or conditions to treatment.

Description

[Technical Field]

[0001] The present invention relates to novel compounds of formula (I), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, which can be used to image and quantify alpha-synuclein aggregates. Furthermore, the compounds can be used to diagnose diseases, disorders, or conditions associated with alpha-synuclein (α-synuclein, A-synuclein, a-synuclein, A-syn, α-syn, aSyn, a-syn) aggregates, such as Parkinson's disease or multiple system atrophy, determine predisposition to such diseases, disorders, or conditions, prognose such diseases, disorders, or conditions, monitor disease progression in patients suffering from such diseases, disorders, or conditions, and predict the responsiveness of patients suffering from such diseases, disorders, or conditions to 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 uses thereof. [Background technology]

[0002] Many age-related diseases are based on or associated with the extracellular or intracellular deposition of amyloid or amyloid-like proteins, which contribute to the pathogenesis and progression of the disease. The best-characterized amyloid protein that forms extracellular aggregates is amyloid beta (Abeta or Aβ).

[0003] Amyloid-like proteins that primarily form intracellular aggregates include, but are not limited to, tau, alpha-synuclein, and huntingtin (HTT). Diseases associated with alpha-synuclein aggregates are generally classified as synucleinopathies (or alpha-synucleinopathies), including, but not limited to, Parkinson's disease (PD) or multiple system atrophy (MSA). Synucleinopathies involving primarily neuronal aggregates include, but are not limited to, Parkinson's disease (sporadic, familial with SNCA (the gene encoding the alpha-synuclein protein) mutations or SNCA gene duplication or triplication, familial with mutations in other genes other than SNCA, pure autonomic failure, and Lewy body dysphagia), SNCA duplication carriers, dementia with Lewy bodies (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's syndrome. Synucleinopathies involving 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 include traumatic brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and Niemann-Pick disease type C1, frontotemporal dementia with chromosome 17-linked parkinsonism), motor neuron diseases, Huntington's disease, amyotrophic lateral sclerosis (sporadic, familial and Guam ALS-dementia complex), neuroaxonal dystrophies, neurodegeneration type 1 with cerebral iron accumulation (Hallervorden-Spatz syndrome), prion diseases, Creutzfeldt-Jakob disease, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, Gaucher disease, Krabbe disease,and other lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder, but are not limited to these disorders (Jellinger, Mov. Disord. 2003, 18 Suppl. 6, S2-12; Galvin et al. JAMA Neurology 2001, 58 (2), pp. 186-190; Kovari et al., Acta Neuropathol. 2007, 114(3), pp. 295-8; Saito et al., J. Neuropathol. Exp. Neurol. 2004, 63(4), pp. 323-328; McKee et al., Brain, 2013, 136(Pt 1), pp. 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. 2018 Aug. 22; 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).

[0004] Alpha-synuclein is a naturally unfolded protein of 140 amino acids (Iwai et al., Biochemistry 1995, 34(32), pp. 10139-10145). The alpha-synuclein sequence can be divided into three major domains: 1) the N-terminal region encompassing residues 1-60, which contains an 11-mer amphipathic imperfect repeat with a highly conserved hexamer (KTKEGV). This region has been implicated in regulating alpha-synuclein binding to membranes and its internalization; 2) the hydrophobic non-amyloid beta component (NAC) domain spanning residues 61-95, which is essential for alpha-synuclein fibrillization; and 3) the C-terminal region spanning residues 96-140, which is highly acidic and proline-rich and lacks unique structural trends. Alpha-synuclein has been shown to undergo several post-translational modifications, including truncation, phosphorylation, ubiquitination, oxidation, and / or transglutaminase covalent cross-linking (Fujiwara et al., Nat. Cell. Biol. 2002, 4(2); 160-164; Hasegawa et al., J. Biol. Chem. 2002, 277(50), 49071-49076; Li et al., Proc. Natl. Acad. Sci. USA 2005, 102(6), 2162-2167; Oueslati et al., Prog. Brain Res. 2010, 183, 115-145; Schmid et al., J. Biol. Chem. 2009, 284(19), 13128-13142). Interestingly, the majority of these modifications involve residues within the C-terminal region.

[0005] Several phosphorylation sites have been detected in the carboxyl-terminal region at Tyr-125, -133, and -136, as well as at Ser-129 (Negro et al., FASEB. J 2002, 16(2), pp. 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), pp. 3879-3884; Nakamura et al., Biochem. Biophys. Res. Commun. 2001, 280(4), pp. 1085-1092). Phosphorylation by Src family kinases does not inhibit or enhance the tendency of alpha-synuclein to polymerize. Alpha-synuclein is phosphorylated in vitro by the protein tyrosine kinase p72. sykAlpha-synuclein has been shown to be an excellent substrate for alpha-synuclein (Syk), and upon extensive Tyr-phosphorylation by Syk or tyrosine kinases with similar specificity, it loses its ability to form oligomers, suggesting a putative role for these tyrosine kinases in preventing neurodegeneration (Negro et al., FASEB J. 2002, 16(2), pp. 210-212). Alpha-synuclein can be Ser-phosphorylated by the protein kinases CKI and CKII (Okochi et al., J. Biol. Chem. 2000, 275(1), pp. 390-397). Residue Ser-129 is also phosphorylated by G-protein-coupled receptor protein kinases (Pronin et al., J. Biol. Chem. 2000, 275(34), pp. 26515-26522). Extensive and selective phosphorylation of alpha-synuclein at Ser-129 is evident in synucleinopathy lesions, including Lewy bodies (Fujiwara et al., Nat. Cell. Biol. 2002, 4(2); pp. 160-164). Other post-translational modifications at the carboxyl terminus, including glycosylation at Ser-129 (McLean et al., Neurosci Lett. 2002, 323(3), pp. 219-223) and nitration at Tyr-125, -133, and -136 (Takahashi et al., Brain Res. 2002, 938(1-2), pp. 73-80), may influence alpha-synuclein aggregation. Proteolytic truncation of the carboxyl-terminal region has been reported to play a role in alpha-synuclein fibril formation in various neurodegenerative diseases (Rochet et al., Biochemistry 2000, 39(35), pp. 10619-10626). Full-length and partially truncated insoluble aggregates of alpha-synuclein have been detected in highly purified Lewy bodies (Crowther et al., FEBS Lett. 1998, 436(3), pp. 309-312).

[0006] Abnormal protein aggregation appears to be a common feature of the aging brain and several neurodegenerative diseases (Trojanowski et al., Cell Death Differ. 1998, 5(10), pp. 832-837; Koo et al., Proc. Natl. Acad. Sci. 1999, 96(18), pp. 9989-9990; Hu et al., Chin. Sci. Bull. 2001, 46, pp. 1-3); however, its precise role in the disease process remains unknown. In in vitro models, alpha-synuclein (or some of its truncated forms) readily assembles into filaments similar to those isolated from the brains of patients with Lewy body (LB) dementia and familial PD (Crowther et al., FEBS Lett. 1998, 436(3), pp. 309-312). Alpha-synuclein and its mutant forms (A53T and A30P) have a random coil conformation and do not form significant secondary structures at low concentrations in aqueous solution. However, at high concentrations, they tend to self-aggregate, forming amyloid fibrils (Wood et al., J. Biol. Chem. 1999, 274(28), 19509-19512). Some differences in the aggregation behavior of mutant and wild-type proteins associated with PD have been documented. Monomeric alpha-synuclein aggregates form stable fibrils in vitro via a metastable oligomeric (i.e., prefibrillar) state (Volles et al., Biochemistry 2002, 41(14), 4595-4602).

[0007] Parkinson's disease (PD) is the most common neurodegenerative movement disorder. PD is primarily idiopathic; however, in at least 5% of PD patients, pathology is associated with mutations in one or several specific genes. Several point mutations have been described in the alpha-synuclein gene (A30P, E46K, H50Q, G51D, A53T) that cause familial PD with autosomal dominant inheritance. Furthermore, duplications and triplications of the alpha-synuclein gene have been described in patients with PD, highlighting the role of alpha-synuclein in PD pathogenesis (Lesage et al., Hum. Mol. Genet., 2009, 18, 48-59). The etiology of PD remains unclear. However, increasing evidence suggests a role for pathogenic misfolding of the alpha-synuclein protein, which leads to the formation of amyloid-like fibrils. Indeed, PD is characterized by the presence of intracellular alpha-synuclein aggregate structures called Lewy bodies and neurites, primarily in substantia nigra neurons, and the death of dopaminergic neurons in the substantia nigra and elsewhere. Alpha-synuclein is a naturally unfolded presynaptic protein that can misfold and aggregate into large oligomeric and fibrillar forms, which have been linked to the pathogenesis of PD. Recent studies have implicated small soluble oligomeric and prefibrillar forms of alpha-synuclein as the most neurotoxic species (Lashuel et al., J. Mol. Biol., 2002, 322, 1089-102). However, the precise role of alpha-synuclein in neuronal toxicity remains unclear (reviewed in Cookson, Annu. Rev. Biochem., 2005, 74, 29-52).

[0008] In addition to Parkinson's disease, the accumulation of aggregated alpha-synuclein into Lewy bodies is a characteristic of all Lewy body diseases, including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) (Capouch et al., Neurol. Ther. 2018, 7, 249-263). In DLB, Lewy bodies are widely distributed throughout the brain cortex, and in addition to Lewy bodies and neurites, many thread-like and punctate structures (Lewy puncta) have been found to be immunopositive for alpha-synuclein phosphorylated at Ser-129 (Outeiro et al., Mol. Neurodegener. 2019, 14, 5).

[0009] Alpha-synuclein aggregates are also found in multiple system atrophy (MSA). MSA is a rare, sporadic neurodegenerative disorder manifesting as rapidly progressive autonomic and motor dysfunction and heterogeneous cognitive decline. Examples of such disorders include Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy. This disease can be clinically subclassified into parkinsonian (MSA-P) or cerebellar (MSA-C) variants depending on the predominant motor phenotype (Fanciulli et al., N. Engl. J. Med. 2015;372, 249-63). It is characterized by aggregation of alpha-synuclein in the cytoplasm of oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). GCIs, consisting primarily of fibrillar forms of alpha-synuclein, are a 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 thought to play a central role in the pathogenesis of MSA. Correlations between GCI volume and the degree of neuronal loss have been reported in both the striatonigral and olivopontocerebellar regions (Stefanova et al., Neuropathol Appl Neurobiol. 2016, 42, 20-32).

[0010] Furthermore, a causal link between GCI and the induction of neuronal loss has been demonstrated in transgenic mice overexpressing human alpha-synuclein in oligodendrocytes under various oligodendrocyte-specific promoters. A key event in the pathophysiological cascade is thought to be permissive templating of misfolded alpha-synuclein ("prion-like" propagation).

[0011] The diagnosis of Parkinson's disease is largely clinical and depends on the presence of a specific set of symptoms and signs (early core features include bradykinesia, rigidity, resting tremor, and postural instability), the absence of irregular features, a slowly evolving course, and response to symptomatic drug treatment, which is primarily limited to dopamine replacement therapy. Accurate diagnosis requires sophisticated clinical techniques and is subject to a degree of subjectivity and error, as 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, and dystonic tremor) (Guideline No. 113: Diagnosis and pharmacological management of Parkinson's disease, January 2010, SIGN). Definitive confirmation of the lesion can only be achieved by postmortem neuropathological analysis.

[0012] Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with Parkinson's disease (PD) usually appear normal. These techniques are nevertheless useful in ruling out other conditions that may contribute to parkinsonism, such as basal ganglia tumors, vascular lesions, and hydrocephalus. A specific technique of MRI, diffusion MRI, has been reported to be useful in distinguishing between typical and 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 include isoflurane ( 123I) (trade name DaTSCAN) and iometopan (Dopascan), or fluorodeoxyglucose ( 18 F)( 18 F-FDG) and dihydrotetrabenazine ( 11 C)( 11 The pattern of decreased dopaminergic activity in the basal ganglia can aid in the diagnosis of PD, especially during the symptomatic stage (Brooks, J. Nucl. Med., 2010, 51, 596-609; Redmond, Neuroscientist, 2002, 8, 457-88; Wood, Nat. Rev. Neurol., 2014, 10, 305).

[0013] 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, investigated in different body fluids (cerebrospinal fluid (CSF), plasma, saliva), include not only alpha-synuclein levels but also DJ-1, tau, and Abeta, as well as neurofilament proteins, interleukins, osteopontin, and hypocretin (Schapira Curr. Opin. Neurol. 2013;26(4):395-400). However, to date, none of these biomarkers, alone or in combination, can be used as definitive diagnostic tests. To the authors' knowledge, there are currently no approved alpha-synuclein diagnostics on the market, despite the critical need for Parkinson's disease research and drug development (Eberling et al., J Parkinsons Dis. 2013;3(4):565-7).

[0014] The ability to image alpha-synuclein deposits in the brain would be a major advancement for alpha-synucleopathies research, including Parkinson's disease (PD) and MSA research, diagnosis, and drug development. The accumulation of aggregated alpha-synuclein in the brain is considered a key pathological hallmark of PD and MSA and can begin years before the onset of symptoms. Therefore, alpha-synuclein is a priority target for drug development, not only because of its potential contribution to neurodegeneration but also because it offers the potential to treat disease that is still asymptomatic or presymptomatic. In vivo imaging of alpha-synuclein pathology could be useful as a biomarker (i) to potentially detect the presence of disease early, (ii) to assess disease progression, and (iii) as a pharmacodynamic tool for drug development. The development of alpha-synuclein PET imaging agents is now considered important for the accurate diagnosis of synucleinopathies and to support the clinical development of alpha-synuclein-targeting therapeutics, starting with the optimal selection of study populations (Eberling, Dave and Frasier, J. Parkinson's Disease, 3, 565-567 (2013)).

[0015] More recently, the first noninvasive imaging of pathological alpha-synuclein (a-syn) in the human brain has been reported, presenting positive clinical proof-of-concept data for an a-syn positron emission tomography (PET) tracer as an imaging agent to identify patients with MSA (Capotosti F.; Discovery of a novel and promising PET-tracer for alpha-synuclein; Oral presentation; ADPD 2022 International Conference; Barcelona, ​​Spain; March 18, 2022; Smith R.; Initial scans using a novel PET-tracer for alpha-synuclein; Oral presentation; ADPD 2022 International Conference; Barcelona, ​​Spain; March 18, 2022).

[0016] There is clearly a need to find molecular probes with high alpha-synuclein selectivity that recognize and bind to pathological alpha-synuclein. Alpha-synuclein imaging compounds should bind to their targets with high affinity and selectivity to minimize background signal interference due to nonspecific off-target binding and to reduce the required dosage.

[0017] To image alpha-synuclein aggregates associated with neurological diseases, such as Parkinson's disease or multiple system atrophy, imaging compounds must penetrate the blood-brain barrier and enter the relevant regions of the brain. To target intracellular amyloid-like inclusions, such as alpha-synuclein, cell permeability is an additional requirement for imaging compounds. A further prerequisite is rapid washout of the compound from the brain (or other target organs) to avoid unnecessary accumulation of the compound, which may increase the risk of undesired side effects.

[0018] WO2011 / 128455 refers to certain compounds suitable for treating disorders associated with amyloid or amyloid-like proteins. U.S. Patent Application Publication No. 2012 / 0302755 relates to certain imaging agents for detecting neurological dysfunction. Further compounds for diagnosing neurodegenerative disorders in the olfactory epithelium are discussed in WO2012 / 037928.

[0019] WO2010 / 063701 refers to an in vivo imaging agent for use in a method for determining the presence of or susceptibility to Parkinson's disease, the in vivo imaging agent comprising an alpha-synuclein binding agent labeled with an in vivo imaging moiety, the in vivo imaging agent binding to alpha-synuclein with binding affinity.

[0020] US2014 / 0142089 relates to a method for preventing or treating a degenerative brain disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a specific compound, its pharmaceutically acceptable salts, isomers, solvates, hydrates, and combinations thereof.

[0021] WO2009 / 155017 describes aryl or heteroaryl substituted azabenzoxazole derivatives, which are said to be useful as tracers in positron emission tomography (PET) imaging to study amyloid deposition in the brain in vivo and enable the diagnosis of Alzheimer's disease.

[0022] WO2016 / 033445 refers to certain compounds for imaging huntingtin protein.

[0023] WO2017 / 153601, WO2019 / 234243 and WO2021 / 224489 refer to bicyclic compounds for imaging alpha-synuclein aggregates. [Prior art documents] [Patent documents]

[0024] [Patent Document 1] WO2011 / 128455 [Patent Document 2] U.S. Patent Application Publication No. 2012 / 0302755 [Patent Document 3] WO2012 / 037928 [Patent Document 4] WO2010 / 063701 [Patent Document 5] U.S. Patent Application Publication No. 2014 / 0142089 [Patent Document 6] WO2009 / 155017 [Patent Document 7] WO2016 / 033445 [Patent Document 8] WO2017 / 153601 [Patent Document 9] WO2019 / 234243 [Patent Document 10] WO2021 / 224489 [Non-patent literature]

[0025] [Non-Patent Document 1] Jellinger, Mov. Disord. 2003, 18 Suppl. 6, S2~12 [Non-patent document 2] Galvin et al. JAMA Neurology 2001, 58 (2), pp. 186-190 [Non-patent document 3] Kovari et al., Acta Neuropathol. 2007, 114(3), pp. 295-8. [Non-patent document 4] Saito et al., J. Neuropathol. Exp. Neurol. 2004, 63(4), pp. 323-328 [Non-Patent Document 5] McKee et al., Brain, 2013, 136(Pt 1), pp. 43-64 [Non-licensed Document 6] Puschmann, Parkinsonism Relat. Disord. 2012, 18S1, S24~S27 [Non-licensed Document 7] Usenovic, J. Neurosci. 2012, 32(12), pp. 4240-4246 [Non-licensed Document 8] Winder-Rhodes, Mov. Disord. 2012, 27(2), pp. 312-315 [Non-licensed Document 9] Ferman, J. Int. Neuropsychol. Soc. 2002, 8(7), pp. 907-914 [Non-licensed Document 10] Smith, J. Pathol. 2014; 232: 509-521. [Non-licensed Document 11] Lippa, Ann Neurol. March 1999; 45(3): 353-7 pages [Non-licensed Document 12] Schmitz, Mol. Neurobiol. August 22, 2018 [Non-licensed Document 13] Charles, Neurosci. Lett. July 28, 2000; 289(1): 29-32 [Non-licensed Document 14] Wilhelmsen, Arch Neurol. March 2004; 61(3): 398-406 [Non-licensed Document 15] Yamaguchi, J. Neuropathol. Exp. Neurol. 2004, 80th Annual Meeting, Volume 63 [Non-licensed Document 16] Askanas, J. Neuropathol. Exp. Neurol. July 2000; 59(7): 592-8 pages [Non-licensed Document 17] Iwai, Biochemistry 1995, 34(32), pages 10139~10145 [Non-licensed Document 18] Fujiwara, Nat. Cell. Biol. 2002, 4(2); 160-164 [Non-licensed Document 19] Hasegawa, J. Biol. Chem. 2002, 277(50), pp. 49071-49076 [Non-licensed Document 20] Li, Proc. Natl. Acad. Sci. USA, 2005, 102(6), pp. 2162-2167 [Non-licensed Document 21] Oueslati, Prog. Brain Res. 2010, 183, pp. 115-145 [Non-licensed Document 22] Schmid, J. Biol. Chem. 2009, 284(19), pp. 13128-13142 [Non-licensed Document 23] Negro, FASEB J. 2002, 16(2), pages 210~212 [Non-licensed Document 24] Ellis, J. Biol. Chem. 2001, 276(6), pp. 3879-3884 [Non-licensed Document 25] Nakamura, Biochem. Biophys. Res. Commun. 2001, 280(4), pp. 1085-1092 [Non-licensed Document 26] Okochi, J. Biol. Chem. 2000, 275(1), pages 390~397 [Non-licensed Document 27] Pronin, J. Biol. Chem. 2000, 275(34), pp. 26515~26522 [Non-licensed Document 28] McLean, Neurosci. Lett. 2002, 323(3), pp. 219-223 [Non-licensed Document 29] Takahashi, Brain Res. 2002, 938(1-2), pages 73~80 [Non-licensed Document 30] Rochet, Biochemistry 2000, 39(35), pages 10619~10626 [Non-licensed Document 31] Crowther, FEBS Lett. 1998, 436(3), pages 309~312 [Non-licensed Document 32] Trojanowski, 1998, Cell Death Differ. 1998, 5(10), pp. 832-837. [Non-licensed Document 33] Koo, Proc. Natl. Acad. Sci. 1999, 96(18), pp. 9989~9990 [Non-licensed Document 34] Hu, Chin.Sci.Bull. 2001, 46, pp. 1-3 [Non-licensed Document 35] Woodら, J. Biol. Chem. 1999, 274(28), pages 19509~19512 [Non-licensed Document 36] Vollesら, Biochemistry 2002, 41(14), pages 4595~4602 [Non-licensed Document 37] Lesage, Hum. Mol. Genet., 2009, 18, R48~59 [Non-licensed Document 38] Lashuel, J. Mol. Biol., 2002, 322, pp. 1089-102. [Non-licensed Document 39] Cookson, Annu. Rev. Biochem., 2005, 74, pp. 29-52. [Non-licensed Document 40] Capouchら, Neurol. Ther. 2018, 7, pages 249~263 [Non-licensed Document 41] Outeiro, Mol. Neurodegener. 2019, pp. 14, 5 [Non-licensed Document 42] Fanciulli, N. Engl. J. Med. 2015; 372, 249-63. [Non-licensed Document 43] Galvin, Arch Neurol. 2001, 58, pp. 186-90. [Non-licensed Document 44] Stefanova, Neuropathol. Appl. Neurobiol. 2016, pp. 42, 20~32 [Non-licensed Document 45] Guideline No. 113: Diagnosis and pharmacological management of Parkinson's disease, January 2010. SIGN [Non-licensed Document 46] Brooks, J. Nucl. Med., 2010, 51, pp. 596-609 [Non-licensed Document 47] Redmond, Neuroscientist, 2002, 8, pp. 457-88 [Non-licensed Document 48] Wood, Nat. Rev. Neurol., 2014, 10, 305 pages [Non-licensed Document 49] Schapira Curr. Opin. Neurol. 2013;26(4):395-400 pages [Non-licensed Document 50] Eberlingら, J Parkinsons Dis. 2013;3(4):565~7 pages [Non-licensed Document 51] Capotosti F.; Discovery of a novel and promising PET-tracer for alpha-synuclein; Oral presentation; ADPD 2022 International Conference; Barcelona, ​​Spain; March 18, 2022 [Non-licensed Document 52] Smith R.;Initial scans using a novel PET-tracer for alpha-synuclein;Oral presentation;ADPD 2022 International Conference;Barcelona, ​​Spain;March 18, 2022 [Non-licensed Document 53] Synthesis (1982), pp. 85-125, Table 2, Carey and Sundberg [Non-licensed Document 54] Organische Synthese (1995), pp. 279-281, table 5.8 [Non-licensed Document 55] Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71~83 pages, スキーム1, 2, 10 and 15, etc. [Non-licensed Document 56] Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions (2006), Schubiger PA, Friebe M., Lehmann L. (eds.), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50, page 25 Skim 4, page 28 Skim 5, page 30 Table 4, page 33 Illustration 7 [Non-licensed Document 57] Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, 1990, 1445 pages [Non-licensed Document 58] Remington's Pharmaceutical Sciences, 15th edition, Mack Publishing Co., New Jersey (1975) [Non-licensed Document 59] Ying-hui Chou et al. JAMA Neurol. 2015 April 1;72(4):432-440 [Non-Patent Document 60] Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49 [Non-Patent Document 61] L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, pp. 2853-2873 [Non-Patent Document 62] J. Fluorine Chem., 27 (1985): pp. 177-191 [Non-Patent Document 63] TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons Summary of the Invention [Problem to be solved by the invention]

[0026] There remains a need for new classes of suitable imaging compounds that bind to alpha-synuclein with reasonably high affinity. [Means for solving the problem]

[0027] The present invention provides compounds that can be used for diagnosing diseases, disorders, or disorders associated with alpha-synuclein aggregates, such as Parkinson's disease or MSA, determining the prognosis of such diseases, disorders, or disorders, and monitoring the progression of such diseases, disorders, or disorders. In particular, the compounds should be suitable for determining a predisposition to such diseases, disorders, or disorders, monitoring the progression of such diseases, disorders, or disorders, or predicting the responsiveness of patients suffering from such diseases, disorders, or disorders to treatment with a certain pharmaceutical agent. Furthermore, the compounds should be suitable for positron emission tomography (PET) imaging of diseases, disorders, or disorders associated with alpha-synuclein aggregates and / or for detecting, and optionally quantifying, alpha-synuclein aggregates.

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

[0029] Within certain embodiments, the compound of formula (I)

[0030] [ka]

[0031] (In the formula,

[0032] [ka]

[0033] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, R 1is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0034] Within certain embodiments, the compound of formula (I)

[0035] [ka]

[0036] (In the formula,

[0037] [ka]

[0038] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0039] In another aspect, the present invention provides compounds of the following sub-formula (Ia):

[0040] [ka]

[0041] (In the formula, R 1 and R 2 is defined above, R 3 is halo or C1-C4 alkyl, and q is 0, 1, or 2), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[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) as defined herein, or a diagnostic composition, that may be used for imaging alpha-synuclein aggregates.

[0044] In another aspect, the compound of formula (I), or diagnostic composition, may be for use in positron emission tomography imaging of alpha-synuclein aggregates.

[0045] In another aspect, the compound of formula (I) or diagnostic composition as defined herein may be for use 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.

[0046] In yet another aspect, the compounds of formula (I) or diagnostic compositions defined herein may be for use in diagnostic methods.

[0047] In a further aspect, the present invention provides a method of diagnosing an alpha-synuclein aggregate-associated disease, disorder, or abnormality in a subject, comprising: (a) administering to a subject a compound of formula (I), or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; and (c) detecting a compound that binds to alpha-synuclein aggregates This refers to a method including:

[0048] In another aspect, the invention provides a method for positron emission tomography (PET) imaging of alpha-synuclein aggregates in tissue of a subject, the method comprising: (a) administering to a subject a compound of formula (I), or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; and (c) detecting compounds that bind to alpha-synuclein aggregates by collecting positron emission tomography (PET) images of the subject's tissue. This refers to a method including:

[0049] In a further aspect, the present invention provides a method for detecting, and optionally quantifying, alpha-synuclein aggregates in tissue of a subject, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally quantifying the amount of compound that binds to alpha-synuclein aggregates The present invention covers a method including:

[0050] The present invention provides a method for collecting data for diagnosing a disease, disorder, or abnormality associated with alpha-synuclein aggregates, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region. The present invention also covers methods including the following.

[0051] The present invention provides a method for collecting data for determining a predisposition to a disease, disorder, or condition associated with alpha-synuclein aggregates, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region. The present invention also relates to a method comprising:

[0052] In a further aspect, the present invention provides a method of collecting data for prognosing an alpha-synuclein aggregate-associated disease, disorder, or condition, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention also relates to a method comprising:

[0053] In another aspect, the invention provides a method of collecting data to monitor the progression of an alpha-synuclein aggregate-associated disease, disorder, or condition in a patient, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention covers a method including:

[0054] In a further aspect, the present invention provides a method for collecting data to predict responsiveness to a pharmaceutical agent in a patient suffering from a disease, disorder, or condition associated with alpha-synuclein aggregates, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound of formula (I) or a diagnostic composition comprising a compound of formula (I) as defined herein; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention relates to a method comprising:

[0055] In another aspect, the present invention provides a compound of formula (III-F)

[0056] [ka]

[0057] (In the formula,

[0058] [ka]

[0059] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F optionally, at least one C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1F is a 4- to 6-membered heterocyclyl, or R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is C1-C4 alkoxy or C1-C4 alkyl, or 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; LG is a leaving group, Further covered are compounds wherein n is at least 1 (e.g., 1 or 2 or 3), preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0060] In a preferred embodiment, the present invention provides a compound of formula (III-F)

[0061] [ka]

[0062] (In the formula,

[0063] [ka]

[0064] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F is a 4- to 6-membered heterocyclyl, or R 1F is C1-C4 alkoxy or C1-C4 alkyl, 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; LG is a leaving group, n is at least 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0065] In another preferred embodiment, the present invention provides a compound of formula (III-F')

[0066] [ka]

[0067] (In the formula,

[0068] [ka]

[0069] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; R 2F is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl; LG is a leaving group), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0070] A further aspect of the present invention is a compound of formula (IF)

[0071] [ka]

[0072] (In the formula,

[0073] [ka]

[0074] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F optionally, at least one C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1F is a 4- to 6-membered heterocyclyl, or R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is C1-C4 alkoxy or C1-C4 alkyl, or 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; n relates to a compound in which n is at least 1 (eg, 1, 2 or 3), preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0075] In a preferred embodiment, the present invention provides a compound of formula (IF)

[0076] [ka]

[0077] (In the formula,

[0078] [ka]

[0079] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F is a 4- to 6-membered heterocyclyl, or R 1F is C1-C4 alkoxy or C1-C4 alkyl, 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; n is at least 1, preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0080] In a further aspect, the present invention provides a compound of formula (I-F')

[0081] [ka]

[0082] (In the formula,

[0083] [ka]

[0084] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; R 2F is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl. or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0085] In another aspect, the present invention provides a compound of formula (III-H)

[0086] [ka]

[0087] (In the formula,

[0088] [ka]

[0089] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; X is bromo, chloro or iodo; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (III-H) contains at least one X), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0090] In a preferred embodiment, the compound of formula (III-H)

[0091] [ka]

[0092] (In the formula,

[0093] [ka]

[0094] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; X is bromo, chloro or iodo; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (III-H) contains at least one X), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0095] In another aspect, the present invention provides a compound of formula (IH)

[0096] [ka]

[0097] (In the formula,

[0098] [ka]

[0099] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4R 5 or C1-C4 alkyl, preferably halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; Y is D, CD3, T, or CT3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (IH) contains at least one D, CD3, T or CT3, and D is 2 H (deuterium) and T is 3 H (tritium)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the compound of formula (IH) comprises at least one T or CT3. In one embodiment, the compound of formula (IH) comprises at least one D or CD3.

[0100] In a preferred embodiment, the present invention provides a compound of formula (IH)

[0101] [ka]

[0102] (In the formula,

[0103] [ka]

[0104] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; Y is D, CD3, T, or CT3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (IH) contains at least one D, CD3, T, or CT3, wherein D is deuterium and T is 3 H (tritium)) or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0105] In another aspect, the present invention provides a compound of formula (III-F) wherein the leaving group (LG) is 18 so that it can be replaced by F 18 F-fluorinating agents (e.g., K 18 F, Rb18 F, Cs 18 F, Na 18 F, 18 F Tetra (C 1~6 (Alkyl)ammonium salt, Kryptofix

[0222] 18 F, tetrabutylammonium [ 18

[0023] The present invention is further directed to a method of preparing a compound of formula (IF) by reacting a compound of formula (IF) with a fluoride (F) or any other suitable agent.

[0106] In another aspect, the present invention provides a compound of formula (III-H) wherein X is replaced by T or CT. 3 Further directed to methods of preparing compounds of formula (IH) by reacting with a 3 H radiolabeling agent (e.g., tritium gas or any other suitable agent).

[0107] In another aspect, the present invention provides a method for preparing a compound of formula (III-H) containing D such that X is replaced by D or CD (D is deuterium), preferably in the presence of a catalyst such as Pd / C. 2 Further directed to methods of preparing compounds of formula (IH) by reacting with a H radiolabeling agent (e.g., DO, D4-methanol, or any other suitable agent).

[0108] In another aspect, the present invention is further directed to the use of the compounds of formula (I) as in vitro analytical standards or in vitro screening tools.

[0109] In another aspect, the present invention is further directed to a test kit for detecting and / or diagnosing a disease, disorder or abnormality associated with alpha-synuclein aggregates, the test kit comprising at least one compound of formula (I), preferably at least one detectably labeled compound, more preferably at least one compound of formula (IF) or (IH), as defined herein.

[0110] The present invention is further directed to a kit for preparing a radiopharmaceutical preparation, the kit comprising a sealed vial containing at least one compound of formula (III-F) or (III-H).

[0111] definition For purposes of interpreting this specification, the following definitions will apply unless otherwise specified and where appropriate, and terms used in the singular will include the plural and vice versa. It should also be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a reference to one or more compounds, and so forth.

[0112] The term "C1-C4 alkyl" refers to a saturated straight or branched hydrocarbon chain containing no unsaturation, having from 1 to 4 carbon atoms, and consisting solely of carbon and hydrogen atoms, attached to the remainder of the molecule by a single bond. Examples of suitable alkyl groups having 1 to 4 carbon atoms include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-methylethyl, n-butyl, t-butyl, and isobutyl.

[0113] The term "C1-C4 alkoxy" refers to a radical of formula -ORa, where Ra is a C1-C4 alkyl radical as generally defined above. Examples of C1-C4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0114] The term "halogen C1-C4 alkyl" or "halo C1-C4 alkyl" refers to a C1-C4 alkyl group as defined above that is substituted with one or more (e.g., 1, 2 or 3, preferably 1 or 2, more preferably 1) halo groups as defined below. Examples of "halo C1-C4 alkyl" include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0115] The term "halogen C1-C4 alkoxy" refers to a C1-C4 alkoxy group as defined above that is substituted with one or more (e.g., 1, 2 or 3, preferably 1 or 2, more preferably 1) halo groups as defined below. Examples of "halo C1-C4 alkoxy" include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 2,2-difluorobutoxy, and 4-bromobutoxy.

[0116] The term "heterocyclyl" refers to a stable 4- to 6-membered non-aromatic monocyclic ring group containing one or two heteroatoms selected from, for example, N, O, or S. Heterocyclyl groups can be unsaturated or saturated. Heterocyclyl groups can be attached via a carbon atom or a heteroatom. Examples include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, or morpholinyl, preferably azetidinyl, pyrrolidinyl, or piperidinyl, more preferably pyrrolidinyl.

[0117] The term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heteroaryl group can be attached via a carbon atom or a heteroatom selected from N, O, and S. Examples of heteroaryl include, but are not limited to, thiopyranyl, dioxanyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, isothiazolyl, pyrazolyl, thiazolyl, or pyridyl, with pyridyl, isothiazolyl, pyrazolyl, and thiazolyl being preferred.

[0118] The term "Hal" or "halogen" or "halo" refers to F, Cl, Br and I. For diagnostic and pharmaceutical applications, F (e.g. 19 F and 18 F) is particularly preferred.

[0119] The term "leaving group" (LG) as used herein refers to any leaving group, an atom or group of atoms that can be replaced by another atom or group of atoms. Examples include, for example, Synthesis (1982), pp. 85-125, table 2; Carey and Sundberg, Organische Synthese (1995), pp. 279-281, table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, pp. 7, 71-83, Schemes 1, 2, 10, and 15). (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions (2006), Schubiger PA, Friebe M., Lehmann L. (eds.), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50, Scheme 4 on page 25, Scheme 5 on page 28, Table 4 on page 30, and Figure 7 on page 33.) Preferably, the "leaving group" (LG) is a halogen, C 1~ C4 alkyl sulfonate and C 6~ C 10aryl sulfonates, C 6~ C 10 The arylsulfonate may be optionally substituted with -CH3 or -NO2.

[0120] Unless otherwise specified, the term "compound of the invention" refers to a compound of formula (I) or a subformula thereof (e.g., (Ia), (IF), (IH*), (IH)), or a detectably labeled compound thereof, a stereoisomer (including diastereomeric mixtures and individual diastereoisomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), a racemic mixture, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. It is understood that each reference to a compound of formula (I) also covers its subformulas (e.g., (Ia), (IF), (IH*), (IH)). Compounds of formula (III-F) and (III-H) are referred to as precursors of the compounds of the invention.

[0121] The compounds of the present invention and their precursors having one or more optically active carbons can exist as racemates and racemic mixtures, stereoisomers (including diastereomeric mixtures and individual diastereoisomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers and rotamers. All isomeric forms are included in the present invention.

[0122] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds in which the unchanged form has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues, such as amines; alkali or organic salts of acidic residues, such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the unchanged form, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. Pharmaceutically acceptable salts of the compounds of the present invention and their precursors can be synthesized from the unchanged form containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, page 1445, the disclosure of which is hereby incorporated by reference.

[0123] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals within the bounds of good medical practice and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0124] "Solvates" may be formed from compounds of the invention and any suitable pharmaceutically acceptable solvent. Examples include C1-4 alcohols (e.g., methanol or ethanol).

[0125] The patient or subject in the present invention is typically an animal, particularly a mammal, and more particularly a human.

[0126] Alpha-synuclein aggregates are multimeric beta-sheet-rich aggregates of alpha-synuclein monomers that can form soluble oligomers or soluble / insoluble prefibrils or mature fibrils, associated with intracellular deposits detected as various Lewy pathologies in Parkinson's disease and other synucleinopathies. Alpha-synuclein aggregates constituting Lewy pathologies can be detected as having the following morphologies: Lewy bodies, Lewy neurites, immature Lewy bodies or pale bodies, and perikarya deposits with diffuse, granular, punctate, or polymorphic patterns. Furthermore, alpha-synuclein aggregates are the major component of intracellular fibrillar inclusions (also called glial cytoplasmic inclusions) detected in oligodendrocytes, as well as intracellular fibrillar inclusions (called neuronal cytoplasmic inclusions) in neuronal cell bodies, axons, and nuclei, which are histological hallmarks of multiple system atrophy. Alpha-synuclein aggregates in Lewy pathology often display a substantial increase in post-translational modifications, such as phosphorylation, ubiquitination, nitration and truncation.

[0127] Lewy bodies are abnormal aggregates of proteins that develop inside nerve cells in Parkinson's disease (PD), dementia with Lewy bodies, and other synucleinopathies. Lewy bodies appear as spherical masses that replace other cellular components. Morphologically, Lewy bodies can be classified as brainstem or cortical. Typical brainstem Lewy bodies are eosinophilic cytoplasmic inclusions consisting of a dense core surrounded by a halo of 5-10 nm-wide radial fibers, the main structural component of which is alpha-synuclein. Cortical Lewy bodies differ in the absence of the halo. The presence of Lewy bodies is a hallmark of Parkinson's disease.

[0128] Lewy neurites are abnormal neuronal processes in pathological neurons that contain granules, abnormal alpha-synuclein (a-syn) filaments similar to those found in Lewy bodies, punctate varicose structures, and axonal spheroids. Like Lewy bodies, Lewy neurites are characteristic of α-synucleinopathies, such as dementia with Lewy bodies and Parkinson's disease.

[0129] Neuroglial cytoplasmic inclusions (GCIs or Papp-Lantos bodies) are argyrophilic cytoplasmic aggregates in oligodendrocytes (oligodendrocytes) composed of filamentous alpha-synuclein. Morphologically, they appear triangular, semilunar, or sickle-shaped. In MSA, in addition to GCIs, inclusions composed of alpha-synuclein filaments are detected in neurons in the cytoplasm or beneath the nuclear membrane; these are called neuronal cytoplasmic inclusions and neuronal nuclear inclusions, respectively. GCIs are recognized as the defining morphological feature of MSA, and their widespread distribution constitutes the basis for a definitive postmortem neuropathological diagnosis of MSA.

[0130] The terms "disease," "disorder," or "condition" are used interchangeably herein.

[0131] Compounds of formula (I) can bind to alpha-synuclein aggregates. The type of binding with compounds of formula (I) is not elucidated, and any type of binding is covered by the present invention. Terms such as "compounds that bind to alpha-synuclein aggregates" are used interchangeably herein and are not intended to be limited to any particular type of binding.

[0132] The preferred definitions provided in the "Definitions" section apply to all of the embodiments described below unless otherwise specified. Various embodiments of the invention are described herein, and it is recognized that the features specified in each embodiment may be combined with other specified features to obtain further embodiments of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0133] Compounds of the Invention 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. All of the embodiments and preferred embodiments shown with respect to formula (I) are also applicable to formulas (Ia), (III-F), (IF), (III-H), (IH) and (IH). * ) and vice versa. It is also understood that preferred embodiments given with respect to formula (III-F) apply equally to formula (IF) and vice versa. Preferred embodiments given with respect to formula (III-H) apply equally to formula (IH) and (IH * ) respectively, and vice versa.

[0134] The present invention relates to a compound of formula (I)

[0135] [ka]

[0136] (In the formula,

[0137] [ka]

[0138] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl;

[0139] [ka]

[0140] If is replaced,

[0141] [ka]

[0142] is substituted with one, two or three, preferably one or two, more preferably one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo, or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl, or R 1is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0143] Throughout this application, R 4 and R 5 are independently selected from H, C1-C4 alkyl and haloC1-C4 alkyl, preferably R 4 and R 5 At least one of them is not H.

[0144] In one embodiment,

[0145] [ka]

[0146] teeth,

[0147] [ka]

[0148] is selected from the group consisting of which can be attached to the triazoloheterocycle at any available position; Also,

[0149] [ka]

[0150] may be optionally substituted by one or more substituents selected from halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl.

[0151] In a preferred embodiment,

[0152] [ka]

[0153] teeth,

[0154] [ka]

[0155] is selected from the group consisting of which can be attached to the triazoloheterocycle at any available position; Also,

[0156] [ka]

[0157] may be optionally substituted by one or more substituents selected from halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl.

[0158] [ka]

[0159] The optional substituents are preferably halo or C1-C4 alkyl.

[0160] In a preferred embodiment,

[0161] [ka]

[0162] is a 6-membered heteroaryl containing at least one N, preferably

[0163] [ka]

[0164] is R at any available position. 1 and more preferably pyridyl, which may be substituted by

[0165] [ka]

[0166] teeth,

[0167] [ka]

[0168] and R 1 is as defined above.

[0169] In one embodiment, R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl (e.g., 1 to 3, preferably 1 or 2, more preferably 1). In a preferred embodiment, R 1 is a 4- to 6-membered heterocyclyl optionally substituted with at least one halo (e.g., 1 to 3, preferably 1 or 2, more preferably 1). In a preferred embodiment, R 1is a 4- to 6-membered heterocyclyl substituted with at least one halo. Preferably, the heterocyclyl is substituted with at least one halo, more preferably with one or two halo, and even more preferably with one halo. In another preferred embodiment, R 1 is an unsubstituted 4- to 6-membered heterocyclyl.

[0170] In one embodiment, R 1 is as follows:

[0171] [ka]

[0172] (In the formula, R 1' is independently selected from halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl, where s=0, 1, 2 or 3).

[0173] In one embodiment, R 1 is as follows:

[0174] [ka]

[0175] (In the formula, R 1a is a 4- to 6-membered heterocyclyl selected from F or H, preferably F. In another preferred embodiment, R 1a is H.

[0176] Preferably, R 1 is as follows:

[0177] [ka]

[0178] (In the formula, R 1ais a 4- or 5-membered heterocyclyl selected from F or H, preferably F. In another preferred embodiment, R 1a is H.

[0179] In yet another embodiment, R 1 teeth,

[0180] [ka]

[0181] is a 5-membered heterocyclyl. In yet another embodiment, R 1 teeth,

[0182] [ka]

[0183] is a 5-membered heterocyclyl.

[0184] In another embodiment, R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl. In some embodiments, R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl. Preferably, R 1 is haloC1-C4 alkyl or halo, more preferably R 1 is -O-(CH2) x -Hal (x=1 to 4, preferably 1 to 3, more preferably 1 or 2, even more preferably 2), and even more preferably -O-CH-CH-F. In another preferred embodiment, R 1 is NR 4 R 5 and preferably R 4 and R 5 are independently selected from H, C1-C4 alkyl and haloC1-C4 alkyl.

[0185] In still further embodiments, R 1 is —NH—C3-C6 cycloalkyl or —C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or —C3-C6 cycloalkyl of —NH—C3-C6 cycloalkyl is optionally substituted with at least one halo.

[0186] In each of the embodiments, F is preferably 19 F or 18 It's F.

[0187] R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl, preferably haloC1-C4 alkyl or C1-C4 alkyl.

[0188] In a preferred embodiment, R 2 is as follows:

[0189] [ka]

[0190] , preferably

[0191] [ka]

[0192] (In the formula, R 2a is independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 2b is selected from H, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl; s is a 5- or 6-membered heteroaryl selected from 0, 1, or 2 (preferably 0 or 1, more preferably 0). In another preferred embodiment, s is 1.

[0193] More preferably, R 2 is as follows:

[0194] [ka]

[0195] , preferably

[0196] [ka]

[0197] (In the formula, R 2b is a 5- or 6-membered heteroaryl selected from halo C1-C4 alkyl, halo C1-C4 alkoxy, alkoxy, H or C1-C4 alkyl, preferably H, halo C1-C4 alkyl (preferably halo is F) or C1-C4 alkyl, preferably selected from H or C1-C4 alkyl.

[0198] In another preferred embodiment, the present invention provides a compound of formula (Ia)

[0199] [ka]

[0200] (In the formula, R 1 and R 2 is as defined above, and R 3 is halo or C1-C4 alkyl, and q is 0, 1, or 2), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0201] In one embodiment, the present invention provides a compound of formula (I), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is

[0202] [ka] [ka] [ka] [ka]

[0203] is selected from.

[0204] In one embodiment, the present invention provides a compound of formula (I), wherein the compound is

[0205] [ka] [ka] [ka] [ka]

[0206] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0207] 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 18 F, 2H and 3 H. Most preferably, the radioisotope is selected from: 18 F and 3 H.

[0208] In one embodiment, the present invention provides a compound comprising R 1 but,

[0209] [ka]

[0210] The present invention provides a compound of formula (I) wherein

[0211] In another embodiment, the present invention provides a compound comprising R 1 but, -O-CH2-CH2- 18 F The present invention provides a compound of formula (I) wherein

[0212] In another embodiment, the present invention provides a compound comprising R 2 but,

[0213] [ka]

[0214] and R 2b But -CH2-CH2- 18 F or -CH2-CH2-CH2- 18 F The present invention provides a compound of formula (I) wherein

[0215] In another embodiment, the present invention provides a compound comprising R 2 but,

[0216] [ka]

[0217] The present invention provides a compound of formula (I) wherein

[0218] In one embodiment, the present invention provides a compound comprising a compound of formula (IF)

[0219] [ka]

[0220] (In the formula,

[0221] [ka]

[0222] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F optionally, at least one C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl, preferably a 4- to 6-membered heterocyclyl, substituted with C1-C4 alkyl; or R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably C1-C4 alkoxy or C1-C4 alkyl, 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; wherein n is at least 1 (e.g., 1, 2, or 3), preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0223] In one embodiment, R 1F is -NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy or C1-C4 alkyl or heterocyclyl. 1F -( 18 F) n is as follows:

[0224] [ka]

[0225] (In the formula, R 1' teeth, 18 F, where s=1, 2 or 3, preferably s=1).

[0226] In a preferred embodiment, -R 1F -( 18 F) n is as follows:

[0227] [ka]

[0228] is selected from.

[0229] More preferably, -R 1F -( 18 F) n is as follows:

[0230] [ka]

[0231] is selected from.

[0232] Even more preferably, -R1F -( 18 F) n teeth

[0233] [ka]

[0234] is.

[0235] In another embodiment, -R 1F -( 18 F) n is -O-(CH2) x - 18 F (x=1 to 4, preferably 1 to 3, more preferably 1 or 2, even more preferably 2), even more preferably —O—CH—CH— 18 It's F.

[0236] In another embodiment, the present invention provides The compound has a detectably labeled formula (I-F')

[0237] [ka]

[0238] (In the formula,

[0239] [ka]

[0240] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, R1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; R 2F is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0241] In a preferred embodiment, -R 2F -( 18 F) n is as follows:

[0242] [ka]

[0243] (In the formula, R 2b is -CH2-CH2- 18 F or -CH2-CH2-CH2- 18 F, or

[0244] [ka]

[0245] is selected from

[0246] The detectably labeled compound of formula (IF) or (IF') comprises at least one 18 Preferably, the detectably labeled compound of formula (IF) or (IF') comprises one 18 Contains F.

[0247] In one embodiment, the present invention provides a compound having the formula (IH * )

[0248] [ka]

[0249] (In the formula,

[0250] [ka]

[0251] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably a 4- to 6-membered heterocyclyl optionally substituted with at least one halo; or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy or C1-C4 alkyl, or R 1is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl and haloC1-C4 alkyl; However, the formula (IH * ) compound is at least one 2 H (deuterium "D") or 3 The present invention provides a detectably labeled compound of formula (I), which is a compound of formula (IH), preferably containing one, two or three Ds or Ts, even more preferably two or three Ds or Ts, or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof. Preferably, the compound of formula (IH * ) compounds containing at least one 3 H (tritium "T"), preferably one, two or three Ts, even more preferably two or three Ts. 3 H can be present as T or as -CT3. 2 H can be present as D or as -CD3.

[0252] In a preferred embodiment, the compound is a detectably labeled compound of formula (IH)

[0253] [ka]

[0254] (In the formula,

[0255] [ka]

[0256] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably a 4- to 6-membered heterocyclyl optionally substituted with at least one halo; or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; Y is D, CD3, T, or CT3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (IH) contains at least one D, CD3, T or CT3, and D is 2 H (deuterium) and T is 3 H (tritium)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof. In one embodiment, the compound of formula (IH) comprises at least one D or CD3. In another embodiment, the compound of formula (IH) comprises at least one T or CT3.

[0257] It is understood that deuterium or tritium can be present in any available position where hydrogen is present. For example, R 2 In the R group, there can be deuterium or tritium directly attached to the 5- or 6-membered heteroaryl (e.g., in the form of D or T), or deuterium or tritium can be present in haloC1-C4 alkyl, haloC1-C4 alkoxy, -C1-C4 alkoxy, and -C1-C4 alkyl (e.g., in the form of CD3 or CT3). 1 In the case of a 4- to 6-membered heterocyclyl of the formula: deuterium or tritium may, for example, be directly attached to the 4- to 6-membered heterocyclyl.

[0258] In one preferred embodiment,

[0259] [ka]

[0260] is a 6-membered heteroaryl optionally substituted with one halo or C1-C4 alkyl, and m is 1, 2 or 3, preferably 1.

[0261] In one embodiment, R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, -C1-C4 alkoxy, and -C1-C4 alkyl, and p is 1, 2, or 3, preferably 1.

[0262] Preferably, R 2 is as follows:

[0263] [ka]

[0264] , preferably

[0265] [ka]

[0266] (In the formula, R 2a is independently selected from T, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 2b is selected from H, T, haloC1-C4 alkyl and C1-C4 alkyl, where haloC1-C4 alkyl and C1-C4 alkyl optionally contain one or more T (preferably R 2b is selected from T or CT3), s is a 5- or 6-membered heteroaryl selected from 0, 1, or 2 (preferably 0 or 1, more preferably 0).

[0267] Preferably, R 2a is -T, -OCH3, -CH3 or -H, and R 2b is selected from -H, -T, or -CT3.

[0268] Preferably, R 2 is as follows:

[0269] [ka]

[0270] , preferably

[0271] [ka]

[0272] (In the formula, R 2b is a 5- or 6-membered heteroaryl selected from T, H, or C1-C4 alkyl (eg, CT3), preferably selected from T, H, or C1-C4 alkyl (eg, CT3).

[0273] In a preferred embodiment, the compound of formula (IH * Detectably labeled compounds of formula (IH) or (IH) contain one, two or three T's. Preferably, the detectably labeled compounds of formula (IH) * ) or (IH) comprises one T. In another embodiment, the detectably labeled compound of formula (IH * ) or (IH) comprises two T's. In another embodiment, the detectably labeled compound of formula (IH * The detectably labeled compound of (IH) or (IH) contains three Ts, for example, -CT3.

[0274] In another embodiment, R 2 is as follows:

[0275] [ka]

[0276] , preferably

[0277] [ka]

[0278] (In the formula, R 2a is independently selected from D, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 2bis selected from H, D, haloC1-C4 alkyl and C1-C4 alkyl, where haloC1-C4 alkyl and C1-C4 alkyl optionally contain one or more D (preferably R 2b is selected from D or CD3), s is a 5- or 6-membered heteroaryl selected from 0, 1, or 2 (preferably 0).

[0279] Preferably, R 2a is -D, -OCH3, -CH3 or -H, and R 2b is selected from -H, -D or -CD3. Preferably, R 2 is as follows:

[0280] [ka]

[0281] (In the formula, R 2b is a 5- or 6-membered heteroaryl selected from D, H, or C1-C4 alkyl (eg, CD3).

[0282] In one embodiment, a compound of formula (IH * Detectably labeled compounds of formula (IH) or (IH) contain one, two or three D. Preferably, the compounds of formula (IH) * ) or (IH) comprises one D. In another embodiment, the detectably labeled compound of formula (IH * ) or (IH) comprises two D. In another embodiment, the detectably labeled compound of formula (IH * The detectably labeled compound of (IH) or (IH) contains three Ds, for example -CD3.

[0283] In another embodiment, the present invention provides a compound of formula (IH * a detectably labeled compound of formula (IH) or (IH), 3 H Tritium ("T") 2H may be replaced by deuterium ("D"). A deuterated compound is a compound of formula (III-H) prepared by: 2 It can be prepared by reacting with a 3 H radiolabeled agent.

[0284] The compounds of the present invention and their precursors can be detectably labeled. The type of label is not particularly limited and depends on the detection method selected. Examples of possible labels include isotopes, such as radionuclides, positron emitters and gamma emitters, and preferably, the detectable label is a radioisotope. For the detectably labeled compounds of the present invention and their precursors that contain a radioisotope, positron emitter or gamma emitter, it should be understood that the radioisotope, positron emitter or gamma emitter must be present in an amount that is not the same as the natural amount of the radioisotope, positron emitter or gamma emitter, respectively. Furthermore, the amount used should allow their detection by the detection method selected. Examples of suitable isotopes, such as radionuclides, positron emitters and gamma emitters, are: 2 H, 3 H, 11 C. 13 N, 15 O and 18 F, preferably 2 H, 3 H and 18 Contains F.

[0285] 18 F-labeled compounds are particularly suitable for imaging applications, such as PET. 19 The corresponding fluorine-containing compounds have the F isotope, 18 It is of particular interest because it can be used as an analytical standard and reference during the manufacture, quality control, release, and clinical use of the F-analogues.

[0286] Additionally, isotopes such as deuterium, i.e. 2 Substitution with H or D offers certain diagnostic and therapeutic advantages due to increased metabolic stability, for example, due to reduced defluorination, increased in vivo half-life, or reduced dosing requirements, while maintaining or improving the efficacy of the original compound.

[0287] Isotopic variations of the compounds of the present invention and precursors thereof can generally be prepared by conventional procedures, e.g., using appropriate isotopic variations of suitable reagents that are commercially available or prepared by known synthetic techniques, by the illustrative methods or preparations described in the Examples and Preparations.

[0288] Radionuclides, positron emitters, and gamma emitters can be incorporated into the compounds of the present invention and their precursors by methods conventional in the field of organic synthesis.Typically, they are introduced by using correspondingly labeled starting materials when preparing the desired compounds of the present invention and their precursors.Exemplary methods for introducing detectable labels are described, for example, in US2012 / 0302755.

[0289] The position at which the detectable label should be attached to the compounds of the present invention and their precursors is not particularly limited. Radionuclides, positron emitters, and gamma emitters can be attached, for example, at any position at which the corresponding non-emitting atom can also be attached. For example, 18 F may be attached at any position suitable for attaching F. The same applies to other radionuclides, positron emitters and gamma emitters. For ease of synthesis, R 1 teeth 18 It is replaced by F. 3 The H can be attached at any available position where an H occurs. 2 When H is used as the detectable label, it can be attached at any available position where H occurs.

[0290] In another embodiment, the present invention provides a compound of formula (III-F) which is a precursor of the compound of formula (IF)

[0291] [ka]

[0292] (In the formula,

[0293] [ka]

[0294] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1F optionally, at least one C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably R 1F is a 4- to 6-membered heterocyclyl, or R 1F is C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably R 1F is C1-C4 alkoxy or C1-C4 alkyl, or 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 haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H and C1-C4 alkyl; LG is a leaving group, It further relates to compounds wherein n is at least 1 (eg, 1, 2 or 3, preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0295] In another preferred embodiment, (LG) n -R 1F is as follows:

[0296] [ka]

[0297] wherein x is at least 1 (eg, 1 to 3), preferably 1 or 2, and even more preferably 2.

[0298] More preferably, (LG) n -R 1F is as follows:

[0299] [ka]

[0300] wherein x is 1 or 2, more preferably 2.

[0301] Even more preferably, (LG) n -R 1F teeth,

[0302] [ka]

[0303] is.

[0304] In another embodiment, the present invention provides a compound of formula (III-F') which is a precursor of the compound of formula (IF')

[0305] [ka]

[0306] (In the formula,

[0307] [ka]

[0308] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, or R 1 is -NH-C3-C6 cycloalkyl or -C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; R 2F is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkoxy and C1-C4 alkyl; LG is a leaving group), or a stereoisomer, a racemic mixture, a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0309] In a preferred embodiment, -R 2F -( LG ) is as follows

[0310] [ka]

[0311] (In the formula, R 2bis -CH2-CH2-LG or -CH2-CH2-CH2-LG, or

[0312] [ka]

[0313] is selected from

[0314] Preferably, the leaving group (LG) of (III-F) or (III-F') is a halogen, a C1-C4 alkylsulfonate, a C1-C4 alkylammonium or a C6-C 10 Aryl sulfonate, C6-C 10 The arylsulfonate may be optionally substituted with -CH3 or -NO2. More preferably, the leaving group (LG) is bromo, chloro, iodo, C6-C4 alkylsulfonate or C6-C 10 Aryl sulfonate, C6-C 10 The arylsulfonate may optionally be substituted with -CH3 or -NO2. Even more preferably, the leaving group (LG) is mesylate, tosylate, or nosylate. Even more preferably, the leaving group (LG) is mesylate or nosylate. More preferably, the leaving group (LG) is mesylate.

[0315] In another embodiment, the present invention provides a compound of formula (III-H) which is a precursor of the compound of formula (IH):

[0316] [ka]

[0317] (In the formula,

[0318] [ka]

[0319] is a 6-membered heteroaryl optionally substituted with at least one halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, or C1-C4 alkyl; R 1 optionally, at least one of halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or a 4- to 6-membered heterocyclyl substituted with C1-C4 alkyl, preferably optionally substituted with at least one halo; or R 1 is halo, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, NR 4 R 5 or C1-C4 alkyl, preferably halo, haloC1-C4 alkyl, haloC1-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 or -C3-C6 cycloalkyl of -NH-C3-C6 cycloalkyl is optionally substituted with at least one halo; R 2 is a 5- or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl; R 4 and R 5 are independently selected from H, C1-C4 alkyl, and haloC1-C4 alkyl; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; X is bromo, chloro or iodo; provided that the compound of formula (III-H) contains at least one X (e.g., one, two, or three Xs, preferably one or two Xs), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0320] In formula (III-H), halo is preferably F, 18 F or 19 It's F.

[0321] X is

[0322] [ka]

[0323] and / or R 2 The halo is attached to a 5- or 6-membered heteroaryl of

[0324] [ka]

[0325] and when X is present, it may be present in addition to halo.

[0326] In a preferred embodiment, R 2 is as follows:

[0327] [ka]

[0328] , preferably

[0329] [ka]

[0330] (In the formula, R 2ais independently selected from X, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy, and C1-C4 alkyl, wherein haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkyl, or C1-C4 alkoxy is optionally substituted with one or more X; s is 0, 1 or 2 (preferably 0 or 1); R 2b is selected from H, X, haloC1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl).

[0331] Preferably, R 2 is as follows:

[0332] [ka]

[0333] , preferably

[0334] [ka]

[0335] (In the formula, R 2a is X, R 2b is selected from H, X, haloC1-C4 alkyl, haloC1-C4 alkoxy, C1-C4 alkoxy and C1-C4 alkyl, preferably selected from H, X, haloC1-C4 alkyl and C1-C4 alkyl, more preferably X. In a further preferred embodiment, R 2b is selected from haloC1-C4 alkyl and haloC1-C4 alkoxy; s is 0, 1 or 2 (preferably 0); The C1-C4 alkyl is optionally substituted with one or more X.

[0336] In a preferred embodiment, the detectably labeled compound of formula (III-H) comprises one, two, or three X. In a preferred embodiment, the detectably labeled compound of formula (III-H) comprises one or two X. In a more preferred embodiment, the detectably labeled compound of formula (III-H) comprises two X. X is selected from bromo, chloro, and iodo. In a preferred embodiment, X is bromine.

[0337] Methods for synthesizing detectably labeled compounds The present invention relates to compounds of formula (I) or subformulas thereof (e.g., (IF), (IF'), (IH * The present invention further relates to a method for preparing compounds of formula (III-F), (III-F') or (III-H), and in particular compounds of formula (III-F), (III-F') or (III-H).

[0338] In one embodiment, the present invention provides a compound of formula (III-F) wherein LG is 18 so that it can be replaced by F 18 Process for preparing compounds of formula (IF) by reacting with an F-fluorinating agent

[0339] [ka]

[0340] (In the formula,

[0341] [ka]

[0342] , R 1F , R 2 , n and LG are as defined herein above).

[0343] In another embodiment, the present invention provides a compound of formula (III-F'), wherein LG is 18 so that it can be replaced by F 18Process for preparing compounds of formula (I-F') by reacting with an F-fluorinating agent

[0344] [ka]

[0345] (In the formula,

[0346] [ka]

[0347] , R 1 , R 2F and LG are as defined herein above).

[0348] 18 Suitable solvents for F-fluorination include DMF, DMSO, acetonitrile, DMA, or mixtures thereof, preferably acetonitrile or DMSO. 18 Suitable agents for F-fluorination are K 18 F, Rb 18 F, Cs 18 F, Na 18 F, 18 F Tetra (C 1~6 (Alkyl)ammonium salt, Kryptofix

[0222] 18 F and tetrabutylammonium [ 18 F] fluoride.

[0349] In one embodiment, the present invention provides a compound of formula (III-H) comprising: 3 Method for preparing a compound of formula (IH) by reacting with a H radiolabeling agent

[0350] [ka]

[0351] (In the formula,

[0352] [ka]

[0353] , R 1 , R 2 , X, Y, m and p are as defined herein above).

[0354] In one embodiment, the present invention provides a compound of formula (III-H * ) compound, 3 H or D radiolabeling agent to form a compound of formula (IH * Method for preparing the compound of

[0355] [ka]

[0356] (In the formula,

[0357] [ka]

[0358] , R 1 , R 2 , X, m and p are as defined herein above, and Y is D, CD3, T or CT3).

[0359] 3 The H radiolabeling agent can be tritium gas. The method can be carried out in the presence of a catalyst such as palladium on carbon (Pd / C), a solvent such as dimethylformamide (DMF), and a base such as N,N-diisopropylethylamine (DIEA).

[0360] In a further embodiment, the compound of formula (III-H * ) is prepared by replacing X with D (D is deuterium, 2 contains D so that H 23 H radiolabeling agent (e.g., D2O, D4-methanol, or any other suitable agent).

[0361] Alternatively, in another embodiment, the present invention provides a compound of formula (III-H * ) compound of formula CT3 (wherein T is 3 H) radiolabeled agents such as 3 H radiolabeling agent so that X is replaced by CT (formula (III-H * ) by reacting a compound of formula (IH * The CT3 radiolabeled agent is ICT3 ( 3 The method may be carried out in the presence of a solvent such as dimethylformamide (DMF) and a base such as cesium carbonate or sodium hydride.

[0362] kit The precursor compounds of the present invention can also be used in kits for preparing radiopharmaceutical preparations. Due to radioactive decay, radiopharmaceuticals are usually prepared immediately before use. The kit typically includes a precursor of the compound of the present invention and an agent that reacts with the precursor to introduce a radiolabel 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 agent can be a radiolabel, e.g. 18 F, 3 It can be an agent that introduces H or D.

[0363] In one embodiment, part of the kit is a test kit for detecting and / or diagnosing a disease, disorder, or abnormality associated with alpha-synuclein aggregates, wherein the test kit comprises at least one precursor of a compound of the invention (e.g., a compound having formula (III-F), (III-H*), or (III-H)).

[0364] In another embodiment, part of the kit is a kit for preparing a radiopharmaceutical preparation, the kit comprising a sealed vial containing at least one precursor of a compound of the invention (e.g., a compound having formula (III-F), (III-H*) or (III-H)).

[0365] In a preferred embodiment, the kit is for use in imaging alpha-synuclein aggregates, preferably by positron emission tomography, or for use for in vitro, ex vivo or in vivo imaging, preferably for use for in vivo imaging, more preferably for use for brain imaging.

[0366] Diagnostic Compositions The compounds of the present invention are particularly suitable for imaging alpha-synuclein aggregates. With respect to alpha-synuclein protein, the compounds are particularly suitable for binding to alpha-synuclein aggregates, including, but not limited to, various types of Lewy bodies and / or Lewy neurites. The imaging can be performed in a mammal, preferably a human. The imaging is preferably in vitro imaging, ex vivo imaging, or in vivo imaging. More preferably, the imaging is in vivo imaging; even more preferably, the imaging is preferably brain imaging. The imaging can also be ocular / retinal imaging. The compounds of the present invention are particularly suitable for use in diagnostic methods.

[0367] The diagnostic method can be performed on mammals, preferably humans. The tissue of interest on which the diagnostic method is performed can be the brain, tissue of the central nervous system, tissue of the eye (e.g., retinal tissue), peripheral organs such as intestinal tissue or other tissue, or body fluids such as cerebrospinal fluid (CSF) or blood. The tissue is preferably brain tissue.

[0368] 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.

[0369] Due to their design and binding properties, the compounds of the invention are suitable for use in the diagnosis of diseases, disorders and disorders associated with alpha-synuclein aggregates. In another embodiment, diagnostic compositions comprising the compounds of the invention are also suitable for use in the diagnosis of diseases, disorders and disorders associated with alpha-synuclein aggregates.

[0370] In yet another embodiment, the compounds of the invention or diagnostic compositions comprising the compounds of the invention are suitable for use in imaging, such as 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, particularly in humans.

[0371] In another embodiment, the compounds or diagnostic compositions of the present invention are particularly suitable for use in positron emission tomography imaging of alpha-synuclein aggregates.

[0372] Diseases associated with alpha-synuclein aggregates are generally classified as synucleinopathies (or α-synucleinopathy). The compounds of the present invention are suitable for use in diagnosing diseases, disorders, or abnormalities associated with, or predisposition to, alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, wherein the diseases, disorders, or abnormalities are selected from (including but not limited to) Parkinson's disease (sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure, and Lewy body dysphagia), SNCA duplication carriers, dementia with Lewy bodies ("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's syndrome. The compounds of the present invention are suitable for use in the diagnosis of diseases, disorders or conditions associated with alpha-synuclein aggregates, including but not limited to neuronal and glial aggregates of alpha-synuclein, including multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy).Other diseases that may have alpha-synuclein-immunoreactive lesions include traumatic brain injury, chronic traumatic encephalopathy, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Niemann-Pick disease type C1), motor neuron diseases, amyotrophic lateral sclerosis (sporadic, familial, and Guam ALS-dementia complex), neuroaxonal dystrophies, neurodegeneration type 1 with cerebral iron accumulation (Hallervorden-Spatz syndrome), prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gaucher disease, and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome), and rapid eye movement (REM) sleep behavior disorder (Jellinger, Mov Disord 2003, 18 Suppl. 6, S2-12; Galvin et al., JAMA Neurology 2001, 58(2), pp. 186-190; Kovari et al., Acta Neuropathol. 2007, 114(3), pp. 295-298; Saito et al., J Neuropathol Exp Neurol. 2004, 63(4), pp. 323-328; McKee et al., Brain, 2013, 136(Pt1), pp. 43-64; Puschmann et al., Parkinsonism Relat Disord 2012, 18S1, S24-S27; Usenovic et al., J Neurosci. 2012, 32(12), pp. 4240-4246; Winder-Rhodes et al., Mov Disord. 2012, 27(2), pp. 312-315; Ferman et al., J Int Neuropsychol Soc. 2002, 8(7), pp. 907-914). Preferably, the compounds of the present invention are suitable for use in diagnosing Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Parkinson's disease dementia, SNCA duplication carriers or Alzheimer's disease, more preferably Parkinson's disease (PD) or multiple system atrophy (MSA).

[0373] In a method for diagnosing a disease, disorder, or condition associated with alpha-synuclein aggregates, e.g., Parkinson's disease, or MSA, or a predisposition thereto, in a subject, the method comprises: (a) administering to a subject a diagnostically effective amount of a compound of the invention, or a diagnostic composition comprising a compound of the invention; (b) distributing the compound of the invention into a target tissue (e.g., brain tissue, tissue of the central nervous system (CNS), tissue of the eye, tissue of a peripheral organ, or other tissue) or body fluid (e.g., cerebrospinal fluid (CSF) or blood); and (c) imaging the tissue or fluid of interest. Includes.

[0374] If the amount of compound that binds to alpha-synuclein aggregates is increased compared to normal control levels, the subject is suffering from or at risk of developing a disease, disorder or condition associated with alpha-synuclein aggregates.

[0375] The compounds of the present invention can be used to image alpha-synuclein aggregates in any patient sample or specific body parts or regions suspected of containing alpha-synuclein aggregates. The compounds can cross the blood-brain barrier. As a result, they are particularly suitable for imaging alpha-synuclein aggregates in the brain, tissues of the central nervous system (CNS), tissues of the eye (e.g., retinal tissue), peripheral organs such as intestinal tissue or other tissues, or body fluids such as cerebrospinal fluid (CSF) or blood.

[0376] For diagnostic applications, the compounds of the present invention are preferably administered in the form of a diagnostic composition containing a compound of the present invention. A "diagnostic composition" is defined herein as a composition containing one or more compounds of the present invention in a form suitable for administration to a patient, e.g., a mammal, e.g., a human, and suitable for use in diagnosing a specific disease, disorder, or abnormality in a tissue. Preferably, the diagnostic composition further comprises a pharmaceutically acceptable excipient, carrier, diluent, or adjuvant. Administration is preferably carried out by injecting the composition as defined below, more preferably as an aqueous solution. Such compositions may optionally contain additional ingredients, such as a buffer; a pharmaceutically acceptable solubilizer (e.g., cyclodextrin or a surfactant, e.g., Pluronic, Tween, or phospholipid); and a pharmaceutically acceptable stabilizer or antioxidant (e.g., ascorbic acid, gentisic acid, or para-aminobenzoic acid). Doses of the compounds of the present invention will vary depending on the exact compound administered, the patient's mass, and other variables apparent to a practitioner skilled in the art.

[0377] While it is possible for the compounds of the invention to be administered alone, it is preferable to formulate them into diagnostic compositions in accordance with standard pharmaceutical practice. Accordingly, the invention also provides diagnostic compositions comprising a diagnostically effective amount of a compound of the invention, optionally in admixture with at least one pharmaceutically acceptable excipient, carrier, diluent, or adjuvant.

[0378] Pharmaceutically acceptable excipients are well known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, 15th ed., Mack Publishing Co., New Jersey (1975). Pharmaceutical excipients can be selected with reference to the intended route of administration and standard pharmaceutical practice. An excipient must be acceptable in the sense of not being harmful to the recipient thereof.

[0379] Pharmaceutically useful excipients, carriers, adjuvants, and diluents that can be used to formulate the diagnostic compositions of the present invention may include, for example, solvents, such as monohydric alcohols, e.g., ethanol, isopropanol, and polyhydric alcohols, e.g., glycols, 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, flavorings, coating agents, preservatives, antioxidants, processing agents, 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.

[0380] The route for administering (delivering) the compound of the present invention includes, but is not limited to, one or more of intravenous, gastrointestinal, intrathecal, intraperitoneal, intramuscular, oral (e.g., as a tablet, capsule, or ingestible liquid), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by an injectable form), intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual.Preferably, the route for administering (delivering) the compound of the present invention is intravenous.

[0381] For example, the compounds may be administered orally in the form of tablets, capsules, ovoids, elixirs, solutions or suspensions, which may contain flavorings or colorants for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0382] 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 acacia. Additionally, lubricants may be included, such as magnesium stearate, stearic acid, glyceryl behenate, and talc. Solid compositions of a similar type may also be used as fillers in gelatin capsules. Preferred excipients in this regard include starch, cellulose, milk sugar (lactose), or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the drugs may be combined with various sweetening or flavoring agents, coloring agents or pigments, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0383] Preferably, for diagnostic applications, the compounds of the present invention are administered parenterally. When the compounds of the present invention are administered parenterally, examples of such administration include one or more of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, or subcutaneous administration of the compound, and / or administration by using injection techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0384] As indicated, the compounds of the present invention can be administered intranasally or by inhalation, conveniently in the form of a dry powder inhaler or aerosol spray from a pressurized container, pump, spray, or nebulizer with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane, e.g., 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA), carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. The pressurized container, pump, spray, or nebulizer can contain a solution or suspension of the active compound, for example, using a mixture of ethanol as a solvent and a propellant, which may further contain a lubricant, such as sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0385] Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, or it can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder.The compounds of the invention can also be administered dermally or transdermally, for example, by the use of a skin patch.

[0386] They can also be administered via pulmonary or rectal routes. They can also be administered via ocular routes. For ophthalmic use, the compounds can be formulated as micronized suspensions in pH-adjusted isotonic sterile saline, or preferably as solutions in pH-adjusted isotonic sterile saline, optionally in combination with preservatives such as benzalkonium chloride. Alternatively, they can be formulated into ointments such as petrolatum.

[0387] For topical application to the skin, the compounds of the invention can be formulated in a suitable 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 in a suitable lotion or cream containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0388] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dose level and frequency of administration for any particular individual may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the precise severity of the condition, and the individual diagnosis.

[0389] The diagnostic compositions of the present invention can be produced by means 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).

[0390] The compounds of the present invention are useful as in vitro analytical standards or in vitro screening tools. They are also useful in in vivo diagnostic methods.

[0391] The compound according to the present invention may also be provided in the form of a mixture, a pharmaceutical composition, or a combination comprising the compound according to the present invention and at least one compound selected from an imaging agent other than the compound according to the present invention, a pharmaceutically acceptable excipient, carrier, diluent, or adjuvant. The imaging agent other than the compound according to the present invention is preferably present in a diagnostically effective amount. More preferably, the imaging agent other than the compound according to the present invention is an Abeta or tau imaging agent.

[0392] Methods of using the present invention In one embodiment, the present invention provides a method for diagnosing an alpha-synuclein aggregate-associated disease, disorder, or abnormality in a subject, comprising: (a) administering to a subject a compound of the present invention or a diagnostic composition comprising a compound of the present invention; (b) binding the compound to alpha-synuclein aggregates; and (c) detecting a compound that binds to alpha-synuclein aggregates The present invention provides a method comprising:

[0393] Optionally, the method further comprises: (d) generating an image representing the location and / or amount of compound bound to the alpha-synuclein aggregates. It may further include:

[0394] In another embodiment, the present invention provides a method for positron emission tomography (PET) imaging of alpha-synuclein aggregates in tissue of a subject, comprising: (a) administering to a subject a compound of the present invention or a diagnostic composition comprising a compound of the present invention; (b) binding the compound to alpha-synuclein aggregates; and (c) detecting compounds that bind to alpha-synuclein aggregates by collecting positron emission tomography (PET) images of the subject's tissue. The present invention provides a method comprising:

[0395] In another embodiment, the present invention provides a method (e.g., an in vivo or in vitro method) for detecting and optionally quantifying alpha-synuclein aggregates in tissue of a subject, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound of the invention or a diagnostic composition comprising a compound of the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally quantifying the amount of compound that binds to alpha-synuclein aggregates The present invention relates to a method comprising:

[0396] In one embodiment, the present invention provides a method of collecting data for diagnosing a disease, disorder, or condition associated with alpha-synuclein aggregates, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound according to the invention or a diagnostic composition comprising a compound according to the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region. This refers to a method including:

[0397] If the amount of compound that binds to alpha-synuclein aggregates is greater than the normal control value, it can be inferred that the patient is suffering from a disease, disorder or abnormality associated with alpha-synuclein aggregates.

[0398] Yet another embodiment of the present invention is a method of collecting data for determining a predisposition to a disease, disorder, or condition associated with alpha-synuclein aggregates, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound according to the invention or a diagnostic composition comprising a compound according to the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region. This refers to a method including:

[0399] If the amount of compound that binds to alpha-synuclein aggregates is higher than the normal control value for healthy / reference subjects, this indicates that the patient is suffering from or at risk of developing an alpha-synuclein aggregate-associated disease, disorder or abnormality. In particular, if the amount of compound that binds to alpha-synuclein aggregates is higher than that expected in someone who does not show clinical evidence of an alpha-synuclein aggregate-associated disease, disorder or abnormality, the patient can be presumed to have a predisposition to an alpha-synuclein aggregate-associated disease, disorder or abnormality.

[0400] In a further aspect, the present invention provides a method of collecting data for prognosing an alpha-synuclein aggregate-associated disease, disorder, or condition, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound according to the invention or a diagnostic composition comprising a compound according to the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention relates to a method comprising:

[0401] The likelihood (e.g., likelihood, duration, and / or extent) of progression and / or recovery from the disease, disorder, or disorder can be estimated by a medical professional based on the presence or absence of a compound that binds to alpha-synuclein aggregates, the amount of compound that binds to alpha-synuclein aggregates, etc. If necessary, steps (a) through (c), and, if present, optional step (d), can be repeated over time to monitor the progression of the disease, disorder, or disorder, and thus to make the estimation more reliable.

[0402] A further aspect is a method of collecting data to monitor the progression (or evolution) of an alpha-synuclein aggregate-associated disease, disorder, or condition in a patient, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound according to the invention or a diagnostic composition comprising a compound according to the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention covers a method including:

[0403] In methods for monitoring progression, the amount of compound that binds to alpha-synuclein aggregates can optionally be compared at various time points during treatment, for example, before and after initiation of treatment, or at various time points after initiation of treatment.

[0404] Typically, the patient is undergoing or has undergone treatment for a disease, disorder or disorder associated with alpha-synuclein aggregates, or is undergoing / has undergone treatment for a synucleinopathy. In particular, treatment may involve the administration of a medicament suitable for the treatment of a disease, disorder or disorder associated with alpha-synuclein aggregates.

[0405] In another embodiment, the present invention provides a method of collecting data for predicting the responsiveness of a patient suffering from an alpha-synuclein aggregate-associated disease, disorder, or condition to treatment with a pharmaceutical agent, comprising: (a) contacting a sample, a specific body part, or a body region suspected of containing alpha-synuclein aggregates with a compound of the invention or a diagnostic composition comprising a compound of the invention; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. The present invention relates to a method comprising:

[0406] In a method for predicting reactivity, the method may include, prior to step (a), steps (i) to (vi): (i) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound of the invention that specifically binds to alpha-synuclein aggregates; (ii) binding the compound to alpha-synuclein aggregates; (iii) detecting the formation of a compound that binds to alpha-synuclein aggregates; (iv) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; (v) optionally, comparing the amount of compound that binds to alpha-synuclein aggregates with a normal control value; and (vi) treating the patient with a medicament It may further include:

[0407] Optionally, the method further comprises, after step (d) or step (e), step (A): (A) comparing the amount of compound that binds to alpha-synuclein aggregates determined in step (iv) with the amount of compound that binds to alpha-synuclein aggregates determined in step (d). It may further include:

[0408] In methods for predicting responsiveness, the amount of compound that binds to alpha-synuclein aggregates can optionally be compared at various time points during treatment, such as before and after initiation of treatment, or at various time points after initiation of treatment. A change, particularly a decrease, in the amount of compound that binds to alpha-synuclein aggregates can indicate that the patient is likely to be responsive to the respective treatment.

[0409] If the amount of compound that binds to alpha-synuclein aggregates decreases over time, the patient can be presumed to be responsive to treatment. If the amount of compound that binds to alpha-synuclein aggregates remains essentially constant or increases over time, the patient can be presumed to be non-responsive to treatment.

[0410] Alternatively, responsiveness can be estimated by determining the amount of compound that binds to alpha-synuclein aggregates. The amount of compound that binds to alpha-synuclein aggregates can be compared to a control value, such as a normal control value, a preclinical control value, or a clinical control value. Alternatively, the control value can refer to a control value of a subject known to be responsive to a treatment, or the control value can refer to a control value of a subject known to be non-responsive to a treatment. The outcome for responsiveness can be "responsive" to a treatment, "non-responsive" to a treatment, or "unknown response" to a treatment. Response to treatment can vary for each patient.

[0411] Optionally, the diagnostic compositions can be used to visualize alpha-synuclein aggregates before, during, and after surgical procedures (e.g., deep brain stimulation (DBS)) and non-invasive brain stimulation (e.g., repetitive transcranial magnetic stimulation (rTMS)). Surgical techniques, including DBS, in addition to currently available optimal medical treatments improve advanced symptoms of PD. Over the past 20 years, rTMS has been closely examined as a possible treatment for PD (Ying-hui Chou et al., JAMA Neurol. 2015 Apr 1;72(4):432-440).

[0412] In any of the above methods, optionally, correlating the presence or absence of a compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region comprises: - determining the amount of the compound that binds to the alpha-synuclein aggregates; - correlating the amount of compound that binds to alpha-synuclein aggregates with the amount of alpha-synuclein aggregates in the sample or in a particular body part or body region; and - optionally comparing the amount of compound that binds to alpha-synuclein aggregates in the sample or in a particular body part or body region with a normal control value in a healthy control subject. Includes.

[0413] The control value can be, for example, a normal control value, a preclinical control value and / or a clinical control value.

[0414] A "healthy control subject" or "healthy volunteer (HV) subject" is one who does not exhibit clinical evidence of a disease, disorder or abnormality associated with alpha-synuclein aggregates.

[0415] In certain embodiments of any of the above methods, the alpha-synuclein aggregates include, but are not limited to, Lewy bodies and / or Lewy neurites.

[0416] If the amount of compound that binds to alpha-synuclein aggregates in any of the methods summarized above is greater than the normal control value, the patient can be predicted to be suffering from or susceptible to developing a disease, disorder or condition associated with alpha-synuclein aggregates or a synucleinopathy.

[0417] A sample or a particular body part or region suspected of containing alpha-synuclein aggregates is contacted with a compound of the invention.

[0418] Any compound of the invention can be used in the methods summarized above. Preferably, a detectably labeled compound of the invention is used in the methods summarized above.

[0419] The specific body part or region includes the whole or partial body area or body part of a patient suspected of containing alpha-synuclein aggregates, preferably of a mammal, more preferably of a human. The specific body part or region may be the brain, the central nervous system, the eye, or a peripheral organ, such as the intestine, preferably the brain.

[0420] The tissue may be brain tissue, tissue of the central nervous system (CNS), tissue of the eye (e.g., retinal tissue), peripheral organs such as intestinal tissue or other tissue, or body fluids such as cerebrospinal fluid (CSF) or blood. The tissue is preferably brain tissue. Preferably, the sample is an in vitro sample from a patient.

[0421] In the above methods, the compounds of the present invention can be contacted with a sample or a particular body part or region suspected of containing alpha-synuclein aggregates by any suitable method.

[0422] In in vitro methods, the compound of the invention and the liquid sample may simply be mixed.

[0423] In in vivo methods, a particular body part or area can be contacted with a compound of the present invention by administering to a patient an effective amount of a compound of the present invention.

[0424] An effective amount of the compound of the present invention is an amount suitable for determining the presence or absence of alpha-synuclein aggregates in a sample, a specific body part, or a body region using a selected analytical technique. The amount is not particularly limited and depends on the compound of formula (I), the type of detectable label, the sensitivity of each analytical method, and each device. The amount can be appropriately selected by those skilled in the art.

[0425] The compound is then allowed to bind to the alpha-synuclein aggregates. Allowing the compound to bind to the alpha-synuclein aggregates includes allowing a sufficient amount of time for the compound of the present invention to bind to the alpha-synuclein aggregates. The amount of time required for binding depends on the type of test (e.g., in vitro or in vivo) and can be determined by one skilled in the art through routine experimentation. For in vivo methods, the amount of time depends on the time required for the compound to reach a particular body part or region suspected of containing alpha-synuclein aggregates. The amount of time should not be excessively extended to avoid washout and / or metabolism of the compound of the present invention.

[0426] Compounds bound to alpha-synuclein aggregates can then be detected by any suitable method. The method for detecting compounds bound to alpha-synuclein aggregates is not particularly limited and depends, inter alia, on the detectable label, the type of sample, the specific body part or region, and whether the method is an in vitro or in vivo method. Examples of possible methods include, but are not limited to, fluorescent or nuclear imaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI). These have been described and allow visualization of the alpha-synuclein biomarker. Fluorescent and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of detectably labeled compounds within a sample or a specific body part or region. The imaging system obtains images of the bound detectable label, such as a radioisotope, particularly a positron emitter or gamma emitter, present in the tested sample, the specific body part, or the tested body region. Preferably, compounds that bind to alpha-synuclein aggregates are detected by an imaging device, such as a PET or SPECT scanner, more preferably PET.

[0427] The amount of compound that binds to alpha-synuclein aggregates can also be determined by visual or quantitative analysis, for example, using PET scan images.

[0428] The compounds according to the invention, or precursors thereof, may also be incorporated into a test kit for detecting alpha-synuclein protein aggregates. The test kit typically comprises a container holding one or more compounds according to the invention, or precursors thereof, and instructions for use of the compounds to bind to alpha-synuclein aggregates and to detect the formation of compounds that bind to alpha-synuclein aggregates, thereby correlating the presence or absence of compounds that bind to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates.

[0429] The term "test kit" generally refers to any diagnostic kit known in the art. More specifically, the term refers to any diagnostic kit described in Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.

[0430] Detectably labeled compounds of the present invention, preferably 18 a compound of formula (IF) labeled with F, or 3 H-labeled formula (IH * The dose of the compound of (IH) or (IH) will vary depending on the exact compound to be administered, the patient's weight, the sample size and type, and other variables apparent to a practitioner of ordinary skill in the art. In general, the dose will preferably be in the range of 0.001 μg / kg to 10 μg / kg, preferably 0.01 μg / kg to 1.0 μg / kg. The radioactive dose may be, for example, 100 to 600 MBq, more preferably 150 to 450 MBq.

[0431] Methods of synthesizing compounds of the present invention The compounds of the present invention can be prepared by the routes described in the following schemes or examples, following the definition of the compound of formula (I). All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "for example") provided herein is intended merely to better elucidate the invention and does not impose limitations on the scope of the invention unless otherwise claimed. In the following general methods, R 1 , R 2 ,

[0432] [ka]

[0433] , LG, and Hal are as previously defined in the above embodiments or are limited to the meaning in the schemes. Unless otherwise specified, starting materials are commercially available or prepared by known synthetic methods.

[0434] General synthetic scheme for preparing compounds of the present invention:

[0435] [ka]

[0436] A commercially available or custom-made aldehyde derivative containing an acid-sensitive protecting group (Pg) on ​​the triazolo moiety can be reacted with a suitable amine via reductive amination to give intermediate A after purification. The halogen atom can then be displaced with a heteroarylboronic acid derivative containing a leaving group (LG) via Suzuki coupling to give intermediate B after purification. LG can then be displaced with a suitable amine derivative via aromatic nucleophilic substitution to give intermediate C after purification. Pg can be removed by acid treatment to give intermediate D after purification. Alternatively, the halogen atom of a commercially available or custom-made aldehyde derivative containing an acid-sensitive Pg on the triazolo moiety can be displaced with a heteroarylboronic acid derivative via Suzuki coupling to give intermediate E after purification. Reductive amination of intermediate E with a suitable amine can be used to give intermediate F after purification. Pg of intermediate F can be removed by acid treatment to give intermediate D after purification. Intermediate D can be cyclized using 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to give the compound of formula G as a free base. Treatment of the compound of formula G with an acid can be used to give a salt of the compound of formula (I).

[0437] [ka]

[0438] Commercially available or custom-made triazolo derivatives containing an ester moiety are treated with a suitable reagent to introduce the acid-sensitive Pg after purification. The halogen atom is then displaced with a heteroarylboronic acid derivative containing a leaving group (LG) via Suzuki coupling to give intermediate B after purification. LG is then displaced with a suitable amine derivative via aromatic nucleophilic substitution to give intermediate C after purification. Reduction of the ester moiety to the corresponding alcohol is used to give intermediate D after purification. Mild oxidation of the alcohol moiety using a reagent such as Dess-Martin periodinane (DMP) is used to give the aldehyde containing intermediate E. Reductive amination of intermediate E with a suitable amine is used to give intermediate F after purification. Pg of intermediate F is removed by acid treatment to give intermediate D after purification. Intermediate D can be cyclized using 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to give the compound of formula H as the free base. Treatment of a compound of formula H with an acid may be used to obtain a salt of a compound of formula (I).

[0439] The present invention 18 General synthesis of F-labeled compounds 18 The compound having formula (I) labeled with F can be prepared by reacting a precursor compound (III-F) with LG contained in the precursor compound. 18 F, as described below, 18 It can be prepared by reacting with an F-fluorinating agent.

[0440] 18Reagents, solvents and conditions that can be used for F-fluorination are well known to those skilled in the art (L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, pp. 2853-2873; J. Fluorine Chem., 27 (1985): pp. 177-191; Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), Schubiger PA, Friebe M., Lehmann L. (eds.), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pp. 15-50). Preferably, 18 The solvent used for F-fluorination is DMF, DMSO, acetonitrile, DMA, or a mixture thereof, preferably the solvent is acetonitrile or DMSO.

[0441] Any suitable 18 F-fluorinating agents may be used. Typical examples are H 18 F, alkali or alkaline earth 18 F-fluoride (e.g., K 18 F, Rb 18 F, Cs 18 F and Na 18 F). Optionally, 18 The F-fluorinating agent may 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, Kryptofix®) or a crown ether (e.g., 18-crown-6). 18 F-fluorinating agent is 18 a tetraalkylammonium salt of F or 18 Tetraalkylphosphonium salts of F, such as 18 F Tetra (C 1~6 alkyl)ammonium salts or 18 F Tetra (C 1~6 The alkyl phosphonium salt may be:18 F-fluorinating agent is K 18 F, H 18 F, Cs 18 F, Na 18 F, 18 F Tetra (C 1~6 (Alkyl)ammonium salt, kryptofix

[0222] 18 F or tetrabutylammonium [ 18 F] fluoride.

[0442] as a radioactive label 18 Although the reaction for F is shown above, other radiolabels may be introduced following similar procedures.

[0443] This invention is illustrated by the following examples which should not be construed as limiting. [Example]

[0444] The compounds of the present disclosure can be prepared by methods of organic synthesis known in the art. It is understood that in all of the methods, protecting groups for sensitive or reactive groups can be used where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0445] Unless otherwise noted, all reagents and solvents were obtained from commercial sources and used without further purification.

[0446] Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v20.

[0447] Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations are carried out under reduced pressure, typically at about 15 to 100 mm Hg (= 20-133 mbar). The structures of final products, intermediates, and starting materials were confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.

[0448] Abbreviation: Abbreviations used are conventional in the art.

[0449] [Table 1A]

[0450] [Table 1B]

[0451] Analytical details, preparation and analytical methods NMR measurements were performed on a DRX-400 MHz NMR spectrometer, a Bruker AV-400 MHz NMR spectrometer, and in deuterated solvents with or without TMS as an internal standard. Chemical shifts (δ) are reported in ppm downfield from TMS, and 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). Deuterated solvents are indicated in parentheses, with chemical shifts for dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents indicated in the NMR spectral data.

[0452] MS were recorded on a Waters Advion CMS mass spectrometer or a UPLC H-Class Plus equipped with a photodiode array detector, and a Qda mass spectrometer.

[0453] Column chromatography was carried out using silica gel (Fluka: silica gel 60, 0.063-0.2 mm) and suitable solvents as specified in the specific examples.

[0454] Flash column chromatography system: Flash purification was performed using a Biotage Isolera One flash purification system using HP-Sil or KP-NH SNAP cartridges (Biotage) and solvent gradients as indicated in the examples.

[0455] TLC was performed on silica gel plates with UV detection.

[0456] Preparation example (Preparation Example 1)

[0457] [ka]

[0458] Compounds were purchased from commercial supplier Aurum Pharmatech LLC.

[0459] (Preparation Example 2)

[0460] [ka]

[0461] Step A: To a stirred solution of 2-fluoroethanol (1.82 mL, 31.2 mmol) and sodium hydride (60% dispersion in mineral oil) (1.25 g, 31.2 mmol) in THF (100 mL) was added 5-bromo-2-fluoropyridine (5.0 g, 28.4 mmol) portionwise over 15 minutes at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were dried over NaSO and concentrated in vacuo to give the title compound as a yellow solid (5.0 g, 79%). 1 H NMR (CDCl3) δ 8.17 (dd, 1H), 7.66 (dd, 1H), 6.73 (dd, 1H), 4.80 (m, 1H), δ 4.68 (m, 1H), 4.57 (m, 1H), 4.50 (m, 1H).

[0462] Step B: To an oven-dried flask was added the title compound from Step A above (5.0 g, 22.7 mmol), bis(pinacolato)diborane (11.5 g, 45.4 mmol), KOAc (6.7 g, 68.9 mmol), and 1,4-dioxane (250 mL) under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1.8 g, 22.7 mmol) was added, and the mixture was heated to 60°C for 5 hours. The solvent was removed under reduced pressure, and the crude material was treated with 40% EtOAc in n-hexane (200 mL) and filtered through a Celite pad. The filtrate was dried over Na2SO4 and concentrated, and the residue was purified by silica gel chromatography (100-200 mesh) using 10% EtOAc in n-hexane to give the title compound as a pale yellow solid (3.5 g, 57%). 1H NMR (CDCl3) δ 8.51 (q, 1H), 7.94 (dd, 1H), 6.78 (dd, 1H), δ 4.81 (m, 1H), 4.69 (m, 1H), 4.64 (m, 1H), 4.57 (m, 1H), δ 1.35 (d, 1H), 1.34 (s, 12H)

[0463] (Preparation Example 3)

[0464] [ka]

[0465] Compounds were purchased from commercial supplier SV ChemBioTech, Inc.

[0466] (Preparation Example 4)

[0467] [ka]

[0468] (2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol), pyrrolidine (0.7 mL, 8.2 mmol), DIPEA (1.6 mL, 9.4 mmol), and NMP (10 mL, 10 vol) were heated at 160° C. for 1 hour under microwave irradiation. Upon completion, the reaction mixture was quenched with ice-cold water (20 mL) and the crude reaction was filtered through a Buchner funnel. The crude solid was washed with pentane (5 mL×3) and dried under high vacuum to give the desired intermediate as a yellow solid (80 mg, 70%). 1 H NMR (DMSO-d6) δ 8.59 (s, 2H), 7.97 (s, 2H), 3.48 (t, 4H), 1.91 (m, 4H). MS (ESI): 193.73 [M+H].

[0469] (Preparation Example 5)

[0470] [ka]

[0471] Step A: 2,5-Dibromopyrazine (5.0 g, 21 mmol), pyrrolidine (1.8 g, 25.2 mmol), CS2CO3 (6.8 g, 21 mmol), and DMSO (50 mL, 10 vol) were heated at 100 °C for 16 h under microwave irradiation. Upon completion, the reaction mixture was quenched with ice-cold water (60 mL) and the crude reaction was filtered through a Buchner funnel. The solid was dried under high vacuum to give the desired product as a yellow solid (4.3 g, 90%). 1 H NMR (CDCl3) δ 8.10 (d, 1H), 7.61 (d, 1H), 3.44 (t, 4H), 2.06-2.02 (m, 4H). MS (ESI): 229.9 [M+H].

[0472] Step B: To a stirred solution of the product of Step A (2.0 g, 8.77 mmol) in THF (80 mL, 40 vol.) was added nBuLi (2.5 M in hexanes) (4.2 mL, 10.5 mmol) dropwise at −78°C under a N atmosphere, and the mixture was stirred for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 mL, 10.5 mmol) was then added. The mixture was stirred at −78°C for 2 h and at room temperature for 3 h. The reaction time was monitored by TLC. Upon completion, the reaction mixture was cooled to 0°C and quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude reaction product was used directly in the next step without further purification. MS(ESI): 276.3 [M+H].

[0473] (Preparation Example 6)

[0474] [ka]

[0475] Step A: To a solution of 4-nitro-1H-pyrazole (2.5 g, 21.9 mmol) in DMF (50 mL, 20 vol.) was added CsCO (21.5 g, 65.9 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (10.2 g, 43.9 mmol). The mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. Upon completion, the solvent was evaporated in vacuo, and water (100 mL) was added to the residue. The aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (100-200 mesh) eluting with 50% EtOAc in hexane to give the desired product as a yellow oil (3.0 g, 78%). 1 H NMR (CDCl3) δ 8.18 (s, 1H), 8.10 (s, 1H), 4.52 (t, 1H), 4.41 (t, 1H), 4.33 (t, 2H), 2.37-2.25 (m, 2H). MS (ESI) 174.05 [M+H].

[0476] Step B: To a solution of the product of Step A (3.2 g, 18.48 mmol) in methanol (96 mL, 30 vol.) was added 10% Pd / C (640 mg, 20% w / w) portionwise under a N atmosphere. The vessel was then filled with H gas, and the mixture was stirred at room temperature for 20 h. The reaction progress was monitored by TLC. Upon completion, the mixture was filtered through Celite, and the Celite was washed with MeOH (3 × 100 mL). The combined filtrates were concentrated in vacuo to give the desired product as a yellow oil (2.6 g, 93%). 1H NMR (CDCl3) δ 7.04 (s, 1H), 6.91 (s, 1H), 4.43 (t, 1H), 4.33 (t, 1H), 4.01 (t, 2H), 3.89 (s, 2H), 2.06 (tt, 2H). MS (ESI) 144.0 [M+H].

[0477] (Preparation Example 7)

[0478] [ka]

[0479] Step A: To a solution of 3-nitro-1H-pyrazole (2.0 g, 17.6 mmol) in DMF (40 mL, 20 vol.) were added CsCO (17.3 g, 53.1 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (8.2 g, 35.4 mmol). The mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. Upon completion, the solvent was evaporated in vacuo, and water (80 mL) was added to the residue. The aqueous layer was extracted with EtOAc (2 × 80 mL), and the combined organic layers were dried over NaSO and concentrated in vacuo. The resulting crude mass was purified by column chromatography on silica gel (100-200 mesh) eluting with 50% EtOAc in hexane to give the desired product as a yellow oil (2.3 g, 75%). 1 H NMR (CDCl3) δ 7.50 (d, 1H), 6.91 (d, 1H), 4.51 (t, 1H), 4.40-4.36 (m, 3H), 2.45-2.27 (m, 2H). MS (ESI) 174.11 [M+H].

[0480] Step B: To a solution of the product of Step A (2.3 g, 13.2 mmol) in methanol (70 mL, 30 vol.) was added 10% Pd / C (230 mg, 10% w / w) portionwise under a N atmosphere. The reaction vessel was filled with H gas, and the mixture was stirred at room temperature for 21 h. The reaction progress was monitored by TLC. Upon completion, the mixture was filtered through Celite, and the Celite was washed with MeOH (3 × 100 mL). The combined filtrates were concentrated in vacuo to give the desired product as a yellow oil (1.7 g, 86%). The compound was sufficiently pure and used directly in the next step without further purification. 1 H NMR (DMSO-D6) δ 7.32 (d, 1H), 5.40-5.39 (m, 1H), 4.87 (s, 2H), 4.45 (t, 1H), 4.33 (t, 1H), 3.93 (t, 2H), 2.11-2.08 (m, 1H), 2.06 -1.98 (m, 1H). MS (ESI) 144.01 [M+H].

[0481] Example 1 (R)-2-(6-(3-fluoropyrrolidin-1-yl)-2-methylpyridin-3-yl)-6-(pyridin-3-yl)-6,7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one hydrochloride

[0482] [ka]

[0483] Step A: To a stirred solution of (3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-carbaldehyde (3.0 g, 9.6 mmol) and pyridin-3-amine (1.17 g, 12.5 mmol) in 1,2-dichloroethane (120 mL) was added molecular sieves 4 Å and glacial AcOH (7.5 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred for 4 h and allowed to reach room temperature. Sodium triacetoxyborohydride (4.0 g, 19.2 mmol) was then added and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO (100 mL) and the product was extracted with 5% MeOH in DCM (3×250 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by HCl distillation with 2% MeOH in DCM (3×250 mL). Purification by column chromatography using silica gel (100-200 mesh) with MeOH gave the title compound as a yellow liquid (3.0 g, 76%). 1 H NMR (400 MHz, DMSO- d6) δ 8.03 (d, 1H), 7.81 (dd, 1H), 7.09 (dd, 1H), 6.99 (dq, 1H), 6.49 (t, 1H), 5.70 (dd, 1H), 4.53 (m, 2H), 3.88 (m, 1H), 3.69 (m, 1H), 2.09 (m, 1H), 1.93 (m, 2H), 1.60 (m, 3H) MS: 338.24 [M+H] +

[0484] Step B: To an oven-dried screw-cap vial was added the title compound from Step A above (0.6 g, 1.78 mmol), (6-fluoro-2-methylpyridin-3-yl)boronic acid (0.55 g, 3.5 mmol), K2CO3 (0.49 g, 3.5 mmol), and a mixture of 1,4-dioxane and water (30 mL, 4 / 1) under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.145 g, 0.178 mmol) was added, and the mixture was heated to 90 °C for 4 hours. The reaction mixture was quenched with ice water and extracted with 10% MeOH in DCM (3 × 30 mL). The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (100-200 mesh) using 4% MeOH in DCM to give the title compound as a brownish liquid (0.45 g, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (t, 1H), 8.09 (d, 1H), 7.81 (q, 1H), 7.09 (m, 1H), 6.51 (t, 1H), 5.78 (m, 1H), 4.60 (ddd, 2H), 3.91 (d, 1H), 3.73 (m, 1H), 2.70 (s, 3H), 2.24 (m, 1H), 2.01 (m, 3H), 1.69 (t, 1H), 1.57 (q, 2H), 1.34 (s, 1H), 1.23 (d, 4H), 1.17 (q, 1H) MS: 369.15 [M+H] +

[0485] Step C: The title compound from Step B above (0.1 g, 0.27 mmol), (R)-3-fluoropyrrolidine hydrochloride (0.051 g, 0.40 mmol), DIPEA (0.14 mL, 0.8 mmol), and NMP (5 mL) were combined in an oven-dried microwave vial under an argon atmosphere. The reaction mixture was heated in a microwave oven at 160 °C for 4 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with 5% MeOH in DCM (3 × 10 mL). The combined organic layers were washed with cold brine solution (2 × 10 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by column chromatography using silica gel (100-200 mesh) with 3% MeOH in DCM to afford the title compound as a white solid (0.050 g, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.99 (d, 1H), 7.80 (q, 1H), 7.08 (dd, 2H), 6.44 (m, 2H), 5.71 (dd, 1H), 5.44 (m, 1H), 4.54 (ddd, 2H), 3.91 (d, 1H), 3.67 (m, 4H), 3.43 (td, 1H), 2.63 (s, 3H), 2.20 (m, 3H), 1.98 (m, 2H), 1.63 (m, 3H)

[0486] Step D: To a stirred solution of the title compound from Step C above (0.050 g, 0.11 mmol) in DCM (2.5 mL) was added a solution of 4 M HCl in 1,4-dioxane (0.5 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 6 h and allowed to reach room temperature. The solvent was removed in vacuo to give the title compound as the hydrochloride salt. The yellow solid was washed with hexane (3×5 mL) and dried under vacuum. MS: 354.25 [M+H] +

[0487] Step E: To an ice-cold solution of the title compound from Step D above (0.04 mg, 0.1 mmol) in 1,2-DCE (2 mL) was added sodium hydride (60% dispersion in mineral oil) (0.004 g, 0.17 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. 1,1'-Carbonyldiimidazole (0.16 g, 1.0 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with ice-cold water, and the product was extracted with 5% MeOH in DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh) using 4% MeOH in DCM to give the title compound as a white solid (0.02 mg, 51%). 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, 1H), 8.46 (m, 1H), 8.19 (d, 1H), 8.16 (d, 1H), 7.54 (d, 1H), 6.51 (d, 1H), 5.46 (d, 1H), 5.26 (s, 2H), 3.72 (m, 3H), 3.48 (m, 1H), 2.73 (s, 3H), 2.22 (m, 2H) MS: 379.9 [M+H] +

[0488] Step F: To a stirred solution of the title compound from Step E above (0.020 g, 0.05 mmol) in DCM (2 mL) under a nitrogen atmosphere was added a solution of 4 M HCl in 1,4-dioxane (0.2 mL) at 0° C. The reaction mixture was stirred for 6 h and allowed to warm to room temperature. The solvent was evaporated and the residue was treated with pentane and dried under vacuum to give the title compound as a yellow solid (0.015 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, 1H), 8.57 (m, 1H), 8.40 (d, 1H), 7.74 (q, 1H), 6.94 (s, 1H), 5.55 (d, 1H), 5.34 (s, 2H), 3.77 (m, 4H), 3.57 (s, 1H), 2.91 (s, 3H), 2.30 (m, 2H) MS: 379.9 [M+H] +

[0489] (Examples 2 to 5) The following examples were prepared following the same procedures as described in Example 1, except using the reagents indicated at the particular step in Table 1 below.

[0490] [Table 2A]

[0491] [Table 2B]

[0492] [Table 2C]

[0493] [Table 2D]

[0494] [Table 2E]

[0495] [Table 2F]

[0496] [Table 2G]

[0497] Example 7 (S)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one hydrochloride

[0498] [ka]

[0499] Step A: To an ice-cold solution of ethyl 5-bromo-1H-1,2,4-triazole-3-carboxylate (2.5 g, 11.3 mmol) in THF (50 mL) was added sodium hydroxide (60% dispersion in mineral oil) (0.59 g, 14.7 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 °C, and 2-(trimethylsilyl)ethoxymethyl chloride (2.4 mL, 13.6 mmol) was added dropwise. The reaction mixture was stirred for 16 hours, allowing it to reach room temperature. The reaction mixture was quenched with ice water, and the reaction mixture was extracted with EtOAc (3 × 75 mL). The combined organic phases were washed with brine (2 × 25 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh) using 10% EtOAc in n-hexane to give the title compound as a yellow oil (0.96 g, 24%). 1 H NMR (400 MHz, CDCl3) δ 5.86 (s, 2H), 4.48 (q, 2H), 3.67 (m, 2H), 1.45 (d, 3H), 0.92 (m, 2H), -17.45 (s, 9H) MS: 352.79 [M+2H] +

[0500] Step B: To an oven-dried screw-cap vial was added the title compound from Step A above (0.2 g, 0.57 mmol), (6-fluoropyridin-3-yl)boronic acid (0.096 g, 0.68 mmol), CsCO (0.371 g, 1.14 mmol), and 1,4-dioxane (8 mL) under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.048 g, 0.06 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.023 g, 0.06 mmol) were added, and the mixture was heated to 80 °C for 3 hours. The reaction was quenched with ice water, and the reaction mixture was extracted with DCM (3 × 30 mL). The combined organic phase was washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) using 20% ​​EtOAc in n-hexane to give the title compound as a yellow liquid (0.170 g, 81%). 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, 1H), 8.54 (td, 1H), 7.02 (dd, 1H), δ 5.95 (s, 2H), 4.54 (q, 2H), 3.71 (t, 2H), 1.48 (t, 3H), 0.95 (t, 2H), -22.7 (s, 9H) MS: 367.25 [M+H] +

[0501] Step C: The title compound from Step B above (3.0 g, 8.2 mmol), (S)-3-fluoropyrrolidine hydrochloride (2.0 g, 16.3 mmol), DIPEA (7.13 mL, 41 mmol), and ethanol (30 mL) were combined in an oven-dried microwave vial under an argon atmosphere. The reaction mixture was heated in a microwave oven at 130° C. for 3 hours. The solvent was removed in vacuo, and the resulting crude material was purified by column chromatography using silica gel (100-200 mesh) with 50% EtOAc in n-hexane to afford the title compound as a white solid (1.8 g, 50%). 1 H NMR (400 MHz, CDCl3) δ 8.94 (d, 1H), 8.20 (dd, 1H), 6.44 (d, 1H), 5.92 (s, 2H), 5.40 (dt, 1H), 4.52 (q, 2H), 3.91 (q, 1H), 3.69 (m, 4H), 3.64 (m, 2H), 2.41 (m, 1H), 2.17 (m, 1H), 1.48 (t, 3H), -23.4 (s, 9H) MS: 436.58 [M+H] +

[0502] Step D: To an ice-cold solution of the title compound from Step C above (1.8 g, 4.13 mmol) in MeOH (90 mL) was added sodium borohydride (1.25 g, 33 mmol) portionwise at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C. and the reaction was quenched by the addition of saturated ammonium chloride (foam!). The solvent was removed in vacuo and the crude material was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were washed with cold brine solution (100 mL), dried over NaSO, and concentrated in vacuo to give the title compound as a white solid (1.6 g, 98%). 1H NMR (400 MHz, CDCl3) δ 8.90 (d, 1H), 8.11 (dd, 1H), 6.44 (d, 1H), 5.55 (s, 2H), 5.39 (dt, 1H), 4.88 (s, 2H), 3.90 (q, 1H), 3.80 (s, 1H), 3.68 (m, 6H), 2.41 (m, 1H), 2.17 (m, 1H), 0.93 (t, 2H), 0.85 (m, 1H), -16.2 (s, 9H) MS: 394.62 [M+H] +

[0503] Step E: To an ice-cold solution of the title compound from Step D above (1.6 g, 4.0 mmol) in DCM (48 mL) was added Dess-Martin periodinane (3.45 g, 8.14 mmol) portionwise at 0 °C under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and the reaction was quenched by the addition of saturated NaHCO (50 mL). The reaction mixture was extracted with DCM (3 × 80 mL). The combined organic layers were washed with cold brine solution (80 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by column chromatography using silica gel (100-200 mesh) with 50% EtOAc in n-hexane to afford the title compound as a white solid (1.3 g, 82%). 1 H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.95 (d,1H), 8.18 (dd, 1H), 6.47 (d, 1H), 5.86 (s, 2H), 5.41 (dt, 1H), 3.93 (q, 1H), 3.71 (m, 6H), 2.43 (m, 1H), 2.18 (m, 1H), 0.94 (t, 2H), -22.03 (s, 9H) MS: 392.26 [M+H] +

[0504] Step F: To a stirred solution of the title compound from Step E above (0.4 g, 1.0 mmol) and 1-methyl-1H-pyrazol-4-amine (0.1 g, 1.0 mmol) in 1,2-dichloroethane (16 mL) was added 4 Å molecular sieves and glacial AcOH (0.8 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (0.43 g, 2.0 mmol) was then added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO (20 mL), and the reaction mixture was extracted with 5% MeOH in DCM (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by column chromatography using silica gel (100-200 mesh) with 3% MeOH in DCM to afford the title compound as a yellow liquid (0.4 g, 83%). MS: 473.59 [M+H] +

[0505] Step G: To a stirred solution of the title compound from Step F above (0.4 mg, 0.85 mmol) in DCM (8.0 mL) under a nitrogen atmosphere was added a solution of 4 M HCl in 1,4-dioxane (2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h, the solvent was evaporated under reduced pressure, and the residue was washed with pentane and dried under vacuum to give the title compound as an off-white solid (0.28 g, 97%). MS: 341.13 [M+H] +

[0506] Step H: To an ice-cold solution of the title compound from Step G above (0.28 g, 0.82 mmol) in 1,2-dichloroethane (17 mL) was added sodium hydride (60% dispersion in mineral oil) (0.033 g, 0.82 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature and held for 30 minutes. 1,1'-Carbonyldiimidazole (1.33 g, 8.2 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with ice-cold water, and the reaction mixture was extracted with 5% MeOH in DCM (3 x 40 mL). The combined organic phases were dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC using 5% MeOH in DCM as the mobile phase. The solvent was removed in vacuo to give the title compound as a pale yellow solid (0.009 g, 3%). 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 6.61 (d, 1H), 5.44 (d, 1H), 4.99 (s, 2H), 3.83 (m, 3H), 3.68 (m, 3H), 3.45 (m, 1H), 2.19 (m, 2H) MS: 368.95 [M+H] +

[0507] Step I: To a stirred solution of the title compound from Step H above (0.006 g, 0.024 mmol) in DCM (1.0 mL) was added a solution of 4 M HCl in 1,4-dioxane (0.6 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the hydrochloride salt. The off-white solid was washed with n-hexane (2 mL) and then dried under vacuum to give the title compound as a white solid (0.004 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, 1H), 8.70 (d, 1H), 8.56 (d, 1H), 8.38 (dd, 2H), 7.72 (q, 1H), 7.00 (d, 1H), 5.54 (d, 1H), 5.32 (s, 2H), 3.85 (m, 3H), 3.61 (td, 1H), 2.26 (m, 2H) MS: 368.90 [M+H] +

[0508] (Examples 8 to 10) The following examples were prepared following the same procedure as described in Example 7, except using the reagents indicated at the particular step in Table 2 below.

[0509] [Table 3]

[0510] Example 11 (2-(6-(2-fluoroethoxy)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-imidazo[1,5-b][1,2,4]triazol-5-one

[0511] [ka]

[0512] Step A: To an oven-dried screw-cap vial, 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole-5-carbaldehyde (1.5 g, 5.7 mmol), the title compound from Preparation 2 (3.1 g, 11.5 mmol), K2CO3 (1.6 g, 11.5 mmol), and a mixture of 1,4-dioxane and water (5 mL, 4 / 1) were added under an argon atmosphere. The reaction mixture was degassed with argon for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.47 g, 0.57 mmol) was added, and the mixture was heated to 60 °C for 5 hours. The reaction mixture was quenched with ice water and extracted with EtOAc (3 × 60 mL). The combined organic phases were dried over Na2SO4, concentrated and the residue was purified by silica gel chromatography (100-200 mesh) using 25% EtOAc in n-hexane to give the title compound as a brownish solid (1.0 g, 55%). 1 H NMR (400 MHz, CDCl3) δ 10.7 (s, 1H), 8.92 (d, 1H), 8.33 (dd, 1H), 6.89 (d, 1H), 6.25 (dd, 1H), 4.83 (t, 1H), 4.74 (t, 1H), 4.68 (t, 1H), 4.62 (t, 1H), 4.12 (m, 1H), 3.78 (td, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.77 (m, 2H), 1.66 (m, 1H) MS: 321.35 [M+H] +

[0513] Step B: To a stirred solution of the title compound from Step A above (0.4 g, 1.3 mmol) and 1-methyl-1H-pyrazol-4-amine (0.18 g, 1.9 mmol) in 1,2-dichloroethane (16 mL) was added 4 Å molecular sieves and glacial AcOH (1.2 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (0.55 g, 2.6 mmol) was then added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (60 mL), and the product was extracted with 5% MeOH in DCM (3 × 60 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel (100-200 mesh) with 4% MeOH in DCM to give the title compound as a brown liquid (0.34 g, 65%). 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1H), 8.23 ​​(dd, 1H), 7.16 (s, 1H), 7.03 (s, 1H), 6.97 (d, 1H), 5.72 (dd, 1H), 5.02 (s, 1H), 4.81 (t, 1H), 4.72 (t, 1H), 4.56 (dt, 2H), 4.28 (dd, 2H), 3.94 (d, 1H), 3.70 (m, 1H), 3.68 (s, 3H), 2.22 (ddd, 1H), 2.01 (m, 1H), 1.89 (td, 1H), 1.65 (m, 1H), 1.58 (m, 2H) MS: 402.43 [M+H] +

[0514] Step C: To a stirred solution of the title compound from Step B above (0.26 g, 0.65 mmol) in DCM (13 mL) was added a solution of 4 M HCl in 1,4-dioxane (2.6 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure to give the hydrochloride salt. The yellow solid was washed with n-hexane (3×5 mL) and dried under vacuum to give the title compound (0.2 g, 87%). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, 1H), 8.29 (dd, 1H), 7.87 (s, 1H), 7.54(s, 1H), 7.07 (d, 1H), 4.82 (t, 1H), 4.73 (dd, 1H), 4.61 (t, 1H), 4.54 (s, 4H), 3.82 (s, 3H) MS: 318.35 [M+H] +

[0515] Step D: To an ice-cold solution of the title compound from Step C above (0.2 mg, 0.63 mmol) in 1,2-dichloroethane (12 mL) was added sodium hydride (60% dispersion in mineral oil) (0.04 g, 0.95 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. 1,1'-Carbonyldiimidazole (1.02 g, 6.3 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice-cold water, and the mixture was extracted with 5% MeOH in DCM (3 × 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) using 3% MeOH in DCM to give the title compound as a white solid (0.09 g, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, 1H), 8.36 (dd, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.05 (d, 1H), 5.07 (s, 2H), 4.79 (m, 2H), 4.60 (m, 2H), 3.88 (s, 3H) MS: 344.15 [M+H] +

[0516] Step E: To a stirred solution of the title compound from Step D above (0.08 g, 0.23 mmol) in DCM (4 mL) was added a solution of 4 M HCl in 1,4-dioxane (0.8 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 5 h and the solvent was evaporated under reduced pressure. The residue was treated with pentane and dried under vacuum to give the title compound as a white solid (0.08 g, 92%). 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, 1H), 8.36 (dd, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.05 (d, 1H), 5.07 (s, 2H), 4.83 (t, 1H), 4.74 (t, 1H), 4.63 (t, 1H), 4.57 (t, 1H), 3.88 (s, 3H) MS: 344.20 [M+H] +

[0517] Example 12 The following examples were prepared following the same procedure as described in Example 11, except using the reagents indicated at the particular step in Table 3 below.

[0518] [Table 4]

[0519] Description of biological assays and corresponding results 1. Preparation of alpha-synuclein (a-syn) aggregates from human Parkinson's disease (PD) brains The procedure 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. The homogenate was then centrifuged at 11,000 × g (12,700 RPM) in a pre-cooled 70.1 rotor (Beckman, 342184) in an ultracentrifuge (Beckman, XL100K) for 20 minutes at 4°C. The pellet was resuspended in extraction buffer [10 mM Tris-HCl pH 7.4, 10% sucrose, 0.85 M NaCl, 1% protease inhibitor (Calbiochem 539131), 1 mM EGTA, 1% phosphatase inhibitor (Sigma P5726 and P0044)] and centrifuged at 15,000 × g (14,800 RPM, 70.1 Ti rotor) for 20 minutes at 4 °C. The pellet was discarded, and sarkosyl (20% stock solution, Sigma L7414) was added to the supernatant to a final concentration of 1% for 1 hour at room temperature and vortexed. The solution was then centrifuged at 100,000 × g (38,000 RPM, 70.1 Ti rotor) for 1 hour at 4 °C. The pellet, containing abundant alpha-synuclein aggregates, was resuspended in PBS and stored at -80°C until use.

[0520] 2. Microradiography Binding Competition Assay for Determination of Binding Affinity in PD Brain-derived Alpha-syn Aggregates Alpha-synuclein aggregates from PD brains were spotted onto microarray slides. The slides were then treated with 25 nM, 30 nM, or 40 nM [ 3The slides were incubated with [H]-alpha-synuclein reference and 1 μM and 100 nM of the example compounds (non-radiolabeled). In some cases, non-radiolabeled example compounds were further evaluated at different concentrations ranging from 0.05 nM to 2 μM. After incubation, the slides were washed and scanned using a real-time autoradiography system (BeaQuant, ai4R). Signal quantification was performed using the image analysis software Beamage (ai4R). Non-specific signal was determined with an excess of non-radiolabeled reference alpha-synuclein ligand (2 μM), and specific binding was calculated by subtracting the non-specific signal from the total signal. Competition was calculated as a percentage, with 0% defined as specific binding in the presence of vehicle and 100% defined as the value obtained in the presence of an excess of non-radiolabeled reference alpha-synuclein ligand. K i Values ​​were calculated in GraphPad Prism 7 by applying nonlinear regression curve fitting using a single-site specific binding model. All measurements were performed with at least two technical replicates. For compounds tested in more than one experiment, the mean or K of independent experimental replicates is reported. i Report the value.

[0521] Results: The exemplary compounds were evaluated against alpha-synuclein aggregates derived from the brains of PD patients. 3 The compounds were evaluated for their potency in competing with the binding of a [H]-reference alpha-synuclein ligand. The results of the microradio binding competition assay for the exemplary compounds tested are shown in Table 4 as % competition at 1 μM and 100 nM. Table 4 shows the K iThe K values ​​are also shown. The K measurements for exemplary compounds 1 to 11 were performed on alpha-synuclein aggregates derived from the same PD brain, whereas the K measurements for exemplary compounds 13 to 17 and 25 were performed on alpha-synuclein aggregates derived from PD brains from different donors. The data demonstrate that the compounds of the present invention bind to alpha-synuclein aggregates derived from human brains. Exemplary compounds 4, 5, 11, and 17 exhibited extremely high affinity (K<100 nM) binding to alpha-synuclein aggregates derived from human PD patient brains.

[0522] [Table 5]

[0523] Table 4: Evaluation of binding affinity to alpha-synuclein aggregates from human PD brain by microradio binding competition assay. Tritiated [ 3 H] percent competition (%) relative to the reference alpha-synuclein ligand, and K i Values ​​are also shown for selected example compounds in PD brain homogenates (nd = not determined; * = two independent experiments performed)

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, 【Chemistry 2】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1 But, Halo, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1 But -NH-C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 is cycloalkyl, -NH-C 3 ~C 6 Cycloalkyl C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 cycloalkyl is optionally substituted with at least one halo; R 2 Optionally, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; R 4 and R 5 is H, C 1 ~C 4 Alkyl and HaloC 1 ~C 4 alkyl), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. Formula (Ia) 【Transformation 3】 (In the formula, R 1 and R 2 is defined in claim 1, R 3 is halo or C 1 ~C 4 is alkyl, and q is 0, 1, or 2), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

3. R 1 But, 【Chemistry 4】 (In the formula, R 1a is F or H, or R 1 But, Haro C 1 ~C 4 3. The compound of claim 1, wherein the aryl group is a 4- to 6-membered heterocyclyl selected from the group consisting of alkoxy-.

4. R 1 but, 【Transformation 5】 and preferably F is 19 F or 18 F, more preferably 18 F, or R 1 But, -OCH 2 -CH 2 4. The compound of claim 3, wherein:

5. R 2 But, 【Transformation 6】 (In the formula, R 2a is Haro C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 alkyl, R 2b H, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 alkyl, 3. The compound of claim 1, wherein s is 0, 1, or 2.

6. R 2 But, 【Transformation 7】 (In the formula, R 2b But, Haro C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, alkoxy, H or C 1 ~C 4 6. The compound of claim 5, wherein the aryl is a 5- or 6-membered heteroaryl selected from the group consisting of alkyl, aryls ...

7. The compound is 【Chemical Engineering 8A】 【Chemical 8B】 10. The compound of claim 1, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, selected from:

8. The compound is 【Chemical Engineering 9A】 【Chemical 9B】 10. The compound of claim 1, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, selected from:

9. 9. The compound of any one of claims 1 to 8, wherein the compound is a detectably labeled compound.

10. The detectably labeled compound is 18 F, 2 H and 3 10. The compound of claim 9, comprising a radioisotope selected from H.

11. R 1 but, 【Chemistry 10】 11. The compound according to claim 9 or 10, wherein

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

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

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

15. 15. The compound for use or diagnostic composition for 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 to 11 or a diagnostic composition according to claim 12 for use in a diagnostic method.

17. The diagnosis is a diagnosis of a disease, disorder or abnormality associated with, or a predisposition to, alpha-synuclein aggregates, and the disease, disorder or abnormality is optionally Parkinson's disease (including sporadic, familial with alpha-synuclein mutations, familial with non-alpha-synuclein mutations, pure autonomic failure or Lewy body dysphagia), SNCA duplicate carriers, dementia with Lewy bodies (LBD), dementia with Lewy bodies (DLB) (including "pure" Lewy bodies), dementia with somatic 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's syndrome, multiple system atrophy (MSA) (including Shy-Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy), traumatic Brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (including Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Niemann-Pick disease type C1, and frontotemporal dementia with chromosome 17-linked parkinsonism), Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial, or Guam ALS-dementia complex), neuroaxonal dystrophy, neurodegeneration with cerebral iron accumulation type 1 ( 17. The compound for use or diagnostic composition for use according to claim 16, wherein the compound for use or the diagnostic composition for use is selected from: Hallervorden-Spatz syndrome, prion diseases, ataxia-telangiectasia, Meige syndrome, subacute sclerosing panencephalitis, Gerstmann-Sträussler-Scheinker disease, inclusion body myositis, Gaucher disease, Krabbe disease, and other lysosomal storage diseases (including Kufor-Rakeb syndrome and Sanfilippo syndrome) and rapid eye movement (REM) sleep behavior disorder.

18. 18. The compound for use or diagnostic composition for use according to claim 17, wherein the disease is Parkinson's disease.

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

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

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

22. The compound for use or the diagnostic composition for use according to claim 16, wherein the disease is SNCA duplication carrier.

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

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

25. 1. A method for diagnosing an alpha-synuclein aggregate-associated disease, disorder, or abnormality in a subject, comprising: (a) administering to a subject a compound according to any one of claims 1 to 11 or a diagnostic composition according to claim 12 comprising a compound according to any one of claims 1 to 11. (b) binding the compound to alpha-synuclein aggregates; and (c) detecting a compound that binds to alpha-synuclein aggregates A method comprising:

26. (d) generating an image representing the location and / or amount of compound bound to the alpha-synuclein aggregates. The diagnostic method of claim 24, further comprising:

27. 1. A method for positron emission tomography (PET) imaging of alpha-synuclein aggregates in tissue of a subject, comprising: (a) administering to a subject a compound according to any one of claims 1 to 11 or a diagnostic composition according to claim 11 comprising a compound according to any one of claims 1 to 11; (b) binding the compound to alpha-synuclein aggregates; and (c) detecting compounds that bind to alpha-synuclein aggregates by collecting positron emission tomography (PET) images of the subject's tissue. A method comprising:

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

29. 1. A method for detecting, and optionally quantifying, alpha-synuclein aggregates in tissue of a subject, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound according to any one of claims 1 to 11 or with a diagnostic composition according to claim 12 comprising a compound according to any one of claims 1 to 11; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates using positron emission tomography; and (d) optionally quantifying the amount of compound that binds to alpha-synuclein aggregates A method comprising:

30. 1. A method of collecting data for diagnosing or determining a predisposition to an alpha-synuclein aggregate-related disease, disorder, or abnormality, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates with a compound according to any one of claims 1 to 11 or with a diagnostic composition according to claim 12 comprising a compound according to any one of claims 1 to 11; (b) binding the compound to alpha-synuclein aggregates; (c) detecting compounds that bind to alpha-synuclein aggregates; and (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region. A method comprising:

31. For prognosing a disease, disorder or abnormality associated with alpha-synuclein aggregates, for monitoring the progression of a disease, disorder or abnormality associated with alpha-synuclein aggregates in a patient; or a method of collecting data for predicting the responsiveness of a patient suffering from an alpha-synuclein aggregate-associated disease, disorder or abnormality to a treatment for the alpha-synuclein aggregate-associated disease, disorder or abnormality, comprising: (a) contacting a sample, a specific body part or a body region suspected of containing alpha-synuclein aggregates with a compound according to any one of claims 1 to 11 or with a diagnostic composition according to claim 12 comprising a compound according to any one of claims 1 to 11; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; (d) optionally correlating the presence or absence of the compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally repeating steps (a) through (c), and, if present, optional step (d), at least once. A method comprising:

32. Optionally, correlating the presence or absence of a compound that binds to alpha-synuclein aggregates with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or body region comprises: - determining the amount of the compound that binds to the alpha-synuclein aggregates; - correlating the amount of compound that binds to alpha-synuclein aggregates with the amount of alpha-synuclein aggregates in the sample or in a particular body part or body region; and - optionally comparing the amount of compound that binds to alpha-synuclein aggregates in the sample or in a particular body part or body region with a normal control value in a healthy control subject.

32. The method of claim 30 or 31, comprising:

33. Formula (III-F) 【Chemistry 11】 (In the formula, 【Chemistry 12】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1F optionally, at least one C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1F But C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1F But -NH-C 3 ~C 6 Cycloalkyl or C 3 ~C 6 is cycloalkyl, R 2 Optionally, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; R 4 and R 5 However, H and C 1 ~C 4 independently selected from alkyl, LG is a leaving group, n is at least 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

34. Formula (III-F) 【Chemistry 13】 (In the formula, 【Chemistry 14】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1 But, Halo, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1 But -NH-C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 is cycloalkyl, -NH-C 3 ~C 6 Cycloalkyl C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 But H, C 1 ~C 4 Alkyl and HaloC 1 ~C 4 independently selected from alkyl, R 2F Optionally, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; LG is a leaving group), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

35. LG is bromo, chloro, iodo, C 1 ~C 4 Alkyl sulfonates and C 6 ~C 10 aryl sulfonates, C 6 ~C 10 The aryl sulfonate is optionally —CH 3 OR -NO 2 35. A compound of formula (III-F) according to claim 33, or a compound of formula (III-F') according to claim 34, optionally substituted with

36. Formula (IF) 【Chemistry 15】 (In the formula, 【Chemistry 16】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1F optionally, at least one C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1F But C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1F But -NH-C 3 ~C 6 Cycloalkyl or C 3 ~C 6 is cycloalkyl, R 2 Optionally, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; R 4 and R 5 However, H and C 1 ~C 4 independently selected from alkyl, n is at least 1, preferably 1), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

37. Formula (I-F') 【Chemistry 17】 (In the formula, [Chemistry 18] optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1 But, Halo, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1 But -NH-C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 is cycloalkyl, -NH-C 3 ~C 6 Cycloalkyl C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 cycloalkyl is optionally substituted with at least one halo; R 4 and R 5 But H, C 1 ~C 4 Alkyl and HaloC 1 ~C 4 independently selected from alkyl, R 2F Optionally, C 1 ~C 4 Alkoxy and C 1 ~C 4 or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

38. Formula (III-H) 【Chemistry 19】 (In the formula, 【Chemistry 20】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1 But, Halo, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1 But -NH-C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 is cycloalkyl, -NH-C 3 ~C 6 Cycloalkyl C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 cycloalkyl is optionally substituted with at least one halo; R 2 Optionally, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; R 4 and R 5 But H, C 1 ~C 4 Alkyl and HaloC 1 ~C 4 independently selected from alkyl, X is bromo, chloro or iodo; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, provided that the compound of formula (III-H) contains at least one X), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

39. Formula (IH) 【Chemistry 21】 (In the formula, 【Chemistry 22】 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy or C 1 ~C 4 a 6-membered heteroaryl substituted with alkyl; R 1 optionally, at least one halo, halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 a 4- to 6-membered heterocyclyl substituted with alkyl, or R 1 But, Halo, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy, NR 4 R 5 Or C 1 ~C 4 is alkyl, or R 1 But -NH-C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 is cycloalkyl, -NH-C 3 ~C 6 Cycloalkyl C 3 ~C 6 Cycloalkyl or -C 3 ~C 6 cycloalkyl is optionally substituted with at least one halo; R 2 Optionally, Halo C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkoxy, C 1 ~C 4 Alkoxy and C 1 ~C 4 a 5- or 6-membered heteroaryl substituted with 1 or 2 substituents independently selected from alkyl; R 4 and R 5 But H, C 1 ~C 4 Alkyl and HaloC 1 ~C 4 independently selected from alkyl, Y, D, CD 3 , T or CT 3 and m is 0, 1, 2 or 3; p is 0, 1, 2 or 3, However, the compound of formula (IH) contains at least one of D, CD 3 , T or CT 3 wherein D is deuterium and T is 3 H (tritium)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

40. The compound of formula (III-F) according to claim 33 or 34, 18 so that it can be replaced by F 18 37. A process for preparing a compound of formula (IF) according to claim 36, comprising reacting with an F-fluorinating agent.

41. The compound of formula (III-F') according to claim 35, 18 so that it can be replaced by F 18 38. A method for preparing a compound of formula (I-F') according to claim 37, comprising reacting with an F-fluorinating agent.

42. 18 F-fluorinating agent is K 18 F, Rb 18 F, Cs 18 F, Na 18 F, Kryptofix[222] 18 F, 18 F Tetra (C 1～6 Alkyl)ammonium salts and tetrabutylammonium [ 18 42. The method of claim 40 or 41, wherein the compound is selected from the group consisting of [F] fluorides.

43. The compound of formula (III-H) according to claim 38, wherein X is D or CD 3 so that it can be replaced by 2 40. A method for preparing a compound of formula (IH) of claim 39, comprising reacting with a H radiolabeling agent.

44. The compound of formula (III-H) of claim 38, wherein X is T or CT 3 CT can be replaced by 3 Like 3 40. A method for preparing a compound of formula (IH) of claim 39, comprising reacting with a H radiolabeling agent.

45. 12. A compound according to any one of claims 1 to 11 for use as an in vitro analytical standard or an in vitro screening tool.

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

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

48. 47. The kit of claim 46, wherein the radiopharmaceutical preparation is for use in imaging alpha-synuclein aggregates, wherein the imaging is preferably performed by positron emission tomography.

49. 47. The kit of claim 46, wherein the radiopharmaceutical preparation is for use for in vitro imaging, ex vivo imaging or in vivo imaging, preferably the use is for in vivo imaging.

50. 47. The kit of claim 46, wherein the radiopharmaceutical preparation is for use in brain imaging.

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